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  • 1. Adami, Hans-Olov
    et al.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, Jan-Erik
    Management of Early Prostate Cancer REPLY2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 22, p. 2151-2151Article in journal (Refereed)
  • 2. Adams, D.
    et al.
    Gonzalez-Duarte, A.
    O'Riordan, W. D.
    Yang, C. -C
    Ueda, M.
    Kristen, A. V.
    Tournev, I.
    Schmidt, H. H.
    Coelho, T.
    Berk, J. L.
    Lin, K. -P
    Vita, G.
    Attarian, S.
    Plante-Bordeneuve, V.
    Mezei, M. M.
    Campistol, J. M.
    Buades, J.
    Brannagan, T. H. , I I I
    Kim, B. J.
    Oh, J.
    Parman, Y.
    Sekijima, Y.
    Hawkins, P. N.
    Solomon, S. D.
    Polydefkis, M.
    Dyck, P. J.
    Gandhi, P. J.
    Goyal, S.
    Chen, J.
    Strahs, A. L.
    Nochur, S. V.
    Sweetser, M. T.
    Garg, P. P.
    Vaishnaw, A. K.
    Gollob, J. A.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 1, p. 11-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.

    METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status).

    RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.

    CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.

  • 3. Afshin, A
    et al.
    Forouzanfar, M. H
    Reitsma, M. B
    Sur, P
    Estep, K
    Lee, A
    Marczak, L
    Mokdad, A. H
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Uppsala universitet.
    Murray, C. J. L
    Health effects of overweight and obesity in 195 countries over 25 years2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain.

    METHODS: We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015.

    RESULTS: In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease.

    CONCLUSIONS: The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem.

  • 4.
    Afshin, Ashkan
    et al.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Forouzanfar, Mohammad H.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Reitsma, Marissa B.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Sur, Patrick
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Estep, Kara
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Lee, Alex
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Marczak, Laurie
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Mokdad, Ali H.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Moradi-Lakeh, Maziar
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Preventat Med & Publ Hlth Res Ctr, Tehran, Iran..
    Naghavi, Mohsen
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Salama, Joseph S.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Vos, Theo
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Abate, Kalkidan H.
    Jimma Univ, Jimma, Ethiopia..
    Abbafati, Cristiana
    Sapienza Univ Rome, Rome, Italy..
    Ahmed, Muktar B.
    Jimma Univ, Jimma, Ethiopia..
    Al-Aly, Ziyad
    Washington Univ, Sch Med, St Louis, MO 63130 USA..
    Alkerwi, Ala'a
    Luxembourg Inst Hlth, Dept Populat Hlth, Strassen, Luxembourg..
    Al-Raddadi, Rajaa
    Joint Program Family & Community Med, Jeddah, Saudi Arabia..
    Amare, Azmeraw T.
    Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia.;Univ Adelaide, Sch Med, Adelaide, SA, Australia..
    Amberbir, Alemayehu
    Dignitas Int, Zomba, Malawi..
    Amegah, Adeladza K.
    Univ Cape Coast, Cape Coast, Ghana..
    Amini, Erfan
    Univ Tehran Med Sci, Urooncol Res Ctr, Tehran, Iran.;Noncommunicable Dis Res Ctr, Tehran, Iran..
    Amrock, Stephen M.
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Anjana, Ranjit M.
    Madras Diabet Res Fdn, Madras, Tamil Nadu, India.;Dr Mohans Diabet Special Ctr, Madras, Tamil Nadu, India..
    Arnlov, Johan
    Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Stockholm, Sweden..
    Asayesh, Hamid
    Qom Univ Med Sci, Dept Emergency Med, Qom, Iran..
    Banerjee, Amitava
    UCL, Farr Inst Hlth Informat Res, London, England..
    Barac, Aleksandra
    Univ Belgrade, Fac Med, Belgrade, Serbia..
    Baye, Estifanos
    Wollo Univ, Dept Publ Hlth, Dessie, Ethiopia.;Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic, Australia..
    Bennett, Derrick A.
    Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England..
    Beyene, Addisu S.
    Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia..
    Biadgilign, Sibhatu
    Independent Publ Hlth Consultants, Addis Ababa, Ethiopia..
    Biryukov, Stan
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Bjertness, Espen
    Univ Oslo, Dept Community Med & Global Hlth, Oslo, Norway..
    Boneya, Dube J.
    Debre Markos Univ, Dept Publ Hlth, Debre Markos, Ethiopia..
    Campos-Nonato, Ismael
    Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico.;Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA..
    Carrero, Juan J.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Cecilio, Pedro
    Univ Porto, Dept Ciencias Biol, Fac Farm, Oporto, Portugal..
    Cercy, Kelly
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Ciobanu, Liliana G.
    Univ Adelaide, Sch Med, Adelaide, SA, Australia..
    Cornaby, Leslie
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Damtew, Solomon A.
    Addis Ababa Univ, Addis Ababa, Ethiopia.;Wolaita Sodo Univ, Coll Hlth Sci & Med, Wolaita, Ethiopia..
    Dandona, Lalit
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Publ Hlth Fdn India, Gurgaon, India..
    Dandona, Rakhi
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Publ Hlth Fdn India, Gurgaon, India..
    Dharmaratne, Samath D.
    Univ Peradeniya, Dept Community Med, Fac Med, Peradeniya, Sri Lanka..
    Duncan, Bruce B.
    Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil..
    Eshrati, Babak
    Arak Univ Med Sci, Arak, Iran..
    Esteghamati, Alireza
    Endocrinol & Metab Res Ctr, Tehran, Iran..
    Feigin, Valery L.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand..
    Fernandes, Joao C.
    Catholic Univ Portugal, Ctr Biotechnol & Fine Chem, Associate Lab, Fac Biotechnol, Oporto, Portugal..
    Furst, Thomas
    Imperial Coll London, Dept Infect Dis Epidemiol, London, England.;Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Gebrehiwot, Tsegaye T.
    Jimma Univ, Jimma, Ethiopia..
    Gold, Audra
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Gona, Philimon N.
    Univ Massachusetts Boston, Boston, MA USA..
    Goto, Atsushi
    Natl Canc Ctr, Div Epidemiol, Ctr Publ Hlth Sci, Tokyo, Japan..
    Habtewold, Tesfa D.
    Debre Berhan Univ, Debre Berhan, Ethiopia.;Univ Groningen, Groningen, Netherlands..
    Hadush, Kokeb T.
    Ambo Univ, Ambo, Ethiopia..
    Hafezi-Nejad, Nima
    Endocrinol & Metab Res Ctr, Tehran, Iran..
    Hay, Simon I.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Univ Oxford, Oxford Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England..
    Horino, Masako
    Bur Child Family & Community Wellness, Nevada Div Publ & Behav Hlth, Carson, CA USA..
    Islami, Farhad
    Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA..
    Kamal, Ritul
    CSIR, Indian Inst Toxicol Res, Epidemiol Div, Lucknow, Uttar Pradesh, India..
    Kasaeian, Amir
    Endrocrinol & Metab Populat Sci Inst, Tehran, Iran.;Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran..
    Katikireddi, Srinivasa V.
    Univ Glasgow, MRC CSO Social & Publ Hlth Sci Unit, Glasgow, Lanark, Scotland..
    Kengne, Andre P.
    South African Med Res Council, Cape Town, South Africa.;Univ Cape Town, Cape Town, South Africa..
    Kesavachandran, Chandrasekharan N.
    CSIR, Indian Inst Toxicol Res, Epidemiol Div, Lucknow, Uttar Pradesh, India..
    Khader, Yousef S.
    Jordan Univ Sci & Technol, Dept Community Med, Publ Hlth & Family Med, Irbid, Jordan..
    Khang, Young-Ho
    Seoul Natl Univ, Coll Med, Dept Hlth Policy & Management, Seoul, South Korea.;Seoul Natl Univ, Med Ctr, Inst Hlth Policy & Management, Seoul, South Korea..
    Khubchandani, Jagdish
    Ball State Univ, Dept Nutr & Hlth Sci, Muncie, IN 47306 USA..
    Kim, Daniel
    Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA..
    Kim, Yun J.
    Southern Univ Coll, Fac Chinese Med, Johor Baharu, Malaysia..
    Kinfu, Yohannes
    Univ Canberra, Ctr Res & Act Publ Hlth, Canberra, ACT, Australia..
    Kosen, Soewarta
    Natl Inst Hlth Res & Dev, Jakarta, Indonesia..
    Ku, Tiffany
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Defo, Barthelemy Kuate
    Univ Montreal, Dept Social & Prevent Med, Montreal, PQ, Canada.;Univ Montreal, Dept Demog, Montreal, PQ, Canada.;Publ Hlth Res Inst, Sch Publ Hlth, Montreal, PQ, Canada..
    Kumar, G. Anil
    Publ Hlth Fdn India, Gurgaon, India..
    Larson, Heidi J.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England..
    Leinsalu, Mall
    Södertörn University, School of Social Sciences, Sociology. Södertörn University, School of Social Sciences, SCOHOST (Stockholm Centre for Health and Social Change). National Institute for Health Development, Tallinn, Estonia..
    Liang, Xiaofeng
    Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China..
    Lim, Stephen S.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Liu, Patrick
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Lopez, Alan D.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia..
    Lozano, Rafael
    Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico..
    Majeed, Azeem
    Imperial Coll London, Dept Primary Care & Publ Hlth, London, England..
    Malekzadeh, Reza
    Digest Dis Res Inst, Tehran, Iran.;Shiraz Univ Med Sci, Noncommunicable Dis Res Ctr, Shiraz, Iran..
    Malta, Deborah C.
    Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil..
    Mazidi, Mohsen
    Chinese Acad Sci, Key State Lab Mol Dev Biol, Inst Genet & Dev Biol, Beijing, Peoples R China..
    McAlinden, Colm
    Univ Hosp Bristol NHS Fdn Trust, Bristol, Avon, England.;Publ Hlth Wales, Swansea, W Glam, Wales..
    McGarvey, Stephen T.
    Brown Univ, Sch Publ Hlth, Providence, RI 02912 USA..
    Mengistu, Desalegn T.
    Mekelle Univ, Mekelle, Ethiopia..
    Mensah, George A.
    NHLBI, NIH, Ctr Translat Res & Implementat Sci, Bldg 10, Bethesda, MD 20892 USA..
    Mensink, Gert B. M.
    Robert Koch Inst, Dept Epidemiol & Hlth Monitoring, Berlin, Germany..
    Mezgebe, Haftay B.
    Mekelle Univ, Mekelle, Ethiopia..
    Mirrakhimov, Erkin M.
    Natl Ctr Cardiol & Internal Dis, Bishkek, Kyrgyzstan.;Kyrgyz State Med Acad, Bishkek, Kyrgyzstan..
    Mueller, Ulrich O.
    Fed Inst Populat Res, Wiesbaden, Germany..
    Noubiap, Jean J.
    Groote Schuur Hosp, Cape Town, South Africa.;Univ Cape Town, Cape Town, South Africa..
    Obermeyer, Carla M.
    Amer Univ Beirut, Ctr Res Populat & Hlth, Fac Hlth Sci, Beirut, Lebanon..
    Ogbo, Felix A.
    Western Sydney Univ, Ctr Hlth Res, Sch Med, Sydney, NSW, Australia..
    Owolabi, Mayowa O.
    Univ Ibadan, Dept Med, Ibadan, Nigeria.;Blossom Specialist Med Ctr, Ibadan, Nigeria..
    Patton, George C.
    Univ Melbourne, Dept Pediat, Murdoch Childrens Res Inst, Melbourne, Vic, Australia..
    Pourmalek, Farshad
    Univ British Columbia, Vancouver, BC, Canada..
    Qorbani, Mostafa
    Alborz Univ Med Sci, Noncommunicable Dis Res Ctr, Karaj, Iran..
    Rafay, Anwar
    Contech Sch Publ Hlth, Lahore, Pakistan..
    Rai, Rajesh K.
    Soc Hlth & Demog Surveillance, Suri, India..
    Ranabhat, Chhabi L.
    Yonsei Univ, Dept Preventat Med, Wonju Coll Med, Wonju, South Korea.;Hlth Sci Fdn & Study Ctr, Kathmandu, Nepal..
    Reinig, Nikolas
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Safiri, Saeid
    Maragheh Univ Med Sci, Managerial Epidemiol Res Ctr, Dept Publ Hlth, Sch Nursing & Midwifery, Maragheh, Iran..
    Salomon, Joshua A.
    Dept Global Hlth & Populat, Boston, MA USA..
    Sanabria, Juan R.
    Case Western Reserve Univ, Sch Med, Ctr Comprehens Canc, Cleveland, OH 44106 USA.;Marshall Univ, Joan C Edwards Sch Med, Huntington, WV USA..
    Santos, Itamar S.
    Univ Sao Paulo, Sao Paulo, Brazil..
    Sartorius, Benn
    South African Med Res Council, Cape Town, South Africa.;Univ KwaZulu Natal, Publ Hlth Med, Sch Nursing & Publ Hlth, Durban, South Africa..
    Sawhney, Monika
    Marshall Univ, Dept Publ Hlth, Huntington, WV USA..
    Schmidhuber, Josef
    Food & Agr Org, Global Perspect Studies Unit, Rome, Italy..
    Schutte, Aletta E.
    South African Med Res Council, Cape Town, South Africa.;North West Univ, Hypertens Africa Res Team, Potchefstroom, South Africa..
    Schmidt, Maria I.
    Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil..
    Sepanlou, Sadaf G.
    Digest Dis Res Inst, Tehran, Iran..
    Shamsizadeh, Moretza
    Hamadan Univ Med Sci, Dept Med Surg Nursing, Sch Nursing & Midwifery, Hamadan, Iran..
    Sheikhbahaei, Sara
    Endocrinol & Metab Res Ctr, Tehran, Iran..
    Shin, Min-Jeong
    Korea Univ, Dept Publ Hlth Sci, Seoul, South Korea..
    Shiri, Rahman
    Finnish Inst Occupat Hlth, Helsinki, Finland..
    Shiue, Ivy
    Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland..
    Roba, Hirbo S.
    Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia..
    Silva, Diego A. S.
    Univ Fed Santa Catarina, Florianopolis, SC, Brazil..
    Silverberg, Jonathan I.
    Feinberg Sch Med, Chicago, IL USA..
    Singh, Jasvinder A.
    Univ Alabama Birmingham, Birmingham, AL USA..
    Stranges, Saverio
    Luxembourg Inst Hlth, Dept Populat Hlth, Strassen, Luxembourg.;Western Univ, Dept Epidemiol & Biostat, Schulich Sch Med & Dent, London, ON, Canada..
    Swaminathan, Soumya
    Indian Council Med Res, Madras, Tamil Nadu, India..
    Tabares-Seisdedos, Rafael
    Univ Valencia, Dept Med, Valencia, Spain..
    Tadese, Fentaw
    Wollo Univ, Dept Publ Hlth, Dessie, Ethiopia..
    Tedla, Bemnet A.
    Univ Gondar, Gondar, Ethiopia.;James Cook Univ, Cairns, Qld, Australia..
    Tegegne, Balewgizie S.
    Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia.;Univ Med Ctr Groningen, Groningen, Netherlands..
    Terkawi, Abdullah S.
    King Fahad Med City, Dept Anesthesiol, Riyadh, Saudi Arabia.;Cleveland Clin, Outcomes Res Consortium, Cleveland, OH 44106 USA.;Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA..
    Thakur, J. S.
    Post Grad Inst Med Educ & Res, Sch Publ Hlth, Chandigarh, India..
    Tonelli, Marcello
    Univ Calgary, Calgary, AB, Canada..
    Topor-Madry, Roman
    Jagiellonian Univ, Med Coll, Inst Publ Hlth, Fac Hlth Sci, Krakow, Poland.;Wroclaw Med Univ, Fac Hlth Sci, Wroclaw, Poland..
    Tyrovolas, Stefanos
    Univ Barcelona, CIBERSAM, Fundacio St Joan de Deu, Parc Sanitari St Joan de Deu, Barcelona, Spain..
    Ukwaja, Kingsley N.
    Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria..
    Uthman, Olalekan A.
    Univ Warwick, Warwick Ctr Appl Hlth Res & Delivery, Div Hlth Sci, Warwick Med Sch Coventry, Coventry, W Midlands, England..
    Vaezghasemi, Masoud
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Vasankari, Tommi
    UKK Inst Hlth Promot Res, Tampere, Finland..
    Vlassov, Vasiliy V.
    Natl Res Univ, Higher Sch Econ, Moscow, Russia..
    Vollset, Stein E.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;Univ Bergen, Norwegian Inst Publ Hlth, Bergen, Norway.;Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway..
    Weiderpass, Elisabete
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Canc Registry Norway, Inst Population Based Canc Res, Dept Res, Oslo, Norway.;Arctic Univ Norway, Univ Tromso, Tromso, Norway.;Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland..
    Werdecker, Andrea
    Fed Inst Populat Res, Wiesbaden, Germany..
    Wesana, Joshua
    Univ Ghent, Fac Biosci Engn, Ghent, Belgium..
    Westerman, Ronny
    Fed Inst Populat Res, Wiesbaden, Germany..
    Yano, Yuichiro
    Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA..
    Yonemoto, Naohiro
    Kyoto Univ, Dept Biostat, Sch Publ Hlth, Kyoto, Japan..
    Yonga, Gerald
    Aga Khan Univ, East Africa, NCD Res Policy Unit, Nairobi, Kenya..
    Zaidi, Zoubida
    Univ Hosp, Setif, Algeria..
    Zenebe, Zerihun M.
    Mekelle Univ, Mekelle, Ethiopia..
    Zipkin, Ben
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Murray, Christopher J. L.
    Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA..
    Health Effects of Overweight and Obesity in 195 Countries over 25 Years2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHODS We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. RESULTS In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. CONCLUSIONS The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. (Funded by the Bill and Melinda Gates Foundation.)

  • 5. Afshin, Ashkan
    et al.
    Forouzanfar, Mohammad H.
    Reitsma, Marissa B.
    Sur, Patrick
    Estep, Kara
    Lee, Alex
    Marczak, Laurie
    Mokdad, Ali H.
    Moradi-Lakeh, Maziar
    Naghavi, Mohsen
    Salama, Joseph S.
    Vos, Theo
    Abate, Kalkidan H.
    Abbafati, Cristiana
    Ahmed, Muktar B.
    Al-Aly, Ziyad
    Alkerwi, Ala'a
    Al-Raddadi, Rajaa
    Amare, Azmeraw T.
    Amberbir, Alemayehu
    Amegah, Adeladza K.
    Amini, Erfan
    Amrock, Stephen M.
    Anjana, Ranjit M.
    Arnlov, Johan
    Asayesh, Hamid
    Banerjee, Amitava
    Barac, Aleksandra
    Baye, Estifanos
    Bennett, Derrick A.
    Beyene, Addisu S.
    Biadgilign, Sibhatu
    Biryukov, Stan
    Bjertness, Espen
    Boneya, Dube J.
    Campos-Nonato, Ismael
    Carrero, Juan J.
    Cecilio, Pedro
    Cercy, Kelly
    Ciobanu, Liliana G.
    Cornaby, Leslie
    Damtew, Solomon A.
    Dandona, Lalit
    Dandona, Rakhi
    Dharmaratne, Samath D.
    Duncan, Bruce B.
    Eshrati, Babak
    Esteghamati, Alireza
    Feigin, Valery L.
    Fernandes, Joao C.
    Furst, Thomas
    Gebrehiwot, Tsegaye T.
    Gold, Audra
    Gona, Philimon N.
    Goto, Atsushi
    Habtewold, Tesfa D.
    Hadush, Kokeb T.
    Hafezi-Nejad, Nima
    Hay, Simon I.
    Horino, Masako
    Islami, Farhad
    Kamal, Ritul
    Kasaeian, Amir
    Katikireddi, Srinivasa V.
    Kengne, Andre P.
    Kesavachandran, Chandrasekharan N.
    Khader, Yousef S.
    Khang, Young-Ho
    Khubchandani, Jagdish
    Kim, Daniel
    Kim, Yun J.
    Kinfu, Yohannes
    Kosen, Soewarta
    Ku, Tiffany
    Defo, Barthelemy Kuate
    Kumar, G. Anil
    Larson, Heidi J.
    Leinsalu, Mall
    Liang, Xiaofeng
    Lim, Stephen S.
    Liu, Patrick
    Lopez, Alan D.
    Lozano, Rafael
    Majeed, Azeem
    Malekzadeh, Reza
    Malta, Deborah C.
    Mazidi, Mohsen
    McAlinden, Colm
    McGarvey, Stephen T.
    Mengistu, Desalegn T.
    Mensah, George A.
    Mensink, Gert B. M.
    Mezgebe, Haftay B.
    Mirrakhimov, Erkin M.
    Mueller, Ulrich O.
    Noubiap, Jean J.
    Obermeyer, Carla M.
    Ogbo, Felix A.
    Owolabi, Mayowa O.
    Patton, George C.
    Pourmalek, Farshad
    Qorbani, Mostafa
    Rafay, Anwar
    Rai, Rajesh K.
    Ranabhat, Chhabi L.
    Reinig, Nikolas
    Safiri, Saeid
    Salomon, Joshua A.
    Sanabria, Juan R.
    Santos, Itamar S.
    Sartorius, Benn
    Sawhney, Monika
    Schmidhuber, Josef
    Schutte, Aletta E.
    Schmidt, Maria I.
    Sepanlou, Sadaf G.
    Shamsizadeh, Moretza
    Sheikhbahaei, Sara
    Shin, Min-Jeong
    Shiri, Rahman
    Shiue, Ivy
    Roba, Hirbo S.
    Silva, Diego A. S.
    Silverberg, Jonathan I.
    Singh, Jasvinder A.
    Stranges, Saverio
    Swaminathan, Soumya
    Tabares-Seisdedos, Rafael
    Tadese, Fentaw
    Tedla, Bemnet A.
    Tegegne, Balewgizie S.
    Terkawi, Abdullah S.
    Thakur, J. S.
    Tonelli, Marcello
    Topor-Madry, Roman
    Tyrovolas, Stefanos
    Ukwaja, Kingsley N.
    Uthman, Olalekan A.
    Vaezghasemi, Masoud
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Vasankari, Tommi
    Vlassov, Vasiliy V.
    Vollset, Stein E.
    Weiderpass, Elisabete
    Werdecker, Andrea
    Wesana, Joshua
    Westerman, Ronny
    Yano, Yuichiro
    Yonemoto, Naohiro
    Yonga, Gerald
    Zaidi, Zoubida
    Zenebe, Zerihun M.
    Zipkin, Ben
    Murray, Christopher J. L.
    Health Effects of Overweight and Obesity in 195 Countries over 25 Years2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHODS We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. RESULTS In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. CONCLUSIONS The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. 

  • 6. Ahrenstedt, O
    et al.
    Knutson, L
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson-Ekdahl, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Odlind, B
    Hällgren, R
    Enhanced local production of complement components in the small intestines of patients with Crohn's disease.1990In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 322, no 19, p. 1345-1349Article in journal (Refereed)
    Abstract [en]

    There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum. The mean (+/- SEM) jejunal-fluid C4 concentration was 2.0 +/- 0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7 +/- 0.1 mg per liter; P less than 0.001). The mean C3 concentration was 1.0 +/- 0.1 mg per liter in the patients and 0.7 +/- 0.1 mg per liter in the controls (P less than 0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid:serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due to at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4). We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages.

  • 7. Ahrenstedt, Örjan
    et al.
    Knutson, L
    Nilsson, B
    Nilsson Ekdahl, Kristina
    University Hospital, Uppsala.
    Odlind, B
    Hällgren, R
    Enhanced local production of the complement components in the small intestine in Crohn's disease1990In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 322, p. 1345-1349Article in journal (Refereed)
    Abstract [en]

    There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum.

    The mean (±SEM) jejunal-fluid C4 concentration was 2.0±0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7±0.1 mg per liter; P<0.001). The mean C3 concentration was 1.0±0.1 mg per liter in the patients and 0.7±0.1 mg per liter in the controls (P<0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4).

    We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages. 

  • 8. Alexander, John H.
    et al.
    Lopes, Renato D.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kilaru, Rakhi
    He, Yaohua
    Mohan, Puneet
    Bhatt, Deepak L.
    Goodman, Shaun
    Verheugt, Freek W.
    Flather, Marcus
    Huber, Kurt
    Liaw, Danny
    Husted, Steen E.
    Lopez-Sendon, Jose
    De Caterina, Raffaele
    Jansky, Petr
    Darius, Harald
    Vinereanu, Dragos
    Cornel, Jan H.
    Cools, Frank
    Atar, Dan
    Luis Leiva-Pons, Jose
    Keltai, Matyas
    Ogawa, Hisao
    Pais, Prem
    Parkhomenko, Alexander
    Ruzyllo, Witold
    Diaz, Rafael
    White, Harvey
    Ruda, Mikhail
    Geraldes, Margarida
    Lawrence, Jack
    Harrington, Robert A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 8, p. 699-708Article in journal (Refereed)
    Abstract [en]

    Background: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.

    Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.

    Results: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.

    Conclusions: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.

  • 9. Alexander, John H.
    et al.
    Lopes, Renato D.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Apixaban after Acute Coronary Syndrome REPLY2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 19, p. 1844-1845Article in journal (Refereed)
  • 10.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pöntynen, Nora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Szinnai, Gabor
    Shikama, Noriko
    Keller, Marcel P
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kinkel, Sarah A
    Husebye, Eystein S
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peltonen, Leena
    Betterle, Corrado
    Perheentupa, Jaakko
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Scott, Hamish S
    Holländer, Georg A
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, no 10, p. 1018-1028Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified. METHODS: We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues. RESULTS: NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. CONCLUSIONS: NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.

  • 11.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal (Refereed)
  • 12. Andersson, RE
    et al.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Tysk, C
    Ekbom, A
    Appendectomy and protection against ulcerative colitis2001In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 344, no 11, p. 808-814Article in journal (Refereed)
    Abstract [en]

    Background: A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further. Methods:We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis. Results: Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87], for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90], and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06, 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P<0.001). Conclusions: Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

  • 13.
    Aspelin, P
    et al.
    Huddinge University Hospital.
    Aubry, P
    Centre Hospitalier Universitaire Bichat.
    Fransson, Sven Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Strasser, R
    Technische Universität, Dresden.
    Willenbrock, R
    Helios Kliniken, Berlin.
    Berg, K
    Rikshospitalet, Oslo.
    Nephrotoxic effects in high-risk patients undergoing angiography2003In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 348, no 6, p. 491-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of iodinated contrast medium can result in nephropathy. Whether iso-osmolar contrast medium is less nephrotoxic than low-osmolar contrast medium in high-risk patients is uncertain. METHODS: We conducted a randomized, double-blind, prospective, multicenter study comparing the nephrotoxic effects of an iso-osmolar, dimeric, nonionic contrast medium, iodixanol, with those of a low-osmolar, nonionic, monomeric contrast medium, iohexol. The study involved 129 patients with diabetes with serum creatinine concentrations of 1.5 to 3.5 mg per deciliter who underwent coronary or aortofemoral angiography. The primary end point was the peak increase from base line in the creatinine concentration during the three days after angiography. Other end points were an increase in the creatinine concentration of 0.5 mg per deciliter or more, an increase of 1.0 mg per deciliter or more, and a change in the creatinine concentration from day 0 to day 7. RESULTS: The creatinine concentration increased significantly less in patients who received iodixanol. From day 0 to day 3, the mean peak increase in creatinine was 0.13 mg per deciliter in the iodixanol group and 0.55 mg per deciliter in the iohexol group (P=0.001, the increase with iodixanol minus the increase with iohexol, -0.42 mg per deciliter [95 percent confidence interval, -0.73 to -0.22]). Two of the 64 patients in the iodixanol group (3 percent) had an increase in the creatinine concentration of 0.5 mg per deciliter or more, as compared with 17 of the 65 patients in the iohexol group (26 percent) (P=0.002, odds ratio for such an increase in the iodixanol group, 0.09 [95 percent confidence interval, 0.02 to 0.41]). No patient receiving iodixanol had an increase of 1.0 mg per deciliter or more, but 10 patients in the iohexol group (15 percent) did. The mean change in the creatinine concentration from day 0 to day 7 was 0.07 mg per deciliter in the iodixanol group and 0.24 mg per deciliter in the iohexol group (P=0.003, value in the iodixanol group minus the value in the iohexol group, -0.17 mg per deciliter [95 percent confidence interval, -0.34 to -0.07]). CONCLUSIONS: Nephropathy induced by contrast medium may be less likely to develop in high-risk patients when iodixanol is used rather than a low-osmolar, nonionic contrast medium.

  • 14.
    Barnett, A.H.
    et al.
    Division of Medical Sciences, University of Birmingham, Birmingham Heartlands Solihull N., Birmingham, United Kingdom, Undergraduate Center, Birmingham Heartlands Hospital, Bordesley Green E., Birmingham B9 5SS, United Kingdom.
    Bain, S.C.
    Division of Medical Sciences, University of Birmingham, Birmingham Heartlands Solihull N., Birmingham, United Kingdom.
    Bouter, P.
    Department of Internal Medicine, Bosch Medicentre, Den Bosch, Netherlands.
    Karlberg, B.
    Östergötlands Läns Landsting.
    Madsbad, S.
    Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
    Jervell, J.
    University Hospital of Oslo, Oslo, Norway.
    Mustonen, J.
    Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
    Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy2004In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 351, no 19, p. 1952-1961Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure, the rates of end-stage renal disease and cardiovascular events, and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.9 ml per minute per 1.73 m2 of body-surface area, where the minus sign denotes a decrement, with telmisartan (in 103 subjects), as compared with -14.9 ml per minute per 1.73 m2 with enalapril (in 113 subjects), for a treatment difference of -3.0 ml per minute per 1.73 m2 (95 percent confidence interval, -7.6 to 1.6 ml per minute per 1.73 m2). The lower boundary of the confidence interval, in favor of enalapril, was greater than the pre-defined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events. Copyright © 2004 Massachusetts Medical Society.

  • 15. Beer, Tomasz M
    et al.
    Armstrong, Andrew J
    Rathkopf, Dana E
    Loriot, Yohann
    Sternberg, Cora N
    Higano, Celestia S
    Iversen, Peter
    Bhattacharya, Suman
    Carles, Joan
    Chowdhury, Simon
    Davis, Ian D
    de Bono, Johann S
    Evans, Christopher P
    Fizazi, Karim
    Joshua, Anthony M
    Kim, Choung-Soo
    Kimura, Go
    Mainwaring, Paul
    Mansbach, Harry
    Miller, Kurt
    Noonberg, Sarah B
    Perabo, Frank
    Phung, De
    Saad, Fred
    Scher, Howard I
    Taplin, Mary-Ellen
    Venner, Peter M
    Tombal, Bertrand
    Enzalutamide in metastatic prostate cancer before chemotherapy.2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.

    METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.

    RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.

    CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

  • 16.
    Bergmark, Karin
    et al.
    Divisions of Gynecological Oncology and Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Division of Gynecological Oncology Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Dickman, Paul W
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Henningsohn, Lars
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Steineck, Gunar
    Division of Clinical Epidemiology, Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
    Vaginal changes and sexuality in women with a history of cervical cancer.1999In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 340, no 18, p. 1383-1389Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In women with cervical cancer, treatment causes changes in vaginal anatomy and function. The effect of these changes on sexual function and the extent, if any, to which they distress women are not known.

    METHODS: In 1996 and 1997, we attempted to contact 332 women with a history of early-stage cervical cancer (age range, 26 to 80 years) who had been treated in 1991 and 1992 at the seven departments of gynecological oncology in Sweden and 489 women without a history of cancer (controls) to ask them to answer an anonymous questionnaire about vaginal changes and sexual function.

    RESULTS: We received completed questionnaires from 256 of the women with a history of cervical cancer and 350 of the controls. A total of 167 of 247 women with a history of cancer (68 percent) and 236 of 330 controls (72 percent) reported that they had regular vaginal intercourse. Twenty-six percent of the women who had cancer and 11 percent of the controls reported insufficient vaginal lubrication for sexual intercourse, 26 percent of the women who had cancer and 3 percent of the controls reported a short vagina, and 23 percent of the women who had cancer and 4 percent of the controls reported an insufficiently elastic vagina. Twenty-six percent of the women who had cancer reported moderate or much distress due to vaginal changes, as compared with 8 percent of the women in the control group. Dyspareunia was also more common among the women who had cervical cancer. The frequency of orgasms and orgasmic pleasure was similar in the two groups. Among the women who had cervical cancer, the type of treatment received had little if any effect on the prevalence of specific vaginal changes.

    CONCLUSIONS: Women who have been treated for cervical cancer have persistent vaginal changes that compromise sexual activity and result in considerable distress.

  • 17.
    Bill-Axelson, A.
    et al.
    Department of Urology, University Hospital, Uppsala, Sweden, Department of Urology, University Hospital, SE-751 85 Uppsala, Sweden.
    Holmberg, L.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Ruutu, M.
    Depatment of Urology, University of Helsinki, University Hospital of Helsinki, Helsinki, Finland.
    Haggman, M.
    Häggman, M., Department of Urology, University Hospital, Uppsala, Sweden.
    Andersson, S.-O.
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Bratell, S.
    Department of Urology, Boras Hospital, Boras, Sweden.
    Spångberg, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Urology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Busch, C.
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Nordling, S.
    Department of Pathology, University of Helsinki, University Hospital of Helsinki, Helsinki, Finland.
    Garmo, H.
    Regional Oncologic Center, University Hospital, Uppsala, Sweden.
    Palmgren, J.
    Dept. Med. Epidemiol. Biostatist., Karolinska Institutet, Stockholm, Sweden.
    Adami, H.-O.
    Dept. Med. Epidemiol. Biostatist., Karolinska Institutet, Stockholm, Sweden, Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States.
    Norlen, B.J.
    Norlén, B.J., Department of Urology, University Hospital, Uppsala, Sweden.
    Johansson, J.-E.
    Department of Urology, Örebro University Hospital, Örebro, Sweden, Ctr. for Assess. of Med. Technology, Örebro University Hospital, Örebro, Sweden.
    Radical prostatectomy versus watchful waiting in early prostate cancer2005In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 352, no 19, p. 1977-1984Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results. METHODS: From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer, the secondary end points were death from any cause, metastasis, and local progression. RESULTS: During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88, P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86, P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44, P<0.001 by Gray's test). CONCLUSIONS: Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial. Copyright © 2005 Massachusetts Medical Society.

  • 18.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Univ, Uppsala, Sweden.
    Garmo, Hans
    Reg Canc Ctr Uppsala Örebro, Uppsala, Sweden.
    Radical Surgery or Watchful Waiting in Prostate Cancer Reply2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 380, no 11, p. 1084-1084Article in journal (Other academic)
  • 19.
    Bill-Axelson, Anna
    et al.
    University of Uppsala Hospital, Sweden .
    Holmberg, Lars
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Garmo, Hans
    University of Uppsala Hospital, Sweden Kings Coll London, England .
    Rider, Jennifer R.
    Brigham and Womens Hospital, MA USA Harvard University, MA USA Harvard University, MA 02115 USA .
    Taari, Kimmo
    University of Helsinki, Finland .
    Busch, Christer
    University of Uppsala Hospital, Sweden .
    Nordling, Stig
    University of Helsinki, Finland .
    Haggman, Michael
    University of Uppsala Hospital, Sweden .
    Andersson, Swen-Olof
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Spångberg, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Andren, Ove
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Palmgren, Juni
    Karolinska Institute, Sweden .
    Steineck, Gunnar
    Karolinska Institute, Sweden Sahlgrens Acad, Sweden .
    Adami, Hans-Olov
    Karolinska Institute, Sweden Harvard University, MA 02115 USA .
    Johansson, Jan-Erik
    University of Örebro, Sweden Örebro University Hospital, Sweden .
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 10, p. 932-942Article in journal (Refereed)
    Abstract [en]

    BackgroundRadical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. MethodsBetween 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. ResultsDuring 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). ConclusionsExtended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.) The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 20.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Regional Cancer Center Uppsala Örebro.
    Garmo, Hans
    Regional Cancer Center Uppsala Örebro.
    Rider, Jennifer R.
    Taari, Kimmo
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Spangberg, Anders
    Andren, Ove
    Palmgren, Juni
    Steineck, Gunnar
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 10, p. 932-942Article in journal (Refereed)
    Abstract [en]

    BackgroundRadical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. MethodsBetween 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. ResultsDuring 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). ConclusionsExtended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.) The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 21.
    Bill-Axelson, Anna
    et al.
    Dept Surg Sci, Univ Uppsala Hosp, Uppsala, Sweden.
    Holmberg, Lars
    Reg Canc Ctr Uppsala Orebro, Univ Uppsala Hosp, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings Coll London, London, England.
    Garmo, Hans
    Reg Canc Ctr Uppsala Orebro, Univ Uppsala Hosp, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings Coll London, London , England.
    Rider, Jennifer R.
    Dept Med, Channing Lab, Brigham & Womens Hosp, Boston MA, USA; Sch Med, Harvard Univ, Boston MA, USA; Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA.
    Taari, Kimmo
    Cent Hosp, Dept Urol, Univ Helsinki, Helsinki, Finland.
    Busch, Christer
    Dept Immunol Genet & Pathol, Univ Uppsala Hosp, Uppsala, Sweden.
    Nordling, Stig
    Dept Pathol, Univ Helsinki, Helsinki, Finland.
    Häggman, Michael
    Dept Surg Sci, Univ Uppsala Hosp, Uppsala, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Spångberg, Anders
    Dept Urol, Linköping, Linköping Univ Hosp, Linköping, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Palmgren, Juni
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Steineck, Gunnar
    Dept Pathol & Oncol, Div Clin Canc Epidemiol, Karolinska Inst, Stockholm, Sweden; Div Clin Canc Epidemiol, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden; Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 10, p. 932-942Article in journal (Refereed)
    Abstract [en]

    Background: Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.

    Methods: Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.

    Results: During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04).

    Conclusions: Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.)

    The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 22.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Med, Div Canc Studies, London, England;Kings Coll London, Sch Canc & Pharmaceut Sci, London, England.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Kings Coll London, Sch Med, Div Canc Studies, London, England.
    Taari, Kimmo
    Helsinki Univ Hosp, Dept Urol, Helsinki, Finland.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Nordling, Stig
    Univ Helsinki, Dept Pathol, Helsinki, Finland.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Andren, Ove
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Steineck, Gunnar
    Sahlgrens Acad, Div Clin Canc Epidemiol, Gothenburg, Sweden.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Harvard TC Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Univ Oslo, Inst Hlth & Soc, Clin Effectiveness Res Grp, Oslo, Norway.
    Johansson, Jan-Erik
    Orebro Univ, Sch Hlth & Med Sci, Orebro, Sweden;Orebro Univ Hosp, Dept Urol, Orebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Prostate Cancer: 29-Year Follow-up2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 24, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term followup is sparse.

    METHODS We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.

    RESULTS By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).

    CONCLUSIONS Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.

  • 23.
    Bill-Axelson, Anna
    et al.
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Holmberg, Lars
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Sweden hSchool of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom.
    Garmo, Hans
    Regional Cancer Center Uppsala, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Sweden, London, United Kingdom.
    Taari, Kimmo
    Department of Urology, Helsinki University Hospital, Helsinki, Finland..
    Busch, Christer
    Uppsala University Hospital, Department of Pathology, Uppsala, Sweden.
    Nordling, Stig
    Department of Pathology, University of Helsinki, Helsinki, Finland.
    Häggman, Michael
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Steineck, Gunnar
    Division of Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.C. Chan School of Public Health, Boston, United States; Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Johansson, Jan-Erik
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Prostate Cancer-29-Year Follow-up2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 24, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term followup is sparse.

    METHODS: We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.

    RESULTS: By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).

    CONCLUSIONS: Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.

  • 24.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Garmo, Hans
    Stark, Jennifer R.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Bratell, Stefan
    Spångberg, Anders
    Linköpings universitet.
    Palmgren, Juni
    Karolinska Inst. Institutionen för Medicinsk Epidemiologi och Biostatistik.
    Steineck, Gunnar
    Karolinska Inst. institutionen för onkologi-patologi..
    Adami, Hans-Olov
    Harvard, Department of Epidemiology.
    Johansson, Jan-Erik
    Örebro Universitet.
    Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 18, p. 1708-1717Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.

    METHODS

    From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.

    RESULTS

    During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).

    CONCLUSIONS

    Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment.

  • 25.
    Bill-Axelson, Anna
    et al.
    Dept. Urology, Uppsala University Hospital, Uppsala, Sweden; Dept, Pathology & Oncology, Div. Clinical Cancer Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Holmberg, Lars
    Regional Oncology Center, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Kings College London, London, England.
    Ruutu, Mirja
    Cent Hosp, Dept Urol, Univ Helsinki, Helsinki, Finland.
    Garmo, Hans
    Reg Oncol Ctr, Univ Uppsala Hospital, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings College London, London, UK.
    Stark, Jennifer R
    Deptartment of Urology, Örebro University Hospital, Örebro, Sweden; Dept Med, Channing Lab, Brigham & Womens Hospital, Boston MA, USA; Sch Med, Harvard University, Boston MA, USA.
    Busch, Christer
    Dept Pathol, Uppsala University Hospital, Uppsala, Sweden.
    Nordling, Stig
    Cent Hosp, Dept Pathol, Univ Helsinki, Helsinki, Finland.
    Häggman, Michael
    Dept Urology, Uppsala University Hospital, Uppsala, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Bratell, Stefan
    Dept Urology, Borås Hospital, Borås, Sweden.
    Spångberg, Anders
    Dept Urology, Linköping University Hospital, Linköping, Sweden.
    Palmgren, Juni
    Dept Med Epidemiol & Biostat, Karolinska Institute, Stockholm, Sweden.
    Steineck, Gunnar
    Dept, Pathology & Oncology, Div. Clinical Cancer Epidemiology, Karolinska Institute, Stockholm, Sweden; Div Clin Canc Epidemiol, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Dept Med Epidemiol & Biostat, Karolinska Institute, Stockholm, Sweden; School of Publ Health, Dept Epidemiology, Harvard Univ, Boston MA, USA.
    Johansson, J-E
    Örebro University, School of Health and Medical Sciences. Dept Urol, Örebro University Hospital, Örebro, Sweden; Center of Assessment Med Technology, Örebro University Hospital, Örebro, Sweden.
    Radical prostatectomy versus watchful waiting in early prostate cancer2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 18, p. 1708-1717Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.

    METHODS: From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.

    RESULTS: During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).

    CONCLUSIONS: Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment.

  • 26.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Sven-Olof
    Bratell, Stefan
    Spångberg, Anders
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Garmo, Hans
    Palmgren, J
    Adami, HO
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, JE
    Radical prostatectomy versus watchful waiting in early prostate cancer2005In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 352, no 19, p. 1977-1944Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.

    METHODS:

    From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.

    RESULTS:

    During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).

    CONCLUSIONS:

    Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

  • 27. Bosch, Jackie
    et al.
    Gerstein, Hertzel C
    Dagenais, Gilles R
    Díaz, Rafael
    Dyal, Leanne
    Jung, Hyejung
    Maggiono, Aldo P
    Probstfield, Jeffrey
    Ramachandran, Ambady
    Riddle, Matthew C
    Rydén, Lars E
    Yusuf, Salim
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Tenerz, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 4, p. 309-18Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown.

    METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here.

    RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.

    CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

  • 28.
    Cannon, Christopher P.
    et al.
    Baim Inst Clin Res, 930 Commonwealth Ave, Boston, MA 02215 USA.;Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Bhatt, Deepak L.
    Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Oldgren, Jonas
    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.
    Lip, Gregory Y. H.
    Univ Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, England..
    Ellis, Stephen G.
    Cleveland Clin, Cleveland, OH 44106 USA..
    Kimura, Takeshi
    Kyoto Univ, Dept Cardiovasc Med, Kyoto, Japan..
    Maeng, Michael
    Aarhus Univ Hosp, Skejby, Denmark..
    Merkely, Bela
    Univ Heart & Vasc Ctr, Budapest, Hungary..
    Zeymer, Uwe
    Klinikum Stadt Ludwigshafen Rhein, Med Klin B, Ludwigshafen, Germany..
    Gropper, Savion
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Nordaby, Matias
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Kleine, Eva
    Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany..
    Harper, Ruth
    Boehringer Ingelheim GmbH & Co KG, Bracknell, Berks, England..
    Manassie, Jenny
    Boehringer Ingelheim GmbH & Co KG, Bracknell, Berks, England..
    Januzzi, James L.
    Baim Inst Clin Res, 930 Commonwealth Ave, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA USA.;Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA..
    ten Berg, Jurrien M.
    St Antonius Hosp, Nieuwegein, Netherlands..
    Steg, Gabriel
    Imperial Coll, London, England.;Univ Paris Diderot, French Alliance Cardiovasc Trials, F CRIN Network, DHU FIRE,INSERM,Unite 1148, Paris, France.;Hop Bichat Assistance Publ, Paris, France..
    Hohnloser, Stefan H.
    Goethe Univ Frankfurt, Dept Med, Div Cardiol, Frankfurt, Germany..
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 16, p. 1513-1524Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.

    METHODS In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y(12) inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y(12) inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (>= 80 years of age; >= 70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.

    RESULTS The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.

    CONCLUSIONS Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y(12) inhibitor than among those who received triple therapy with warfarin, a P2Y(12) inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.

  • 29.
    Cannon, Christopher P.
    et al.
    Baim Institute for Clinical Research, USA; Brigham and Women’s Hospital, Heart and Vascular Center, USA; Harvard Medical School, USA.
    Bhatt, Deepak L.
    Brigham and Women’s Hospital, Heart and Vascular Center, USA; Harvard Medical School, USA.
    Oldgren, Jonas
    Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lip, Gregory Y. H.
    Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
    Ellis, Stephen G.
    Cleveland Clinic, Cleveland, USA.
    Kimura, Takeshi
    Kyoto University, Department of Cardiovascular Medicine, Kyoto, Japan.
    Maeng, Michael
    Aarhus University Hospital, Skejby, Denmark.
    Merkely, Bela
    University Heart and Vascular Center, Budapest, Hungary.
    Zeymer, Uwe
    Klinikum der Stadt Ludwigshafen am Rhein, Medizinische Klinik B, Ludwigshafen, Germany.
    Gropper, Savion
    Boehringer Ingelheim, Ingelheim, Germany.
    Nordaby, Matias
    Boehringer Ingelheim, Ingelheim, Germany.
    Kleine, Eva
    Boehringer Ingelheim, Ingelheim, Germany.
    Harper, Ruth
    Boehringer Ingelheim, Bracknell, UK.
    Manassie, Jenny
    Boehringer Ingelheim, Bracknell, UK.
    Januzzi, James L.
    Baim Institute for Clinical Research, USA; Cardiology Division, Massachusetts General Hospital, USA; Harvard Medical School, USA.
    Ten Berg, Jurrien M.
    St. Antonius Ziekenhuis, Nieuwegein, Netherlands.
    Steg, P. Gabriel
    Imperial College, London, London, UK.
    Hohnloser, Stefan H.
    Johann Wolfgang Goethe University, Department of Medicine, Division of Cardiology, Frankfurt am Main, Germany.
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 16, p. 1513-1524Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.

    METHODS: inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.

    RESULTS: The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.

    CONCLUSIONS: inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864)

  • 30.
    Cannon, Christopher P.
    et al.
    Baim Inst Clin Res, Boston, MA, USA.
    Lip, Gregory Y. H.
    Univ Birmingham, Birmingham, England.
    Oldgren, Jonas
    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.
    Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation: The authors reply2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 378, no 5, p. 485-486Article in journal (Other academic)
  • 31.
    Carlsson, Lena M. S.
    et al.
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Peltonen, Markku
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Ahlin, Sofie
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Anveden, Åsa
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bouchard, Claude
    Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge LA, United States.
    Carlsson, Björn
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jacobson, Peter
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lönroth, Hans
    Institute of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Maglio, Cristina
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Näslund, Ingmar
    Department of Surgery, Örebro University Hospital, Region Örebro län, Örebro, Sweden.
    Pirazzi, Carlo
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Romeo, Stefano
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöholm, Kajsa
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöström, Elisabeth
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wedel, Hans
    Nordic School of Public Health, Gothenburg, Sweden.
    Svensson, Per-Arne
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöström, Lars
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 8, p. 695-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.

    METHODS: In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.

    RESULTS: During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P< 0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P = 0.002 for the interaction) but not by BMI (P = 0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.

    CONCLUSIONS: Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.)

  • 32. Chahal, Harvinder S.
    et al.
    Stals, Karen
    Unterlander, Martina
    Balding, David J.
    Thomas, Mark G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Kumar, Ajith V.
    Besser, G. Michael
    Atkinson, A. Brew
    Morrison, Patrick J.
    Howlett, Trevor A.
    Levy, Miles J.
    Orme, Steve M.
    Akker, Scott A.
    Abel, Richard L.
    Grossman, Ashley B.
    Burger, Joachim
    Ellard, Sian
    Korbonits, Marta
    Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, *RF 1-3* he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

  • 33. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Abrey, Lauren
    Cloughesy, Timothy
    Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 8, p. 709-722Article in journal (Refereed)
    Abstract [en]

    BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. 

  • 34. Connolly, Stuart J
    et al.
    Camm, A John
    Halperin, Jonathan L
    Joyner, Campbell
    Alings, Marco
    Amerena, John
    Atar, Dan
    Avezum, Alvaro
    Blomström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Borggrefe, Martin
    Budaj, Andrzej
    Chen, Shih-Ann
    Ching, Chi Keong
    Commerford, Patrick
    Dans, Antonio
    Davy, Jean-Marc
    Delacrétaz, Etienne
    Di Pasquale, Giuseppe
    Diaz, Rafael
    Dorian, Paul
    Flaker, Greg
    Golitsyn, Sergey
    Gonzalez-Hermosillo, Antonio
    Granger, Christopher B
    Heidbüchel, Hein
    Kautzner, Josef
    Kim, June Soo
    Lanas, Fernando
    Lewis, Basil S
    Merino, Jose L
    Morillo, Carlos
    Murin, Jan
    Narasimhan, Calambur
    Paolasso, Ernesto
    Parkhomenko, Alexander
    Peters, Nicholas S
    Sim, Kui-Hian
    Stiles, Martin K
    Tanomsup, Supachai
    Toivonen, Lauri
    Tomcsányi, János
    Torp-Pedersen, Christian
    Tse, Hung-Fat
    Vardas, Panos
    Vinereanu, Dragos
    Xavier, Denis
    Zhu, Jun
    Zhu, Jun-Ren
    Baret-Cormel, Lydie
    Weinling, Estelle
    Staiger, Christoph
    Yusuf, Salim
    Chrolavicius, Susan
    Afzal, Rizwan
    Hohnloser, Stefan H
    Dronedarone in High-Risk Permanent Atrial Fibrillation2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 365, no 24, p. 2268-2276Article in journal (Refereed)
    Abstract [en]

    Background

    Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular anti-arrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation.

    Methods

    We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death.

    Results

    After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02).

    Conclusions

    Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients.

  • 35. Connolly, Stuart J.
    et al.
    Ezekowitz, Michael D.
    Yusuf, Salim
    Eikelboom, John
    Oldgren, Jonas
    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.
    Parekh, Amit
    Pogue, Janice
    Reilly, Paul A.
    Themeles, Ellison
    Varrone, Jeanne
    Wang, Susan
    Alings, Marco
    Xavier, Denis
    Zhu, Jun
    Diaz, Rafael
    Lewis, Basil S.
    Darius, Harald
    Diener, Hans-Christoph
    Joyner, Campbell D.
    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.
    Dabigatran versus warfarin in patients with atrial fibrillation2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 12, p. 1139-1151Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

  • 36. Connolly, Stuart J.
    et al.
    Ezekowitz, Michael D.
    Yusuf, Salim
    Reilly, Paul A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Newly Identified Events in the RE-LY Trial2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 19, p. 1875-1876Article in journal (Refereed)
  • 37. Connolly, Stuart J.
    et al.
    Pogue, Janice
    Hart, Robert G.
    Hohnloser, Stefan H.
    Pfeffer, Marc
    Chrolavicius, Susan
    Yusuf, Salim
    Effect of clopidogrel added to aspirin in patients with atrial fibrillation2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 20, p. 2066-2078Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. METHODS: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. RESULTS: At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001). CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)

  • 38. Connolly, Stuart J.
    et al.
    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.
    Yusuf, Salim
    Additional Events in the RE-LY Trial2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 15, p. 1464-1465Article in journal (Refereed)
  • 39.
    Cosedis Nielsen, Jens
    et al.
    Aarhus University Hospital, Denmark.
    Johannessen, Arne
    Gentofte University Hospital, Copenhagen, Denmark.
    Raatikainen, Pekka
    Tampere University Hospital, Finland.
    Hindricks, Gerhard
    Leipzig University Hospital, Germany.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Kongstad, Ole
    Lund University Hospital, Sweden.
    Pehrson, Steen
    Rigshospitalet, Copenhagen, Denmark.
    Englund, Anders
    University Hospital Örebro, Sweden.
    Hartikainen, Juha
    Kuopio University Hospital, Finland.
    Spange Mortensen, Leif
    UNI-C, Danish Information Technology Center for Education and Research, Aarhus, Denmark.
    Steen Hansen, Peter
    Aarhus University Hospital, Denmark.
    Radiofrequency Ablation as Initial Therapy in Paroxysm Atrial Fibrillation2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 17, p. 1587-1595Article in journal (Refereed)
    Abstract [en]

    Background

    There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation.

    Methods

    We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis.

    Results

    There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation.

    Conclusions

    In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years.

  • 40. Crosby, Jacy
    et al.
    Peloso, Gina M.
    Auer, Paul L.
    Crosslin, David R.
    Stitziel, Nathan O.
    Lange, Leslie A.
    Lu, Yingchang
    Tang, Zheng-zheng
    Zhang, He
    Hindy, George
    Masca, Nicholas
    Stirrups, Kathleen
    Kanoni, Stavroula
    Do, Ron
    Jun, Goo
    Hu, Youna
    Kang, Hyun Min
    Xue, Chenyi
    Goel, Anuj
    Farrall, Martin
    Duga, Stefano
    Merlini, Pier Angelica
    Asselta, Rosanna
    Girelli, Domenico
    Olivieri, Oliviero
    Martinelli, Nicola
    Yin, Wu
    Reilly, Dermot
    Speliotes, Elizabeth
    Fox, Caroline S.
    Hveem, Kristian
    Holmen, Oddgeir L.
    Nikpay, Majid
    Farlow, Deborah N.
    Assimes, Themistocles L.
    Franceschini, Nora
    Robinson, Jennifer
    North, Kari E.
    Martin, Lisa W.
    DePristo, Mark
    Gupta, Namrata
    Andersson Escher, Stefan
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Skellefteå Hospital, Skellefteå .
    Van Zuydam, Natalie
    Palmer, Colin N. A.
    Wareham, Nicholas
    Koch, Werner
    Meitinger, Thomas
    Peters, Annette
    Lieb, Wolfgang
    Erbel, Raimund
    Konig, Inke R.
    Kruppa, Jochen
    Degenhardt, Franziska
    Gottesman, Omri
    Bottinger, Erwin P.
    O'Donnell, Christopher J.
    Psaty, Bruce M.
    Ballantyne, Christie M.
    Abecasis, Goncalo
    Ordovas, Jose M.
    Melander, Olle
    Watkins, Hugh
    Orho-Melander, Marju
    Ardissino, Diego
    Loos, Ruth J. F.
    McPherson, Ruth
    Willer, Cristen J.
    Erdmann, Jeanette
    Hall, Alistair S.
    Samani, Nilesh J.
    Deloukas, Panos
    Schunkert, Heribert
    Wilson, James G.
    Kooperberg, Charles
    Rich, Stephen S.
    Tracy, Russell P.
    Lin, Dan-Yu
    Altshuler, David
    Gabriel, Stacey
    Nickerson, Deborah A.
    Jarvik, Gail P.
    Cupples, L. Adrienne
    Reiner, Alex P.
    Boerwinkle, Eric
    Kathiresan, Sekar
    Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 1, p. 22-31Article in journal (Refereed)
    Abstract [en]

    Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

  • 41.
    Cunningham, A. L.
    et al.
    Westmead Inst Med Res, Westmead, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Lal, H.
    GSK Vaccines, King Of Prussia, PA USA..
    Kovac, M.
    GSK Vaccines, Wavre, Belgium..
    Chlibek, R.
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic..
    Hwang, S. -J
    Diez-Domingo, J.
    Fdn Fomento Invest Sanitaria & Biomed, Vaccine Res Unit, Valencia, Spain..
    Godeaux, O.
    GSK Vaccines, Wavre, Belgium..
    Levin, M. J.
    Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA..
    McElhaney, J. E.
    Hlth Sci North Res Inst, Sudbury, ON, Canada..
    Puig-Barbera, J.
    Fdn Fomento Invest Sanitaria & Biomed, Vaccine Res Unit, Valencia, Spain..
    Abeele, C. Vanden
    GSK Vaccines, Wavre, Belgium..
    Vesikari, T.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Watanabe, D.
    Aichi Med Univ, Dept Dermatol, Nagakute, Aichi, Japan..
    Zahaf, T.
    GSK Vaccines, Wavre, Belgium..
    Ahonen, A.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Athan, E.
    Deakin Univ, Barwon Hlth, Dept Infect Dis, Geelong, Vic, Australia..
    Barba-Gomez, J. F.
    Inst Dermatol Jalisco Dr Jose Barba Rubio, Zapopan, Mexico..
    Campora, L.
    GSK Vaccines, Wavre, Belgium..
    de Looze, F.
    Univ Queensland, Sch Med, AusTrials, Brisbane, Qld, Australia.;Univ Queensland, Sch Med, Discipline Gen Practice, Brisbane, Qld, Australia..
    Downey, H. J.
    Jacksonville Ctr Clin Res, Jacksonville, FL USA..
    Ghesquiere, W.
    Univ British Columbia, Infect Dis Sect, Victoria, BC, Canada..
    Gorfinkel, I.
    PrimeHlth Clin Res, Toronto, ON, Canada..
    Korhonen, T.
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland..
    Leung, E.
    United Christian Hosp, Dept Med & Geriatr, Div Geriatr Med, Hong Kong, Hong Kong, Peoples R China..
    McNeil, S. A.
    Dalhousie Univ, IWK Hlth Ctr, Canadian Ctr Vaccinol, Halifax, NS, Canada.;Dalhousie Univ, Nova Scotia Hlth Author, Halifax, NS, Canada..
    Oostvogels, L.
    GSK Vaccines, Wavre, Belgium..
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Sormland Cty Council, Clin Res Ctr, Eskilstuna, Sweden..
    Smetana, J.
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic..
    Weckx, L.
    Univ Fed Sao Paulo, Ctr Referencia Imunobiol Especiais, Sao Paulo, Brazil..
    Yeo, W.
    Univ Wollongong, Grad Sch Med, Illawarra Hlth & Med Res Inst, Wollongong, NSW, Australia..
    Heineman, T. C.
    GSK Vaccines, King Of Prussia, PA USA..
    Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older2016In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 375, no 11, p. 1019-1032Article in journal (Refereed)
    Abstract [en]

    BACKGROUND A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01(B) adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). METHODS This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1: 1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTS In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONS In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.govnumbers, NCT01165177 and NCT01165229.)

  • 42.
    De Bruyne, Bernard
    et al.
    Cardiovasc Ctr Aalst, Onze Lieve Vrouw Hosp, Aalst, Belgium.
    Fearon, William F.
    Med Ctr, Stanford Univ, Stanford CA, USA.; Palo Alto Vet Affairs Hlth Care Syst, Stanford CA, USA.
    Pijls, Nico H. J.
    Dept Cardiol, Catharina Hosp, Eindhoven, Netherlands; Dept Biomed Engn, Eindhoven Univ Technol, Eindhoven, Netherlands.
    Barbato, Emanuele
    Cardiovasc Ctr Aalst, Onze Lieve Vrouw Hosp, Aalst, Belgium.
    Tonino, Pim
    Dept Cardiol, Catharina Hosp, Eindhoven, Netherlands; Dept Biomed Engn, Eindhoven Univ Technol, Eindhoven, Netherlands.
    Piroth, Zsolt
    Hungarian Inst Cardiol, Budapest, Hungary.
    Jagic, Nikola
    Clin Ctr Kragujevac, Kragujeva, Serbia.
    Mobius-Winckler, Sven
    Heart Ctr Leipzig, Leipzig, Germany.
    Rioufol, Gilles
    Cardiovasc Hosp, Lyon, France.
    Witt, Nils
    Södersjukhuset, Karolinska Inst, Stockholm, Sweden.
    Kala, Petr
    Univ Hosp, Brno, Czech Republic.
    MacCarthy, Philip
    Kings Coll Hosp, London, England.
    Engstroem, Thomas
    Rigshosp, Univ Copenhagen Hosp,Copenhagen, Denmark.
    Oldroyd, Keith
    Golden Jubilee Natl Hosp, Glasgow, UK.
    Mavromatis, Kreton
    Atlanta Vet Affairs Med Ctr, Decatur GA, USA.
    Manoharan, Ganesh
    Royal Victoria Hosp, Belfast, North Ireland.
    Verlee, Peter
    Eastern Maine Med Ctr, Bangor, UK.
    Fröbert, Ole
    Örebro University Hospital.
    Curzen, Nick
    Southampton Univ Hosp NHS Trust, Southampton, England.
    Johnson, Jane B.
    St Jude Med, St Paul MN, USA.
    Limacher, Andreas
    Inst Social & Prevent Med, Univ Bern, Bern, Switzerland; Dept Clin Res, Clin Trials Unit, Univ Bern, Bern, Switzerland.
    Nueesch, Eveline
    Inst Social & Prevent Med, Univ Bern, Bern, Switzerland; Dept Clin Res, Clin Trials Unit, Univ Bern, Bern, Switzerland.
    Jueni, Peter
    Inst Social & Prevent Med, Univ Bern, Bern, Switzerland; Dept Clin Res, Clin Trials Unit, Univ Bern, Bern, Switzerland.
    Fractional Flow Reserve-Guided PCI for Stable Coronary Artery Disease2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 13, p. 1208-1217Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy.

    METHODS: In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years.

    RESULTS: The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P = 0.01). In a landmark analysis, the rate of death or myocardial infarction from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P = 0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years.

    CONCLUSIONS: In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone.

  • 43.
    De Bruyne, Bernard
    et al.
    Onze-Lieve-Vrouw Clinic, Cardiovascular Center Aalst, Aalst, Belgium .
    Fröbert, Ole
    Örebro University Hospital, Region Örebro län, Örebro, Sweden.
    Fearon, William F.
    Stanford University Medical Center, Stanford CA, USA.
    Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 11, p. 991-1001Article in journal (Refereed)
    Abstract [en]

    Background: The preferred initial treatment for patients with stable coronary artery disease is the best available medical therapy. We hypothesized that in patients with functionally significant stenoses, as determined by measurement of fractional flow reserve (FFR), percutaneous coronary intervention (PCI) plus the best available medical therapy would be superior to the best available medical therapy alone.

    Methods: In patients with stable coronary artery disease for whom PCI was being considered, we assessed all stenoses by measuring FFR. Patients in whom at least one stenosis was functionally significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy (PCI group) or the best available medical therapy alone (medical-therapy group). Patients in whom all stenoses had an FFR of more than 0.80 were entered into a registry and received the best available medical therapy. The primary end point was a composite of death, myocardial infarction, or urgent revascularization.

    Results: Recruitment was halted prematurely after enrollment of 1220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary endpoint event: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical-therapy group (1.6% vs. 11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P<0.001); in particular, in the PCI group, fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography (hazard ratio, 0.13; 95% CI, 0.04 to 0.43; P<0.001). Among patients in the registry, 3.0% had a primary end-point event.

    Conclusions: In patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization. In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01132495.)

  • 44. Demoulin, Jean-Baptiste
    et al.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Scleroderma2009In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 361, no 8, p. 826-827Article in journal (Refereed)
    Abstract [en]

    In their review article on scleroderma, Gabrielli et al. incorporate their earlier observations that all patients with this disease have activating antibodies to platelet-derived growth factor (PDGF) receptors (PDGFRs). These antibodies were described as being specific for scleroderma and for chronic extensive graft-versus-host disease, two conditions that share some clinical features. The review does not reflect the current debate on the existence of such antibodies. Researchers from several centers, including ours, have challenged the results of Gabrielli et al.

  • 45. Druker, Brian J.
    et al.
    Guilhot, Francois
    O'Brien, Stephen G.
    Gathmann, Insa
    Kantarjian, Hagop
    Gattermann, Norbert
    Deininger, Michael W. N.
    Silver, Richard T.
    Goldman, John M.
    Stone, Richard M.
    Cervantes, Francisco
    Hochhaus, Andreas
    Powell, Bayard L.
    Gabrilove, Janice L.
    Rousselot, Philippe
    Reiffers, Josy
    Cornelissen, Jan J.
    Hughes, Timothy
    Agis, Hermine
    Fischer, Thomas
    Verhoef, Gregor
    Shepherd, John
    Saglio, Giuseppe
    Gratwohl, Alois
    Nielsen, Johan L.
    Radich, Jerald P.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Taylor, Kerry
    Baccarani, Michele
    So, Charlene
    Letvak, Laurie
    Larson, Richard A.
    Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia2006In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 355, no 23, p. 2408-2417Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

  • 46.
    Eich, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Visualization of early engraftment in clinical islet transplantation by positron-emission tomography2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 26, p. 2754-2755Article in journal (Refereed)
  • 47.
    Ekbom, K.
    et al.
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Waldenlind, E.
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Richard, Levi
    Söder Hospital, Karolinska Institute, Stockholm, Sweden.
    Andersson, B.
    Gãvle Hospital, Gãvle, Sweden.
    Boivie, J.
    University Hospital, Linköping, Sweden.
    Dizdar, N.
    University Hospital, Linköping, Sweden.
    Bousser, M.G.
    Hôpital St. Antoine, Paris, France.
    Tehindrazanirivelo, A.
    Hôpital St. Antoine, Paris, France.
    Lutz, G.
    Hôpital St. Antoine, Paris, France.
    Hannerz, J.
    Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
    Hardebo, J.E.
    University Hospital, Lund. Sweden.
    Henry, P.
    Hôpital Pellegrin—Tripode, Bordeaux, France.
    Rosazza, M.
    Hôpital Pellegrin—Tripode, Bordeaux, France.
    Krabbe, A.
    Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Kinnman, J.
    Halmstad Hospital, Halmstad, Sweden.
    Persson, L.I.
    Sahlgrenska Hospital, University of University of Gothenburg, Gothenburg, Sweden.
    Prusinski, A.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Durko, A.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Kozubski, W.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Rozniecki, M.D.
    Neurology Clinic, Medical Academy, Lodz, Poland.
    Wysocka-Bakowska, M.M.
    Neurology Clinic, Medical Medical Academy, Warsaw, Poland.
    Cole, J.A.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Patel, P.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Pilgrim, AJ.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Winter, O'B.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Donoghue, S.
    Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
    Treatment of acute cluster headache with sumatriptan1991In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, no 325, p. 322-326Article in journal (Refereed)
  • 48.
    Erlinge, D.
    et al.
    Lund University, Sweden.
    Omerovic, E.
    Sahlgrens University Hospital, Sweden.
    Frobert, O.
    Örebro University, Sweden.
    Linder, R.
    Danderyd Hospital, Sweden.
    Danielewicz, M.
    Karlstad Hospital, Sweden.
    Hamid, M.
    Mälarsjukhuset, Sweden.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Henareh, L.
    Karolinska University Hospital, Sweden.
    Wagner, H.
    Helsingborg Lasarett, Sweden.
    Hardhammar, P.
    Halmstad County Hospital, Sweden.
    Sjogren, I.
    Falun Central Hospital, Sweden.
    Stewart, J.
    Skaraborgs Hospital, Sweden.
    Grimfjard, P.
    Västmanlands Sjukhus, Sweden.
    Jensen, J.
    Karolinska Institute, Sweden.
    Aasa, M.
    Södersjukhuset AB, Sweden.
    Robertsson, L.
    Södra Älvsborgs Sjukhus, Sweden.
    Lindroos, P.
    Karolinska Institute, Sweden.
    Haupt, J.
    Sunderby Sjukhus, Sweden.
    Wikstrom, H.
    Kristianstad Hospital, Sweden.
    Ulvenstam, A.
    Östersund Hospital, Sweden.
    Bhiladvala, P.
    Lund University, Sweden.
    Lindvall, B.
    Sundsvall Hospital, Sweden.
    Lundin, A.
    Lund University, Sweden.
    Todt, T.
    Lund University, Sweden.
    Ioanes, D.
    Sahlgrens University Hospital, Sweden.
    Ramunddal, T.
    Sahlgrens University Hospital, Sweden.
    Kellerth, T.
    Örebro University, Sweden.
    Zagozdzon, L.
    Örebro University, Sweden.
    Gotberg, M.
    Lund University, Sweden.
    Andersson, J.
    Umeå University, Sweden.
    Angeras, O.
    Sahlgrens University Hospital, Sweden.
    Ostlund, O.
    Uppsala University, Sweden.
    Lagerqvist, B.
    Uppsala University, Sweden.
    Held, C.
    Uppsala University, Sweden.
    Wallentin, L.
    Uppsala University, Sweden.
    Schersten, F.
    Lund University, Sweden.
    Eriksson, P.
    Umeå University, Sweden.
    Koul, S.
    Lund University, Sweden.
    James, S.
    Uppsala University, Sweden.
    Bivalirudin versus Heparin Monotherapy in Myocardial Infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 12, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y 12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. METHODS In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y(12) inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. RESULTS A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76). CONCLUSIONS Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others;

  • 49. Erlinge, D.
    et al.
    Omerovic, E.
    Frobert, O.
    Linder, Robert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Danielewicz, M.
    Hamid, M.
    Swahn, E.
    Henareh, L.
    Wagner, H.
    Hårdhammar, P.
    Sjögren, I.
    Stewart, J.
    Grimfjärd, P.
    Jensen, J.
    Aasa, M.
    Robertsson, L.
    Lindroos, P.
    Haupt, J.
    Wikström, H.
    Ulvenstam, A.
    Bhiladvala, P.
    Lindvall, B.
    Lundin, A.
    Tödt, T.
    Ioanes, D.
    Råmunddal, T.
    Kellerth, T.
    Zagozdzon, L.
    Götberg, M.
    Andersson, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Angerås, O.
    Östlund, O.
    Lagerqvist, B.
    Held, C.
    Wallentin, L.
    Scherstén, F.
    Eriksson, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Koul, S.
    James, S.
    Bivalirudin versus heparin monotherapy in myocardial infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 12, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y 12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors.

    METHODS In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y(12) inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up.

    RESULTS A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76).

    CONCLUSIONS Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART Clinical-TrialsRegister.eu number, 2012-005260-10; ClinicalTrials.gov number, NCT02311231.)

  • 50.
    Erlinge, D.
    et al.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Omerovic, E.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Fröbert, O.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Linder, R.
    Danderyd Hosp, Dept Cardiol, Danderyd, Sweden..
    Danielewicz, M.
    Karlstad Hosp, PCI Unit, Karlstad, Sweden..
    Hamid, M.
    Malarsjukhuset, Dept Cardiol, Eskilstuna, Sweden..
    Swahn, E.
    Linkoping Univ Hosp, Dept Cardiol, Linkoping, Sweden..
    Henareh, L.
    Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Wagner, H.
    Helsingborg Lasarett, Dept Cardiol, Helsingborg, Sweden..
    Hårdhammar, P.
    Halmstad Cty Hosp, Dept Cardiol, Halmstad, Sweden..
    Sjögren, I.
    Falun Cent Hosp, Dept Cardiol, Falun, Sweden..
    Stewart, J.
    Skaraborgs Hosp, Dept Cardiol, Skovde, Sweden..
    Grimfjärd, P.
    Vastmanlands Sjukhus, Dept Internal Med, Vasteras, Sweden..
    Jensen, J.
    Karolinska Inst, Capio St Gorans Hosp, Dept Cardiol, Stockholm, Sweden..
    Aasa, M.
    Sodersjukhuset AB, Dept Cardiol, Stockholm, Sweden..
    Robertsson, L.
    Sodra Alvsborgs Sjukhus, Dept Cardiol, Boras, Sweden..
    Lindroos, P.
    Karolinska Inst, Capio St Gorans Hosp, Dept Cardiol, Stockholm, Sweden..
    Haupt, J.
    Sunderby Sjukhus, Dept Cardiol, Lulea, Sweden..
    Wikström, H.
    Kristianstad Hosp, Dept Cardiol, Kristianstad, Sweden..
    Ulvenstam, A.
    Ostersund Hosp, Dept Cardiol, Ostersund, Sweden..
    Bhiladvala, P.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Lindvall, B.
    Sundsvall Hosp, Dept Cardiol, Sundsvall, Sweden..
    Lundin, A.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Tödt, T.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Ioanes, D.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Råmunddal, T.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Kellerth, T.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Zagozdzon, L.
    Rebro Univ, Fac Hlth, Dept Cardiol, Orebro, Sweden..
    Götberg, M.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Andersson, J.
    Umea Univ, Dept Cardiol, Umea, Sweden..
    Angerås, O.
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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.
    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.
    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.
    Schersten, F.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Eriksson, P.
    Umea Univ, Dept Cardiol, Umea, Sweden..
    Koul, S.
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bivalirudin versus Heparin Monotherapy in Myocardial Infarction2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 12, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y 12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. METHODS In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y(12) inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. RESULTS A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76). CONCLUSIONS Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others;

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