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  • 1. Alexander, John H
    et al.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lopes, Renato D
    Hijazi, Ziad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hohnloser, Stefan H
    Ezekowitz, Justin A
    Halvorsen, Sigrun
    Hanna, Michael
    Commerford, Patrick
    Ruzyllo, Witold
    Huber, Kurt
    Al-Khatib, Sana M
    Granger, Christopher B
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine: A Secondary Analysis of a Randomized Clinical Trial2016In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 1, no 6, p. 673-681Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.

    OBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.

    DESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016.

    MAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat.

    RESULTS: Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance.

    CONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.

  • 2.
    Bjorck, Fredrik
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lip, Gregory Y. H.
    Univ Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, England.;Aalborg Univ, Dept Clin Med, Aalborg Thrombosis Res Unit, Aalborg, Denmark..
    Wester, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.;Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Svensson, Peter J.
    Lund Univ, Dept Coagulat Disorders, Malmo, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Outcomes in a Warfarin-Treated Population With Atrial Fibrillation2016In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 1, no 2, p. 172-180Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs. OBJECTIVES To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control. DESIGN, SETTING, AND PARTICIPANTS A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications. EXPOSURES Use of warfarin with and without concomitant therapy with aspirin. MAIN OUTCOMES AND MEASURES Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding. RESULTS Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA(2)DS(2)-VASc (cardiac failure or dysfunction, hypertension, age >= 75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44%(0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07%(2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04%(2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates. CONCLUSIONS AND RELEVANCE Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.

  • 3.
    Cowper, Patricia A.
    et al.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Sheng, Shubin
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Lopes, Renato D.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Anstrom, Kevin J.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Stafford, Judith A.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Davidson-Ray, Linda
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Al-Khatib, Sana M.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Ansell, Jack
    Hofstra Northwell Sch Med, Dept Med, Hemstead, NY USA..
    Dorian, Paul
    Univ Toronto, Div Cardiol, Toronto, ON, Canada..
    Husted, Steen
    Aarhus Univ, Aarhus, Denmark..
    McMurray, John J. V.
    Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Glasgow, Lanark, Scotland..
    Steg, P. Gabriel
    Univ Paris Diderot, Dept Hosp Univ Fibrosis Inflammat Remodeling, AP HP, Sorbonne Paris Cite,French Alliance Cardiovasc Cl, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, INSERM, U 1148, Paris, France.;Imperial Coll, Royal Brompton Hosp, Natl Heart & Lung Inst, London, England..
    Alexander, John H.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Granger, Christopher B.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Mark, Daniel B.
    Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA..
    Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial2017In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 2, no 5, p. 525-534Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial.

    OBJECTIVE To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system.

    DESIGN, SETTING, AND PARTICIPANTS This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011.

    INTERVENTIONS Apixaban therapy vs warfarin therapy.

    MAIN OUTCOMES AND MEASURES Within-trial resource use and costwere compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed.

    RESULTS Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, -$ 60; 95% CI, -$ 2728 to $ 2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($ 53 925 per quality-adjusted life year, with 98% likelihood of meeting a $ 100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon.

    CONCLUSIONS AND RELEVANCE Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness.

  • 4.
    Gregson, John
    et al.
    London Sch Hyg & Trop Med, London, England.
    Kaptoge, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Bolton, Thomas
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Pennells, Lisa
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Willeit, Peter
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Med Univ Innsbruck, Innsbruck, Austria.
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, MRC Biostat Unit, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Bell, Steven
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England.
    Sweeting, Michael
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England.
    Rimm, Eric B.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Kabrhel, Christopher
    Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Zoller, Bengt
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Assmann, Gerd
    Assmann Fdn Prevent, Munster, Germany.
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.
    Folsom, Aaron R.
    Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA.
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Fletcher, Astrid
    London Sch Hyg & Trop Med, London, England.
    Norman, Paul E.
    Univ Western Australia, Perth, WA, Australia.
    Nordestgaard, Borge G.
    Copenhagen Univ Hosp, Dept Clin Biochem, Herlev & Gentofte Hosp, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark;Copenhagen Univ Hosp, Copenhagen City Heart Study, Frederiksberg Hosp, Copenhagen, Denmark.
    Kitamura, Akihiko
    Osaka Univ, Osaka, Japan;Tokyo Metropolitan Inst Gerontol, Tokyo, Japan.
    Mahmoodi, Bakhtawar K.
    Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands.
    Whincup, Peter H.
    St Georges Univ London, London, England.
    Knuiman, Matthew
    Univ Western Australia, Perth, WA, Australia.
    Salomaa, Veikko
    Nat Inst Hlth & Welf, Helsinki, Finland;Natl Inst Hlth & Welf, Helsinki, Finland.
    Meisinger, Christa
    Ludwig Maximilian Univ Munich, Munich, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Neuherberg, Germany.
    Koenig, Wolfgang
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany;Univ Ulm, Dept Internal Med Cardiol 2, Med Ctr, Ulm, Germany.
    Kavousi, Maryam
    Erasmus Univ, Erasmus Univ Med Ctr, Rotterdam, Netherlands.
    Voelzke, Henry
    Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.
    Cooper, Jackie A.
    UCL, UCL Med Sch, London, England.
    Ninomiya, Toshiharu
    Kyushu Univ, Fukuoka, Fukuoka, Japan.
    Casiglia, Edoardo
    Univ Padua, Padua, Italy.
    Rodriguez, Beatriz
    Univ Hawaii, Honolulu, HI 96822 USA.
    Ben-Shlomo, Yoav
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
    Despres, Jean-Pierre
    Univ Laval, Inst Nutraceut & Funct Foods, Quebec City, PQ, Canada.
    Simons, Leon
    Univ New South Wales, Sydney, NSW, Australia.
    Barrett-Connor, Elizabeth
    Univ Calif San Diego, San Diego, CA 92103 USA.
    Bjorkelund, Cecilia
    Univ Gothenburg, Gothenburg, Sweden.
    Notdurfter, Marlene
    Bruneck Hosp, Dept Internal Med, Brunico, Italy.
    Kromhout, Daan
    Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands;Wageningen Univ, Wageningen, Netherlands.
    Price, Jackie
    Univ Edinburgh, Edinburgh, Midlothian, Scotland.
    Sutherland, Susan E.
    Med Univ South Carolina, Charleston, SC 29425 USA.
    Sundstroem, Johan
    Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.
    Kauhanen, Jussi
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
    Gallacher, John
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England;Univ Oxford, Oxford, England.
    Beulens, Joline W. J.
    VU Univ Med Ctr Amsterdam, Amsterdam, Netherlands;Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Dankner, Rachel
    Tel Aviv Univ, Tel Aviv, Israel.
    Cooper, Cyrus
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England.
    Giampaoli, Simona
    NIH, ISS, Rome, Italy;Natl Hlth Inst Hlth, ISS, Rome, Italy.
    Deen, Jason F.
    Univ Washington, Sch Med, Ctr Hlth Equ Divers & Inclus, Seattle, WA USA.
    Gomez de la Camara, Agustin
    Clin Res & Clin Trials Unit, Plataforma Innovat Tecnol Med & Sanitarias, Madrid, Spain.
    Kuller, Lewis H.
    Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA.
    Rosengren, Annika
    Univ Gothenburg, Gothenburg, Sweden.
    Svensson, Peter J.
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Nagel, Dorothea
    Ludwig Maximilian Univ Munich, Munich, Germany.
    Crespo, Carlos J.
    Portland State Univ, Portland, OR 97207 USA.
    Brenner, Hermann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA.
    Albertorio-Diaz, Juan R.
    US Ctr Dis Control & Prevent, Atlanta, GA USA.
    Atkins, Robert
    Monash Univ, Melbourne, Vic, Australia.
    Brunner, Eric J.
    UCL, Dept Epidemiol & Publ Hlth, London, England;UCL, London, England.
    Shipley, Martin
    UCL, Dept Epidemiol & Publ Hlth, London, England;UCL, London, England.
    Njolstad, Inger
    Norwegian Inst Publ Hlth, Oslo, Norway;Arctic Univ Norway, Tromso, Norway.
    Lawlor, Deborah A.
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England;Univ Bristol, Bristol, Avon, England.
    van der Schouw, Yvonne T.
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Selmer, Randi Marie
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Trevisan, Maurizio
    CUNY, Sch Med, New York, NY 10031 USA;CUNY City Coll, New York, NY USA.
    Verschuren, W. M. Monique
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands;Natl Inst Publ Hlth & Environm, Ctr Nutr Prevent & Hlth Serv, RIVM, Bilthoven, Netherlands.
    Greenland, Philip
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA;Northwestern Univ, Chicago, IL 60611 USA.
    Wassertheil-Smoller, Sylvia
    Albert Einstein Coll Med, New York, NY USA.
    Lowe, Gordon D. O.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Wood, Angela M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Butterworth, Adam S.
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Thompson, Simon G.
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Danesh, John
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Di Angelantonio, Emanuele
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, NIH, Res Blood & Transplant Res Unit Donor Hlth & Geno, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Meade, Tom
    London Sch Hyg & Trop Med, London, England.
    Rosamond, Wayne
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Whitsel, Eric
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Cushman, Mary
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Barr, Elizabeth L. M.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia.
    Shaw, Jonathan E.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia.
    Zimmet, Paul Z.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia.
    Kiechl, Stefan
    Bruneck Hosp, Dept Internal Med, Brunico, Italy.
    Weger, Siegfried
    Bruneck Hosp, Dept Internal Med, Brunico, Italy.
    Willeit, Johann
    Bruneck Hosp, Dept Internal Med, Brunico, Italy.
    Amuzu, Antoinette
    UCL, London, England.
    Dale, Caroline
    UCL, London, England.
    Casas, Juan P.
    UCL, London, England.
    Tikhonoff, Valerie
    Univ Padua, Padua, Italy.
    Nietert, Paul
    Med Univ South Carolina, Charleston, SC 29425 USA.
    Tybjaerg-Hansen, Anne
    Univ Copenhagen, Copenhagen, Denmark.
    Frikke-Schmidt, Ruth
    Univ Copenhagen, Copenhagen, Denmark.
    Jensen, Gorm B.
    Univ Copenhagen, Copenhagen, Denmark.
    Lora Pablos, David
    Hosp 12 Octubre, Madrid, Spain.
    Cancelas Navia, Pilar
    Hosp 12 Octubre, Madrid, Spain.
    McLachlan, Stela
    Univ Edinburgh, Edinburgh, Midlothian, Scotland.
    Schoettker, Ben
    German Canc Res Ctr, Heidelberg, Germany.
    Saum, Kai-Uwe
    German Canc Res Ctr, Heidelberg, Germany.
    Holleczek, Bernd
    German Canc Res Ctr, Heidelberg, Germany.
    Ariansen, Inger
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Meyer, Haakon E.
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Haheim, Lise Lund
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Vartiainen, Erkki
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Jousilahti, Pekka
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Harald, Kennet
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Wilhelmsen, Lars
    Univ Gothenburg, Gothenburg, Sweden.
    Dennison, Elaine
    Univ Southampton, Southampton, Hants, England.
    Syddall, Holly
    Univ Southampton, Southampton, Hants, England.
    Westbury, Leo
    Univ Southampton, Southampton, Hants, England.
    Flicker, Leon
    Univ Western Australia, Perth, WA, Australia.
    Hankey, Graeme J.
    Univ Western Australia, Perth, WA, Australia.
    Golledge, Jonathan
    James Cook Univ, Townsville, Qld, Australia.
    Doi, Yasufumi
    Kyushu Univ, Fukuoka, Fukuoka, Japan.
    Kiyohara, Yutaka
    Kyushu Univ, Fukuoka, Fukuoka, Japan.
    Elders, Petra
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Stehouwer, Coen
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Jensen, Majken
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Iso, Hiroyasu
    Osaka Univ, Grad Sch Med, Suita, Osaka, Japan.
    Yamagishi, Kazumasa
    Univ Tsukuba, Tsukuba, Ibaraki, Japan.
    Sudhir, Kurl
    Univ Eastern Finland, Keupio, Finland.
    Tuomainen, Tomi-Pekka
    Univ Eastern Finland, Keupio, Finland.
    Salonen, Jukka T.
    Univ Eastern Finland, Keupio, Finland.
    Boer, Jolanda M. A.
    Natl Inst Publ Hlth & Environm, RIVM, Bilthoven, Netherlands.
    Blokstra, Anneke
    Natl Inst Publ Hlth & Environm, RIVM, Bilthoven, Netherlands.
    Melander, Olle
    Lund Univ, Lund, Sweden.
    Nilsson, Peter M.
    Lund Univ, Lund, Sweden.
    Engstrom, Gunnar
    Lund Univ, Lund, Sweden.
    Palmieri, Luigi
    Natl Hlth Inst Hlth, ISS, Rome, Italy.
    Vanuzzo, Diego
    Natl Hlth Inst Hlth, ISS, Rome, Italy.
    Peters, Annette
    German Res Ctr Environm Hlth, Neuherberg, Germany.
    Thorand, Barbara
    German Res Ctr Environm Hlth, Neuherberg, Germany.
    Heier, Margit
    German Res Ctr Environm Hlth, Neuherberg, Germany.
    Hu, Frank B.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Manson, JoAnn E.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Meijer, Karina
    Univ Groningen, Groningen, Netherlands.
    Gansevoort, Ron T.
    Univ Groningen, Groningen, Netherlands.
    Schulte, Helmut
    Univ Munster, Munster, Germany.
    Sluijs, Ivonne
    Univ Med Ctr Utrecht, Utrecht, Netherlands.
    Cantin, Bernard
    Univ Laval, Quebec City, PQ, Canada.
    Lamarche, Benoit
    Univ Laval, Quebec City, PQ, Canada.
    Dagenais, Gilles R.
    Univ Laval, Quebec City, PQ, Canada.
    McEvoy, Linda
    Univ Calif San Diego, San Diego, CA 92103 USA.
    Laughlin, Gail
    Univ Calif San Diego, San Diego, CA 92103 USA.
    Daniels, Lori B.
    Univ Calif San Diego, San Diego, CA 92103 USA.
    Aspelund, Thor
    Univ Iceland, Reykjavik, Iceland.
    Gudmundsson, Elias Freyr
    Univ Iceland, Reykjavik, Iceland.
    Thorsson, Bolli
    Univ Iceland, Reykjavik, Iceland.
    Leening, Maarten J. G.
    Erasmus MC, Rotterdam, Netherlands.
    Ikram, M. Arfan
    Erasmus MC, Rotterdam, Netherlands.
    Franco, Oscar H.
    Erasmus MC, Rotterdam, Netherlands.
    Tunstall-Pedoe, Hugh
    Dundee Univ, Dundee, Scotland.
    Werner, Andre
    Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.
    Devereux, Richard
    Weill Cornell Med, New York, NY USA.
    Jolly, Stacey
    Cleveland Clin, Phoenix, AZ USA.
    Smith, George Davey
    Univ Bristol, Bristol, Avon, England.
    Can, Gunay
    Trakya Univ, Edirne, Turkey.
    Yuksel, Husniye
    Atasehir Florence Nightingale Hosp, Istanbul, Turkey.
    Altay, Servet
    Trakya Univ, Edirne, Turkey.
    Ingelsson, Martin
    Arctic Univ Norway, Tromso, Norway.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Claessen, Heiner
    German Canc Res Ctr, Heidelberg, Germany;German Diabet Ctr, Dusseldorf, Germany.
    Rothenbacher, Dietrich
    Univ Ulm, Ulm, Germany.
    Parikh, Nisha, I
    Univ Calif San Francisco, San Francisco, CA 94143 USA.
    Eaton, Charles
    Care New England, Pawtucket, RI USA.
    Kivimaki, Mika
    UCL, London, England.
    Feskens, Edith
    Wageningen Univ, Wageningen, Netherlands.
    Geleijnse, Johanna M.
    Wageningen Univ, Wageningen, Netherlands.
    Spackman, Sarah
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Walker, Matthew
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England.
    Cardiovascular Risk Factors Associated With Venous Thromboembolism2019In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 4, no 2, p. 163-173Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism.

    DESIGN, SETTING, AND PARTICIPANTS: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018.

    EXPOSURES: A panel of several established cardiovascular risk factors.

    MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI).

    RESULTS: Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers.

    CONCLUSIONS AND RELEVANCE: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

  • 5.
    Hess, Paul L.
    et al.
    Vet Affairs Eastern Colorado & Hlth Care Syst, Denver, CO USA.;Univ Colorado, Sch Med, Dept Med, Aurora, CO USA..
    Wojdyla, Daniel M.
    Duke Clin Res Inst, POB 3850,2400 Pratt St, Durham, NC 27705 USA..
    Al-Khatib, Sana M.
    Duke Univ, Duke Clin Res Inst, Sch Med, Dept Med, Durham, NC USA..
    Lokhnygina, Yuliya
    Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA..
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Armstrong, Paul W.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada..
    Roe, Matthew T.
    Duke Univ, Duke Clin Res Inst, Sch Med, Dept Med, Durham, NC USA..
    Ohman, E. Magnus
    Duke Univ, Duke Clin Res Inst, Sch Med, Dept Med, Durham, NC USA..
    Harrington, Robert A.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Alexander, John H.
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Van de Werf, Frans
    Univ Leuven, Dept Cardiol, Leuven, Belgium..
    Piccini, Jonathan P.
    Duke Univ, Duke Clin Res Inst, Sch Med, Dept Med, Durham, NC USA..
    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, South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.;Med Ctr, Adelaide, SA, Australia..
    Moliterno, David J.
    Univ Kentucky, Gill Heart Inst, Lexington, KY USA.;Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA..
    Mahaffey, Kenneth W.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Tricoci, Pierluigi
    Duke Clin Res Inst, POB 3850,2400 Pratt St, Durham, NC 27705 USA.;Duke Univ, Duke Clin Res Inst, Sch Med, Dept Med, Durham, NC USA..
    Sudden Cardiac Death After Non-ST-Segment Elevation Acute Coronary Syndrome2016In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 1, no 1, p. 73-79Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely. OBJECTIVE To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD. DESIGN, SETTING, AND PARTICIPANTS This pooled cohort analysis merged individual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015. MAIN OUTCOMES AND MEASURES Sudden cardiac death. RESULTS Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men; 32.6% women; median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7%(C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrentmyocardial infarction (hazard ratio [HR], 2.95; 95% CI, 2.29-3.80; P <.001) and any hospitalization (HR, 2.45; 95% CI, 1.98-3.03; P <.001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75; 95% CI, 0.58-0.98; P =.03). CONCLUSIONS AND RELEVANCE In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.

  • 6.
    Hochman, Judith S.
    et al.
    Cardiovascular Clinical Research Center, New York University School of Medicine, New York, New York.
    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.
    Jeffries, Neal
    NHLBI, Bldg 10, Bethesda, MD 20892 USA.
    Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial2019In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 4, no 3, p. 273-286Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE

    It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia.

    OBJECTIVE

    To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles.

    DESIGN, SETTING, AND PARTICIPANTS

    The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (< 50% for imaging stress test and < 70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018.

    MAIN OUTCOMES AND MEASURES

    Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported.

    RESULTS

    A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [ n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging.

    CONCLUSIONS AND RELEVANCE

    The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD.

  • 7.
    Lindholm, Daniel P
    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.
    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.
    Gabrysch, Katja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Storey, Robert F
    Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Cannon, Christopher P
    Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA; Baim Clinical Research Institute, Boston, Massachusetts, USA.
    Mahaffey, Kenneth W
    Stanford Center for Clinical Research, Stanford School of Medicine, Stanford, California, USA.
    Steg, Philippe Gabriel
    Assistance Publique-Hôpitaux de Paris; Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France; NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom.
    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.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, 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.
    Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study2018In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 3, no 12, p. 1160-1166Article in journal (Refereed)
    Abstract [en]

    Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.

    Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.

    Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.

    Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.

    Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.

    Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).

    Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.

    Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

  • 8.
    Povsic, Thomas J.
    et al.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27705 USA.
    Ohman, E. Magnus
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27705 USA.
    Roe, Matthew T.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27705 USA.
    White, Jennifer
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27705 USA.
    Rockhold, Frank W.
    Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27705 USA.
    Montalescot, Gilles
    Sorbonne Univ, Pitie Salpetriere Hosp, Inst Cardiol, ACTION Study Grp, Paris, France.
    Cornet, Jan H.
    Noordwest Ziekenhuisgrp, Dept Cardiol, Alkmaar, Netherlands;Dutch Network Cardiovasc Res, Utrecht, Netherlands.
    Nicolau, Jose C.
    Univ Sao Paulo, Inst Coracao Hosp Clin HCFMUSP, Fac Med, Sao Paulo, Brazil.
    Steg, P. Gabriel
    Univ Paris Diderot, DHU FIRE, AP HP, Paris, France;INSERM, U1148, Paris, France;Imperial Coll, Natl Heart & Lung Inst, Royal Brompton Hosp, London, England.
    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.
    Bode, Christoph
    Univ Freiburg, Fac Med, Internal Med 3, Freiburg, Germany.
    Welsh, Robert C.
    Mazankowski Alberta Heart Inst, Edmonton, AB, Canada;Univ Alberta, Edmonton, AB, Canada.
    Plotnikov, Alexei N.
    Janssen Res & Dev, Raritan, NJ USA.
    Mundl, Hardi
    Bayer AG, Wuppertal, Germany.
    Gibson, C. Michael
    Harvard Med Sch, Beth Israel Deaconess Hosp, PERFUSE Study Grp, Boston, MA 02115 USA.
    P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes2019In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 4, no 7, p. 680-684Article in journal (Refereed)
    Abstract [en]

    Importance  Physician behavior in response to knowledge of a patient’s CYP2C19 clopidogrel metabolizer status is unknown.

    Objective  To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.

    Design, Setting, and Participants  The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.

    Interventions  Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.

    Main Outcomes and Measures  Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.

    Results  Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.

    Conclusions and Relevance  Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.

  • 9.
    Roth, Gregory A
    et al.
    Institute for Health Metrics and Evaluation, University of Washington, Seattle.
    Johnson, Catherine O
    Abate, Kalkidan Hassen
    Jimma University, Jimma, Ethiopia..
    Abd-Allah, Foad
    Ahmed, Muktar
    Alam, Khurshid
    Alam, Tahiya
    Alvis-Guzman, Nelson
    Ansari, Hossein
    Ärnlöv, Johan
    Atey, Tesfay Mehari
    Awasthi, Ashish
    Awoke, Tadesse
    Barac, Aleksandra
    Bärnighausen, Till
    Bedi, Neeraj
    Bennett, Derrick
    Bensenor, Isabela
    Biadgilign, Sibhatu
    Castañeda-Orjuela, Carlos
    Catalá-López, Ferrán
    Davletov, Kairat
    Dharmaratne, Samath
    Ding, Eric L
    Dubey, Manisha
    Faraon, Emerito Jose Aquino
    Farid, Talha
    Farvid, Maryam S
    Feigin, Valery
    Fernandes, João
    Frostad, Joseph
    Gebru, Alemseged
    Geleijnse, Johanna M
    Gona, Philimon Nyakauru
    Griswold, Max
    Hailu, Gessessew Bugssa
    Hankey, Graeme J
    Hassen, Hamid Yimam
    Havmoeller, Rasmus
    Hay, Simon
    Heckbert, Susan R
    Irvine, Caleb Mackay Salpeter
    James, Spencer Lewis
    Jara, Dube
    Kasaeian, Amir
    Khan, Abdur Rahman
    Khera, Sahil
    Khoja, Abdullah T
    Khubchandani, Jagdish
    Kim, Daniel
    Kolte, Dhaval
    Lal, Dharmesh
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Linn, Shai
    Lotufo, Paulo A
    Magdy Abd El Razek, Hassan
    Mazidi, Mohsen
    Meier, Toni
    Mendoza, Walter
    Mensah, George A
    Meretoja, Atte
    Mezgebe, Haftay Berhane
    Mirrakhimov, Erkin
    Mohammed, Shafiu
    Moran, Andrew Edward
    Nguyen, Grant
    Nguyen, Minh
    Ong, Kanyin Liane
    Owolabi, Mayowa
    Pletcher, Martin
    Pourmalek, Farshad
    Purcell, Caroline A
    Qorbani, Mostafa
    Rahman, Mahfuzar
    Rai, Rajesh Kumar
    Ram, Usha
    Reitsma, Marissa Bettay
    Renzaho, Andre M N
    Rios-Blancas, Maria Jesus
    Safiri, Saeid
    Salomon, Joshua A
    Sartorius, Benn
    Sepanlou, Sadaf Ghajarieh
    Shaikh, Masood Ali
    Silva, Diego
    Stranges, Saverio
    Tabarés-Seisdedos, Rafael
    Tadele Atnafu, Niguse
    Thakur, J S
    Topor-Madry, Roman
    Truelsen, Thomas
    Tuzcu, E Murat
    Tyrovolas, Stefanos
    Ukwaja, Kingsley Nnanna
    Vasankari, Tommi
    Vlassov, Vasiliy
    Vollset, Stein Emil
    Wakayo, Tolassa
    Weintraub, Robert
    Wolfe, Charles
    Workicho, Abdulhalik
    Xu, Gelin
    Yadgir, Simon
    Yano, Yuichiro
    Yip, Paul
    Yonemoto, Naohiro
    Younis, Mustafa
    Yu, Chuanhua
    Zaidi, Zoubida
    Zaki, Maysaa El Sayed
    Zipkin, Ben
    Afshin, Ashkan
    Gakidou, Emmanuela
    Lim, Stephen S
    Mokdad, Ali H
    Naghavi, Mohsen
    Vos, Theo
    Murray, Christopher J L
    The Burden of Cardiovascular Diseases Among US States, 1990-20162018In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 3, no 5, p. 375-389Article in journal (Refereed)
    Abstract [en]

    Importance: Cardiovascular disease (CVD) is the leading cause of death in the United States, but regional variation within the United States is large. Comparable and consistent state-level measures of total CVD burden and risk factors have not been produced previously.

    Objective: To quantify and describe levels and trends of lost health due to CVD within the United States from 1990 to 2016 as well as risk factors driving these changes.

    Design, Setting, and Participants: Using the Global Burden of Disease methodology, cardiovascular disease mortality, nonfatal health outcomes, and associated risk factors were analyzed by age group, sex, and year from 1990 to 2016 for all residents in the United States using standardized approaches for data processing and statistical modeling. Burden of disease was estimated for 10 groupings of CVD, and comparative risk analysis was performed. Data were analyzed from August 2016 to July 2017.

    Exposures: Residing in the United States.

    Main Outcomes and Measures: Cardiovascular disease disability-adjusted life-years (DALYs).

    Results: Between 1990 and 2016, age-standardized CVD DALYs for all states decreased. Several states had large rises in their relative rank ordering for total CVD DALYs among states, including Arkansas, Oklahoma, Alabama, Kentucky, Missouri, Indiana, Kansas, Alaska, and Iowa. The rate of decline varied widely across states, and CVD burden increased for a small number of states in the most recent years. Cardiovascular disease DALYs remained twice as large among men compared with women. Ischemic heart disease was the leading cause of CVD DALYs in all states, but the second most common varied by state. Trends were driven by 12 groups of risk factors, with the largest attributable CVD burden due to dietary risk exposures followed by high systolic blood pressure, high body mass index, high total cholesterol level, high fasting plasma glucose level, tobacco smoking, and low levels of physical activity. Increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors.

    Conclusions and Relevance: Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden. Differences in CVD burden are largely attributable to modifiable risk exposures.

  • 10.
    Själander, Sara
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Holmqvist, Fredrik
    Skane Univ Hosp, Arrhythmia Clin, Lund, Sweden.;Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Smith, J. Gustav
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden.;Skane Univ Hosp, Dept Heart Failure & Valvular Dis, Lund, Sweden..
    Platonov, Pyotr G.
    Skane Univ Hosp, Arrhythmia Clin, Lund, Sweden.;Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Kesek, Milos
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Svensson, Peter J.
    Lund Univ, Dept Coagulat Disorders, Malmo, Sweden..
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Tabrizi, Fariborz
    Karolinska Inst, South Hosp, Dept Clin Sci, Stockholm, Sweden.;Arrhythmia Ctr Stockholm, Stockholm, Sweden.;Arrhythmia Ctr Stockholm, Stockholm, Sweden..
    Tapanainen, Jari
    Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Poci, Dritan
    Orebro Univ, Fac Med & Hlth, Dept Cardiol, Orebro, Sweden..
    Jönsson, Anders
    Linkoping Univ Hosp, Dept Cardiol, Linkoping, Sweden..
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Assessment of Use vs Discontinuation of Oral Anticoagulation After Pulmonary Vein Isolation in Patients With Atrial Fibrillation2017In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 2, no 2, p. 146-152Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.

    OBJECTIVES To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.

    DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort studywas conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.

    EXPOSURES Warfarin treatment.

    MAIN OUTCOMES AND MEASURES Ischemic stroke, intracranial hemorrhage, and death.

    RESULTS In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA(2)DS(2)-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA(2)DS(2)-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA(2)DS(2)-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).

    CONCLUSIONS AND RELEVANCE These findings indicate that discontinuation ofwarfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.

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