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  • 1451.
    Vranckx, Pascal
    et al.
    Hartctr Hasselt, Hasselt, Belgium..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Huang, Zhen
    Duke Clin Res Inst, Durham, NC USA..
    Mahaffey, Kenneth W.
    Stanford Univ, Stanford, CA 94305 USA..
    Armstrong, Paul W.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada..
    Van de Werf, Frans
    Univ Leuven, Dept Cardiol, Leuven, Belgium..
    Moliterno, David J.
    Univ Kentucky, Gill Heart Inst, Lexington, KY USA.;Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA..
    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.
    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, Cardiology.
    Aylward, Philip E.
    Flinders Univ S Australia, SAHMRI, Adelaide, SA 5001, Australia.;Med Ctr, Adelaide, SA, Australia..
    Cornel, Jan H.
    Med Ctr Alkmaar, Dept Cardiol, Alkmaar, Netherlands..
    Bode, Christoph
    Univ Klinikum, Internal Med & Cardiol, Freiburg, Germany..
    Huber, Kurt
    Wilhelminen Hosp, Dept Med Cardiol & Intens Care Med 3, Vienna, Austria..
    Nicolau, Jose C.
    Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil..
    Ruzyllo, Witold
    Inst Cardiol, Dept Coronary Artery Dis, Warsaw, Poland.;Inst Cardiol, Cardiac Catheterizat Lab, Warsaw, Poland..
    Harrington, Robert A.
    Stanford Univ, Stanford, CA 94305 USA..
    Tricoci, Pierluigi
    Duke Clin Res Inst, Durham, NC USA..
    Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes: The TRACER Trial2016In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, no 18, p. 2135-2144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed.

    OBJECTIVES This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries).

    METHODS We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death.

    RESULTS During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding.

    CONCLUSIONS In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943)

  • 1452.
    Wachtell, Kristian
    et al.
    Univ Orebro, Fac Hlth, Dept Cardiol, SE-70182 Orebro, Sweden.;Oslo Univ Hosp, Div Cardiovasc & Pulm Dis, Sect Cardiol Intervent, Dept Cardiol, Oslo, Norway..
    Lagerqvist, Bo
    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.
    Olivecrona, Göran K.
    Lund Univ, Clin Sci Sect, Skane Univ Hosp, Dept Coronary Heart Dis, Lund, Sweden..
    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
    Univ Orebro, Fac Hlth, Dept Cardiol, SE-70182 Orebro, Sweden..
    Novel Trial Designs: Lessons Learned from Thrombus Aspiration During ST-Segment Elevation Myocardial Infarction in Scandinavia (TASTE) Trial2016In: Current Cardiology Reports, ISSN 1523-3782, E-ISSN 1534-3170, Vol. 18, no 1, article id 11Article, review/survey (Refereed)
    Abstract [en]

    In ST-elevation myocardial infarction (STEMI), thrombus material is often present in partial or total coronary occlusion of the coronary vessel. However, prior to the thrombus aspiration during ST-Segment Elevation Myocardial Infarction in Scandinavia (TASTE) trial, it remained unclear whether routine thrombus aspiration during percutaneous coronary intervention (PCI) treatment of STEMI would result in patients overall survival benefit. The TASTE trial was a multicenter, prospective, open-label, randomized, controlled clinical trial. In order to randomize patients to treatment and collect data, the infrastructure of a clinical population-based registry was used. Online data collection used the national comprehensive Swedish Coronary Angiography and Angioplasty Registry, a part of the SWEDEHEART registry. Monitoring and adjudication was done as part of the regular registry validation. There was no separate, dedicated monitoring or adjudication of endpoints. Included were 7244 patients with STEMI with chest pain and time of symptoms to hospital admission <24 h, in addition to new electrocardiographic ST-segment elevation or left bundle-branch block. Exclusion criteria were the need for emergency coronary artery bypass grafting. All-cause mortality at 30 days occurred in 2.8 % of the patients in the thrombus-aspiration group, as compared with 3.0 % in the PCI-only group (hazard ratio [HR] 0.94, 95 % confidence interval [CI] 0.72-1.22; p = 0.63). Allcause mortality at 1 year occurred in 5.3 % of the patients in the thrombus-aspiration group, as compared with 5.6 % in the PCI-only group (HR 0.94, 95 % CI 0.78-1.15; p = 0.57). No patients were lost to follow-up at 1 year. The incremental cost for trial execution was approximately US$ 300,000 or $50 per patient. Routine thrombus aspiration during PCI in patients with STEMI did not reduce the rate of all-cause mortality at 1 year. It is possible to design and conductmega-trial at only small cost compared to a similar-sized conventional randomized clinical trial.

  • 1453.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Waran doseras bättre efter genanalys2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 1-2, p. 22-22Article in journal (Refereed)
  • 1454.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kreutz, Reinhold
    Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.
    Bondon-Guitton, Emmanuelle
    Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine de l'Université de Toulouse, Toulouse, France.
    Ibañez, Luisa
    Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Fundació Institut Català de Farmacologia, Barcelona, Spain.
    Carvajal, Alfonso
    Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain.
    Lucena, M Isabel
    S Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga (IBIMA), H Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Madrid, Spain.
    Sancho Ponce, Esther
    Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, Sant Cugat del Vallès, Spain.
    Molokhia, Mariam
    NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London Department of Primary Care and Public Health Sciences, London, U.
    Martin, Javier
    Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Magnusson, Patrik K E
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bengtsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 843-853Article in journal (Refereed)
    Abstract [en]

    Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome‐wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine‐induced agranulocytosis and 5,170 population controls. Sulfasalazine‐induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA‐B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10−8). We HLA‐sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA‐B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA‐B*08:01 haplotype HLA‐DQB1*02:01‐DRB1*03:01‐B*08:01‐C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA‐A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA‐B*08:01 and HLA‐A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA‐B*08:01 or HLA‐A*31:01.

  • 1455.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Smedje, H.
    Karolinska Inst, Div Child & Adolescent Psychiat, Stockholm, Sweden.
    Yue, Q. -Y
    Med Prod Agcy, Uppsala, Sweden.
    Magnusson, P. K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal (Other academic)
  • 1456. Wagner, H.
    et al.
    Jakubowski, J. A.
    Angiolillo, D. J.
    Ten Berg, J. M.
    Small, D. S.
    Zhou, C.
    Bergmeijer, T. O.
    James, Stefan
    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.
    Winters, K. J.
    Erlinge, D.
    Clopidogrel is associated with weaker platelet inhibition, lower active metabolite concentration and more poor responders in higher body weight patients compared with lower body weight patients2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 318-318Article in journal (Other academic)
  • 1457.
    Wagner, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Pedersen, Nancy L.
    Karolinska institutet, MEB.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Simply ask them about their balance-future fracture risk in a nationwide cohort study of twins2009In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 169, no 2, p. 143-149Article in journal (Refereed)
    Abstract [en]

    The principal causal components of an osteoporotic fracture are a fall and weakened bone strength. While bone quality measures have been frequently studied, the ability of simple measures of impaired balance to predict fracture risk has received less attention. Computer-assisted telephone interviews were conducted between 1998 and 2000 among 24,598 Swedish twins aged 55 years or older. Impaired balance at the time of interview was reported by 2,890 (12%) of the twins. Twin pairs who were discordant with regard to impaired balance were selected for analysis and followed for fractures through 2005. In a pairwise analysis, the odds ratio for hip fracture was 3.13 (95% confidence interval (CI): 1.62, 6.05) among twins with impaired balance as compared with their co-twins with normal balance. When previously recognized clinical risk factors for osteoporotic fracture were considered in the model, the odds ratio for hip fracture with impaired balance was 3.88 (95% CI: 1.40, 10.72). Approximately 40% of all hip fractures were attributable to impaired balance. The odds ratios for any fracture and any osteoporotic fracture for twins with impaired balance were 2.00 (95% CI: 1.29, 3.11) and 2.39 (95% CI: 1.49, 3.82), respectively. These results imply that self-reported impaired balance is a novel and readily assessed risk factor for future fractures in the elderly.

  • 1458.
    Wagner, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Pedersen, N. L.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Heritability of impaired balance: a nationwide cohort study in twins2009In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 20, no 4, p. 577-583Article in journal (Refereed)
    Abstract [en]

    In this large population-based twin study, a self-estimated impaired balance, an important risk factor for osteoporotic fractures, had a modest heritability of 0.27. Individual-specific environmental influences seem to be the dominating cause for impaired balance.

    INTRODUCTION: The principal causal components of an osteoporotic fracture are falls and weakened bone strength. While bone strength has a strong genetic origin, the heritable influences on impaired balance that contribute to the risk of injurious falls at older age are uncertain.

    METHODS: To evaluate the heritability and environmental influence on self-reported impaired balance in older men and women, we used data from a sample of 22,998 Swedish twins, 55 to 99 years of age.

    RESULTS: An impaired balance was reported by 2,890 (12.3%) of the twins. The tetrachoric correlation for impaired balance was only slightly lower for like-sex dizygotic twins (0.31) compared to monozygotic twins (0.36). These correlations indicate a modest familial (genetic and shared environmental) influence. Model fitting results indicate that the age- and sex-adjusted heritability for impaired balance was 0.27 (95%CI = 0.01-0.45). Individual-specific environmental influences differed only slightly by sex and age.

    CONCLUSION: These results imply that a self-reported impaired balance, an independent risk factor for osteoporotic fractures, has a modestly heritable etiology in older subjects. Our observation can partly explain the previously observed modest heritability for osteoporotic fractures even though there is a high heritability for bone mineral density.

  • 1459. Wagner, Henrik
    et al.
    Angiolillo, Dominick J.
    ten Berg, Jurrien M.
    Bergmeijer, Thomas O.
    Jakubowski, Joseph A.
    Small, David S.
    Moser, Brian A.
    Zhou, Chunmei
    Brown, Patricia
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Winters, Kenneth J.
    Erlinge, David
    Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients2014In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 38, no 2, p. 127-136Article in journal (Refereed)
    Abstract [en]

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

  • 1460. Wahlgren, Nils
    et al.
    Ahmed, Niaz
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Aichner, Franz
    Bluhmki, Erich
    Davalos, Antoni
    Erila, Terttu
    Ford, Gary A.
    Grond, Martin
    Hacke, Werner
    Hennerici, Michael G.
    Kaste, Markku
    Koehrmann, Martin
    Larrue, Vincent
    Lees, Kennedy R.
    Machnig, Thomas
    Roine, Risto O.
    Toni, Danilo
    Vanhooren, Geert
    Multivariable Analysis of Outcome Predictors and Adjustment of Main Outcome Results to Baseline Data Profile in Randomized Controlled Trials Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)2008In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 39, no 12, p. 3316-3322Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs.Methods-The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P <= 0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P < 0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes.Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration >= 1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months.Results-The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months.Conclusions-The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.

  • 1461. Walfridsson, U.
    et al.
    Rosenqvist, M.
    Agren, P. L.
    Andersson, P.
    Juhlin, T.
    Nilsson, C.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. 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.
    Svensson, P.
    Assessing disease-specific patient reported outcomes within the Swedish National Quality Register AURICULA2015In: European Journal of Cardiovascular Nursing, ISSN 1474-5151, E-ISSN 1873-1953, Vol. 14, no S1, p. S87-S88, article id 239Article in journal (Other academic)
  • 1462.
    Wall, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Kågedal, Matts
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jacobsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Nilsson, Dag
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Frändberg, Pernilla
    Gustavsson, Sven-Åke
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Yates, Roger
    Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study2005In: Drugs in R&D, ISSN 1174-5886, E-ISSN 1179-6901, Vol. 6, no 3, p. 139-147Article in journal (Refereed)
    Abstract [en]

    Objective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information. The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

  • 1463.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Anticoagulation: improve care quality or use new alternatives? Reply2011In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 377, no 9764, p. 465-465Article in journal (Refereed)
  • 1464.
    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.
    Commentary on the OPTIDUAL trial results: how to optimise prolonged dual antiplatelet treatment and independent randomised clinical trials.2016In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 37, no 4, p. 375-377Article in journal (Refereed)
  • 1465.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Different perspectives on outcomes in patients with non-ST-elevation myocardial infarction when observed in clinical trials and in real life2018In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 39, no 42, p. 3821-3824Article in journal (Other academic)
  • 1466.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dual antiplatelet therapy in the drug-eluting stent era2008In: European Heart Journal, Supplement, ISSN 1520-765X, E-ISSN 1554-2815, Vol. 10, no D, p. D38-D44Article in journal (Refereed)
    Abstract [en]

    Data continue to accumulate showing that implantation of coronary stents, particularly drug-eluting stents (DES), is associated with persistent, long-term risk of thrombotic events. Dual antiplatelet therapy with aspirin and clopidogrel has reduced the risk of early and late thrombosis. However, early risk persists due to implantation, stent-related factors, and suboptimal response to clopidogrel, whereas late risk persists due not only to these factors, but to the limited duration of dual antiplatelet therapy as well. Third-generation oral P2Y(12) antagonists that exhibit faster onset of action and greater and more consistent inhibition of platelet aggregation than clopidogrel include the new thienopyridine prasugrel and the reversible P2Y(12) inhibitor AZD6140. Prospective, randomized, Long-term trials are warranted to investigate the benefits and risks of more effective P2Y(12) antagonists as part of dual antiplatelet therapy after both bare-metal stent and DES implantation.

  • 1467.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Genetic substudy of the PLATO trial Reply2011In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 377, no 9766, p. 637-638Article in journal (Refereed)
  • 1468.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use2009In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 30, no 16, p. 1964-1977Article, review/survey (Refereed)
    Abstract [en]

    Currently, clopidogrel is recommended for treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. However, the delayed onset of the effect and the occurrence of poor platelet inhibition responders with clopidogrel as well as non-compliance to dual antiplatelet treatment are associated with a raised risk of stent thrombosis. The molecular target of the active metabolite of clopidogrel and several emerging antiplatelet treatments is the P2Y(12) receptor, which is the main platelet receptor responsible for ADP-induced platelet aggregation. Active metabolites of the thienopyridine prodrugs (ticlopidine, clopidogrel, and prasugrel) covalently bind to the P2Y(12) receptor and are irreversible, indirect platelet inhibitors. The newer, direct-acting P2Y(12) inhibitors (cangrelor and ticagrelor) change the conformation of the P2Y(12) receptor, resulting in reversible, concentration dependent inhibition of the receptor. An understanding of the similarities and differences in the properties and mechanisms of action of these new inhibitors compared with clopidogrel is needed in order to optimize the development and use of these agents in clinical practice. The objectives of this systematic review are to summarize the pharmacokinetics, pharmacodynamics, and pharmacogenetics of the different P2Y(12) inhibitors and to discuss the clinical implications for treatment of patients.

  • 1469.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Budaj, Andrzej
    Cannon, Christopher P.
    Emanuelsson, Håkan
    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.
    Horrow, Jay
    Husted, Steen
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Katus, Hugo
    Mahaffey, Kenneth W.
    Scirica, Benjamin M.
    Skene, Allan
    Steg, Philippe Gabriel
    Storey, Robert F.
    Harrington, Robert A.
    Freij, Anneli
    Thorsén, Mona
    Ticagrelor versus clopidogrel in patients with acute coronary syndromes2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 11, p. 1045-1057Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS: In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS: At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.

  • 1470.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Cannon, Christopher P.
    Held, Claes
    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.
    Himmelmann, Anders
    Husted, Steen
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Mahaffey, Kenneth M.
    Pieper, Karen S.
    Storey, Robert F.
    Steg, Philippe Gabriel
    Harrington, Robert A.
    No misrepresentation of vital status follow-up in PLATO : Predefined analyses guarantee the integrity of the benefits of ticagrelor over clopidogrel in the PLATO trial: Commentary on: DiNicolantonio JJ, Tomek A, Misrepresentation of vital status follow-up: Challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel, International Journal of Cardiology, 2013 Serebruany VL. Discrepancies in the primary PLATO trial publication and the FDA reviews, International Journal of Cardiology, 20142014In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 176, no 1, p. 300-302Article in journal (Refereed)
  • 1471.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Cannon, Christopher P.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Himmelmann, Anders
    Husted, Steen
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo S.
    Mahaffey, Kenneth W.
    Pieper, Karen S.
    Storey, Robert F.
    Steg, Philippe Gabriel
    Harrington, Robert A.
    Review of the accumulated PLATO documentation supports reliable and consistent superiority of ticagrelor over clopidogrel in patients with acute coronary syndrome Commentary on: DiNicolantonio JJ, Tomek A, Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: Serious concerns over the reliability of the PLATO trial, International Journal of Cardiology, 20132014In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 170, no 3, p. E59-E62Article in journal (Refereed)
  • 1472.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Harrington, Robert A.
    The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome2011In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 105, no 5, p. 760-762Article in journal (Other academic)
  • 1473.
    Wallentin, Lars
    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, Cardiology.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, R. C.
    Himmelmann, A.
    Husted, S.
    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.
    Katus, H.
    Steg, G.
    Storey, R. F.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    GDF-15 level in acute coronary syndrome and its relations to cardiovascular risk factors, disease manifestations, treatments and outcome - results from the PLATO-study2013In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 34, no S1, p. 733-733Article in journal (Other academic)
  • 1474.
    Wallentin, Lars C.
    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.
    New frontiers in the management of arterial thrombosis with oral anticoagulants2008In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 100, no 6, p. A15-A19Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its prevalence increases substantially with age. As patients with AF have an almost five-fold greater risk of stroke than those without AF, stroke prevention in AF (SPAF) represents a key therapeutic goal. The current standard of therapy for SPAF involves treatment with a vitamin K antagonist or aspirin; however, these agents are associated with important limitations that restrict their uptake and effective use. There are currently intense efforts to develop a new, effective, and safe antithrombotic treatment for use in SPAF, with research focusing on oral direct thrombin inhibitors (DTIs; e.g. dabigatran etexilate) and factor Xa inhibitors (e.g. apixaban, rivaroxaban). Of these, the oral DTI, dabigatran etexilate, is the most advanced in clinical development. The phase II PETRO study and its long-term extension trial, PETRO-Ex, together formed the basis for the ongoing phase III RE-LY (TM) trial, which is comparing the efficacy of two blinded doses of dabigatran etexilate (110 mg bid and 150 mg bid) with that of open-label warfarin in SPAF for a treatment duration of up to three years. Results are expected in 2009. An ongoing phase 11 dose-finding, safety, and tolerability study (RE-DEEM (TM)) is also assessing dabigatran etexilate in the secondary prevention of cardiac events in post-index myocardial infarction patients. It is expected that the results of this trial will guide the selection of an appropriate dose for further clinical testing in this indication.

  • 1475.
    Wallentin, Lars C.
    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, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Schollin, M.
    Alexander, J. H.
    Bersh, B. J.
    Hanna, M.
    Hylek, E. M.
    McMurray, J. J. V.
    Granger, C. B.
    High sensitivity troponin-T for risk stratification in atrial fibrillation during treatment with apixaban or warfarin2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 53-53Article in journal (Other academic)
  • 1476.
    Wallentin, Lars C.
    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, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Schollin, M.
    Alexander, J. H.
    Hanna, M.
    Hylek, E. M.
    Horowitz, J.
    McMurray, J. J. V.
    Granger, C. B.
    NT-proBNP for risk stratification in atrial fibrillation during treatment with apixaban or warfarin2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 51-51Article in journal (Other academic)
  • 1477.
    Wallentin, Lars C.
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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, Cardiology.
    Granger, C. B.
    Duke Clin Res Inst, Durham, NC USA..
    Koenig, W.
    Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany..
    Stewart, R. A. H.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.;Univ Auckland, Auckland 1, New Zealand..
    Tarka, E.
    GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA..
    De Winter, R. J.
    Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands..
    White, H. D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.;Univ Auckland, Auckland 1, New Zealand..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Biomarker-based risk score for prediction of cardiovascular events in stable coronary heart disease - Experiences from the STABILITY biomarker substudy2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 1041-1042Article in journal (Other academic)
  • 1478.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Emanuelsson, Håkan
    Harrington, Robert A.
    Ticagrelor versus Clopidogrel in Acute Coronary Syndromes REPLY2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 24, p. 2387-2388Article in journal (Refereed)
  • 1479.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Held, Claes
    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.
    Armstrong, Paul W.
    Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB, Canada..
    Cannon, Christopher P.
    Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA.;Harvard Clin Res Inst, Boston, MA USA..
    Davies, Richard Y.
    GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA..
    Granger, Christopher B.
    Duke Univ, Med Ctr, Durham, NC USA..
    Hagström, Emil
    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.
    Harrington, Robert A.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Hochman, Judith S.
    NYU, Langone Med Ctr, Dept Med, New York, NY USA..
    Koenig, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Krug-Gourley, Sue
    GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA..
    Mohler, Emile R., III
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tarka, Elizabeth
    GlaxoSmithKline, Former Employee Metab Pathways & Cardiovasc Thera, King Of Prussia, PA USA..
    Steg, Philippe Gabriel
    FACT, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, DHU FIRE, Paris, France.;Hop Bichat Claude Bernard, INSERUM, U 1148, Paris, France.;Imperial Coll, Royal Brompton Hosp, ICMS, NHLI, London, England..
    Stewart, Ralph A. H.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.;Univ Auckland, Auckland 1, New Zealand..
    Weiss, Robert
    Maine Res Associates, Auburn, ME USA..
    östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.;Univ Auckland, Auckland 1, New Zealand..
    Lipoprotein-Associated Phospholipase A(2) Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease2016In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 6, article id e003407Article in journal (Refereed)
    Abstract [en]

    Background - We evaluated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA(2) inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.

    Methods and Results - Plasma Lp-PLA(2) activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA(2) activity levels and outcomes. At baseline, the median Lp-PLA(2) level was 172.4 mu mol/min per liter (interquartile range 143.1-204.2 mu mol/min per liter). Comparing the highest and lowest Lp-PLA(2) quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a approximate to 65% persistent reduction in median Lp-PLA(2) activity. There were no associations between on-treatment Lp-PLA(2) activity or changes of Lp-PLA(2) activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA(2) activity or changes in Lp-PLA(2) activity levels and the effects of darapladib on outcomes.

    Conclusions - Although high Lp-PLA(2) activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA(2) activity by approximate to 65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA(2) activity.

  • 1480.
    Wallentin, Lars
    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, Cardiology.
    Held, Claes
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Stewart, Ralph
    Auckland City Hospital, Auckland, New Zeeland.
    Budaj, Andrzej
    Cannon, Christopher
    Harrington, Robert
    Koenig, Wolfgang
    Krug-Gourley, Susan
    Steg, Philippe
    Tarka, Elizabeth
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    White, Harvey
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Growth Differentiation Factor-15 (GDF-15) For Prognostication Of Outcomes In Stable Coronary Artery Disease: Experiences From The Stability Trial2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 10, p. A1634-A1634Article in journal (Other academic)
  • 1481.
    Wallentin, Lars
    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, Cardiology.
    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.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H.
    De Caterina, Raffaele
    Hanna, Michael
    Horowitz, John D.
    Hylek, Elaine M.
    Lopes, Renato D.
    Åsberg, Signild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Granger, Christopher B.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation: Insights From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 130, no 21, p. 1847-1858Article in journal (Refereed)
    Abstract [en]

    Background-Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results-The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions-GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I.

  • 1482.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Himmelmann, Anders
    Storey, Robert F.
    Steg, Philippe Gabriel
    Harrington, Robert A.
    Utilisation of novel anti-platelet agents: evidence, guidelines and proven patients' value2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 1, p. 12-14Article in journal (Other academic)
  • 1483.
    Wallentin, Lars
    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, Cardiology.
    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.
    Giannitsis, Evangelos
    Katus, Hugo
    Becker, Richard C.
    Cannon, Christopher P.
    Horrow, Jay
    Husted, Steen
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Steg, Gabriel P.
    Storey, Robert F.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Harrington, Robert
    Outcomes with ticagrelor versus clopidogrel in relation to high sensitivity troponin-T in non-ST-elevation acute coronary syndrome patients managed with early invasive or non-invasive treatment: a substudy from the prospective randomized PLATelet inhibit2013In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 33, no 10, p. E189-E189Article in journal (Other academic)
  • 1484.
    Wallentin, Lars
    et al.
    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.
    Giannitsis, Evangelos
    Katus, Hugo
    Becker, Richard
    Cannon, Christopher
    Cornel, Jan
    Emanuelsson, Håkan
    Husted, Steen
    Harrington, Robert
    Steg, Philippe
    Storey, Robert
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Usefulness of biomarkers for prognostication of outcome with early invasive or noninvasive treatment in non-st-elevation acute coronary syndromes - a substudy from the prospective randomized platelet inhibition and patient outcomes (PLATO) trial2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 59, no 13, p. E497-E497Article in journal (Other academic)
  • 1485.
    Wallentin, Lars
    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.
    James, Stefan
    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.
    Storey, Robert
    Barratt, Bryan
    Horrow, Jay
    Husted, Steen
    Katus, Hugo
    Steg, Philippe
    Becker, Richard
    Greater efficacy of ticagrelor compared to clopidogrel in acute coronary syndrome is not driven by outcomes in poor metabolizers of clopidogrel2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 59, no 13, p. E500-E500Article in journal (Other academic)
  • 1486.
    Wallentin, Lars
    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.
    James, Stefan
    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.
    Storey, Robert F.
    Armstrong, Martin
    Barratt, Bryan J.
    Horrow, Jay
    Husted, Steen
    Katus, Hugo
    Steg, P. Gabriel
    Shah, Svati H.
    Becker, Richard C.
    Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial2010In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 376, no 9749, p. 1320-1328Article in journal (Refereed)
    Abstract [en]

    Background In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. Methods DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C -> T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. Findings 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8.6% versus 11.2% (hazard ratio 0.77, 95% CI 0.60-0.99, p=0.0380) in patients with any loss-of-function allele; and 8.8% versus 10.0% (0.86, 0.74-1.01, p=0.0608) in those without any loss-of-function allele (interaction p=0.46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0.39; 8.8% vs 11.9%; 0.71, 0.55-0.92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5.7% vs 3.8%, p=0.028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11.9%) than did those without any gain-of-function or loss-of-function alleles (9.5%; p=0.022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. Interpretation Ticagrelor is a more efficacious treatment for acute coronary syndromes than is dopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment.

  • 1487.
    Wallentin, Lars
    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, Cardiology.
    Kristensen, Steen Dalby
    Anderson, Jeffrey L.
    Tubaro, Marco
    Sendon, Jose Luis Lopez
    Granger, Christopher B.
    Bode, Christoph
    Huber, Kurt
    Bates, Eric R.
    Valgimigli, Marco
    Steg, Philippe Gabriel
    Ohman, E. Magnus
    How can we optimize the processes of care for acute coronary syndromes to improve outcomes?2014In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 5, p. 622-631Article in journal (Refereed)
    Abstract [en]

    Acute coronary syndromes (ACS), either ST-elevation myocardial infarction or non ST-elevation ACS, are still one of the most common cardiac emergencies with substantial morbidity and mortality. The availability of evidence-based treatments, such as early and intense platelet inhibition and anticoagulation, and timely reperfusion and revascularization, has substantially improved outcomes in patients with ACS. The implementation of streamlined processes of care for patients with ST-elevation myocardial infarction and non ST-elevation ACS over the last decade including both appropriate tools, especially cardiac troponin, for rapid diagnosis and risk stratification and for decision support, and the widespread availability of modern antithrombotic and interventional treatments, have reduced morbidity and mortality to unprecedented low levels. These changes in the process of care require a synchronized approach, and research using a team-based strategy and effective regional networks has allowed healthcare systems to provide modern treatments for most patients with ACS. There are still areas needing improvement, such as the delivery of care to people in rural areas or with delayed time to treatment.

  • 1488.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Uppsala Clinical Research Center: development of a platform to promote national and international clinical science2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    Uppsala Clinical Research Center (UCR) is a non-profit organization that provides service for clinical research aiming for development and improvement of health care in Sweden and worldwide. UCR was started in 2001 with the ambition to shift the focus of clinical research from new medications or devices launched by the industry to problem-based research on issues identified in clinical reality, for example through the national quality registries. In order to accomplish these goals, UCR has established services in: 1) clinical trials of new and old methods in health care; 2) quality development of the health care system supported by internet-based national quality registries; 3) biostatistics, epidemiology, and data management; 4) biobanking of biological materials (Uppsala Biobank); 5) high-throughput biochemical analyses (UCR laboratory); and 6) academic leadership by the members of the UCR research faculty. The UCR clinical trials group provides services for investigator-driven projects in all areas of health care, for global mega-trials on new pharmaceutical treatments and devices, for biobanking including biomarker and genetics analyses, and for clinical events adjudication in national as well as global mega-trials. During the last few years, UCR has been a pioneer in establishing the registry-based randomized clinical trial (R-RCT), which today is an international model on how to perform cost-effective pragmatic randomized trials in the real-world environment. In 2002, UCR started the first national competence center for national quality registries, which pioneered the development of the current internet-based technologies for registering, reporting, and supporting continuous systematic improvement of health care. UCR is currently harboring around 20 national quality registries in all areas of health care. Today, UCR is the leading European center for registry-based quality development and evaluation of new medical treatments in cardiovascular care and has started to support other European countries in implementing the UCR registry platform in order to improve quality of care in the European Union.

  • 1489.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Unstable coronary artery disease2009In: International Textbook of Cardiology, London: Mosby International , 2009, Third edition, p. 367-387Chapter in book (Other academic)
  • 1490.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ärnström, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Husted, Steen
    Hosp Unit West, Dept Med, Herning Holstebro, Denmark..
    Janzon, Magnus
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Div Hlth Care Anal, Dept Med & Hlth Sci, Ctr Med Technol Assessment, Linkoping, Sweden..
    Johnsen, Sören Paaske
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Kontny, Frederic
    Stavanger Univ Hosp, Dept Cardiol, Stavanger, Norway.;Drammen Heart Ctr, Drammen, Norway..
    Kempf, Tibor
    Hannover Med Sch, Dept Cardiol & Angiol, Hannover, Germany..
    Levin, Lars-Åke
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Div Hlth Care Anal, Dept Med & Hlth Sci, Ctr Med Technol Assessment, Linkoping, 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.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Wollert, Kai C.
    Hannover Med Sch, Dept Cardiol & Angiol, Hannover, Germany..
    Swahn, Eva
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Lagerqvist, Bo
    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.
    Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, no 10054, p. 1903-1911Article in journal (Refereed)
    Abstract [en]

    Background The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during 15 years' follow-up. Methods The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden, Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within 7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data with national health-care registers. The primary endpoint was a composite of death or myocardial infarction. Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as the area between mean cumulative count-of-events curves. Analyses were done by intention to treat. Findings At a minimum of 15 years' follow-up on Dec 31, 2014, data for survival status and death were available for 2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204-888; p= 0.0020) compared with the non-invasive strategy. This effect was larger in non-smokers (mean gain 809 days, 95% CI 402-1175; p(interaction) = 0.0182), patients with elevated troponin T (778 days, 357-1165; p (interaction) = 0.0241), and patients with high concentrations of growth differentiation factor-15 (1356 days, 507-1650; p (interaction) = 0.0210). The difference was mainly driven by postponement of new myocardial infarction, whereas the early difference in mortality alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830-1366) postponement of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p< 0.0001). Interpretation During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the preferred option in most patients with non-ST-elevation acute coronary syndrome.

  • 1491.
    Wallentin, Lars
    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, Cardiology.
    Lindholm, Daniel
    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.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wernroth, Lisa
    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.
    Becker, Richard C.
    Cannon, Christopher P.
    Cornel, Jan H.
    Himmelmann, Anders
    Giannitsis, Evangelos
    Harrington, Robert A.
    Held, Claes
    Husted, Steen
    Katus, Hugo A.
    Mahaffey, Kenneth W.
    Steg, Ph. Gabriel
    Storey, Robert F.
    James, Stefan K.
    Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 3, p. 293-303Article in journal (Refereed)
    Abstract [en]

    Background Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. Methods and Results Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT 14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group Conclusions Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. Clinical Trial Registration URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

  • 1492.
    Wallentin, Lars
    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, Cardiology.
    Lopes, Renato D
    Hanna, Michael
    Thomas, Laine
    Hellkamp, Anne
    Nepal, Sunil
    Hylek, Elaine M
    Al-Khatib, Sana M
    Alexander, John H
    Alings, Marco
    Amerena, John
    Ansell, Jack
    Aylward, Philip
    Bartunek, Jozef
    Commerford, Patrick
    De Caterina, Raffaele
    Erol, Cetin
    Harjola, Veli-Pekka
    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, Cardiology.
    Horowitz, John D
    Huber, Kurt
    Husted, Steen
    Keltai, Matyas
    Lanas, Fernando
    Lisheng, Liu
    McMurray, John J V
    Oh, Byung-Hee
    Rosenqvist, Mårten
    Ruzyllo, Witold
    Steg, Philippe Gabriel
    Vinereanu, Dragos
    Xavier, Denis
    Granger, Christopher B
    Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, no 22, p. 2166-2176Article in journal (Refereed)
    Abstract [en]

    Background

    In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR).

    Methods and Results

    The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR.

    Conclusions

    The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control.

    Clinical Trial Registration

    URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

  • 1493.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lopes, Renato D.
    Hanna, Michael
    Thomas, Laine
    Hellkamp, Anne
    Nepal, Sunil
    Hylek, Elaine M.
    Al-Khatib, Sana M.
    Alexander, John H.
    Alings, Marco
    Amerena, John
    Ansell, Jack
    Aylward, Philip
    Bartunek, Jozef
    Commerford, Patrick
    De Caterina, Raffaele
    Erol, Cetin
    Harjola, Veli-Pekka
    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, Cardiology.
    Horowitz, John
    Huber, Kurt
    Husted, Steen
    Keltai, Matyas
    Lanas, Fernando
    Lisheng, Liu
    McMurray, John J. V.
    Oh, Byung-Hee
    Rosenqvist, Marten
    Ruzyllo, Witold
    Steg, Philippe Gabriel
    Vinereanu, Dragos
    Xavier, Denis
    Granger, Christopher B.
    Response to Letter Regarding Article, "Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation"2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 2, p. E21-E22Article in journal (Refereed)
  • 1494.
    Wallentin, Lars
    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, Cardiology.
    Michelsen, Annika E.
    Aukrust, Pal
    Becker, Richard
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Budaj, Andrzej
    Cornel, Jan
    Himmelmann, Anders
    Husted, Steen
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Storey, Robert
    Kontny, Frederic
    Ueland, Thor
    Activated Leukocyte Cell Adhesion Molecule (ALCAM) And Outcomes In Acute Coronary Syndromes: A Plato Biomarker Substudy2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 10, p. A231-A231Article in journal (Other academic)
  • 1495.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Erlinge, David
    Braun, Oscar O.
    Jakubowski, Joseph A.
    Sugidachi, Atsuhiro
    Winters, Kenneth J.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease2008In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 29, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.

  • 1496.
    Wallentin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Yusuf, Salim
    Ezekowitz, Michael D.
    Alings, Marco
    Flather, Marcus
    Franzosi, Maria Grazia
    Pais, Prem
    Dans, Antonio
    Eikelboom, John
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Pogue, Janice
    Reilly, Paul A.
    Yang, Sean
    Connolly, Stuart J.
    Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial2010In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 376, no 9745, p. 975-983Article in journal (Refereed)
    Abstract [en]

    Background Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. Methods In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2.0-3.0. Median follow-up was 2.0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of RE-LY is registered with ClinicalTrials.gov, number NCT00262600. Findings The quartiles of cTTR for patients in the warfarin group were: less than 57.1%, 57.1-65.5%, 65.5-72.6%, and greater than 72.6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0.89) or 150 mg dabigatran (interaction p=0.20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0.71) or 150 mg dabigatran (interaction p=0.89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0.03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0.036 and p=0.0006, respectively) and total mortality (interaction p=0.066 and p=0.052, respectively) with reduced event rates at low cITR, and similar rates at high cTTR. Interpretation The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.

  • 1497.
    Wallentin, Lars
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Zethelius, Bjorn
    Berglund, 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.
    Eggers, Kai M.
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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.
    Wollert, Kai C.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e78797-Article in journal (Refereed)
    Abstract [en]

    The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.

  • 1498.
    Wallert, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    Gustafson, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    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.
    Madison, Guy
    Department of Psychology, Umeå University, Umeå, Sweden.
    Norlund, Fredrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    Olsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    Predicting Adherence to Internet-Delivered Psychotherapy for Symptoms of Depression and Anxiety After Myocardial Infarction: Machine Learning Insights From the U-CARE Heart Randomized Controlled Trial2018In: Journal of Medical Internet Research, ISSN 1438-8871, E-ISSN 1438-8871, Vol. 20, no 10, article id e10754Article in journal (Refereed)
    Abstract [en]

    Background: Low adherence to recommended treatments is a multifactorial problem for patients in rehabilitation after myocardial infarction (MI). In a nationwide trial of internet-delivered cognitive behavior therapy (iCBT) for the high-risk subgroup of patients with MI also reporting symptoms of anxiety, depression, or both (MI-ANXDEP), adherence was low. Since low adherence to psychotherapy leads to a waste of therapeutic resources and risky treatment abortion in MI-ANXDEP patients, identifying early predictors for adherence is potentially valuable for effective targeted care.

    Objectives: The goal of the research was to use supervised machine learning to investigate both established and novel predictors for iCBT adherence in MI-ANXDEP patients.

    Methods: Data were from 90 MI-ANXDEP patients recruited from 25 hospitals in Sweden and randomized to treatment in the iCBT trial Uppsala University Psychosocial Care Programme (U-CARE) Heart study. Time point of prediction was at completion of the first homework assignment. Adherence was defined as having completed more than 2 homework assignments within the 14-week treatment period. A supervised machine learning procedure was applied to identify the most potent predictors for adherence available at the first treatment session from a range of demographic, clinical, psychometric, and linguistic predictors. The internal binary classifier was a random forest model within a 3×10–fold cross-validated recursive feature elimination (RFE) resampling which selected the final predictor subset that best differentiated adherers versus nonadherers.

    Results: Patient mean age was 58.4 years (SD 9.4), 62% (56/90) were men, and 48% (43/90) were adherent. Out of the 34 potential predictors for adherence, RFE selected an optimal subset of 56% (19/34; Accuracy 0.64, 95% CI 0.61-0.68, P<.001). The strongest predictors for adherence were, in order of importance, (1) self-assessed cardiac-related fear, (2) sex, and (3) the number of words the patient used to answer the first homework assignment.

    Conclusions: For developing and testing effective iCBT interventions, investigating factors that predict adherence is important. Adherence to iCBT for MI-ANXDEP patients in the U-CARE Heart trial was best predicted by cardiac-related fear and sex, consistent with previous research, but also by novel linguistic predictors from written patient behavior which conceivably indicate verbal ability or therapeutic alliance. Future research should investigate potential causal mechanisms and seek to determine what underlying constructs the linguistic predictors tap into. Whether these findings replicate for other interventions outside of Sweden, in larger samples, and for patients with other conditions who are offered iCBT should also be investigated.

  • 1499.
    Wallert, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. 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.
    Madison, Guy
    Umea Univ, Dept Psychol, Umea, Sweden.
    Olsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Myocardial infarction and artificial time-­constraint: a theoretical framework and national registry study of yearly, monthly, and weekly incidence variation2016Conference paper (Refereed)
  • 1500.
    Wallert, John
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    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, Cardiology.
    Madison, Guy
    Department of Psychology, Umeå University.
    Olsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    Temporal changes in myocardial infarction incidence rates are associated with periods of perceived psychosocial stress: A SWEDEHEART national registry study2017In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 191, p. 12-20Article in journal (Refereed)
    Abstract [en]

    BackgroundPsychosocial stress might trigger myocardial infarction (MI). Increased MI incidence coincides withrecurrent time periods during the year perceived as particularly stressful in the population.

    MethodsA stress-triggering hypothesis on the risk of MI onset was investigated with Swedish population data on MIhospital admission date and symptom onset date (N = 156,690; 148,176) as registered from 2006 through 2013 in thenational quality registry database Swedish Web-system for Enhancement and Development of Evidence-based care in Heartdisease Evaluated According to Recommended Therapies (SWEDEHEART). Poisson regression was applied to analyze dailyMI rates during days belonging to the Christmas and New Year holidays, turns of the month, Mondays, weekends, andsummer vacation in July compared with remaining control days.

    ResultsAdjusted incidence rate ratios (IRRs) for MI rates were higher during Christmas and New Year holidays(IRR = 1.07 [1.04-1.09],Pb.001) and on Mondays (IRR = 1.11 [1.09-1.13],Pb.001) and lower in July (IRR = 0.92 [0.90-0.94],Pb.001) and over weekends (IRR = 0.88 [0.87-0.89],Pb.001), yet not during the turns of the month (IRR = 1.01[1.00–1.02],P= .891). These findings were also predominantly robust with symptom onset as alternative outcome, whenadjusting for both established and some suggested-but-untested confounders, and in 8 subgroups.

    ConclusionsFluctuations in daily MI incidence rates are systematically related to time periods of presumed psychosocialstress. Further research might clarify mechanisms that are amenable to clinical alteration.

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