The most cited articles published since 2010, extracted from Scopus
Volume 376, Issue 9742, August 2010, Pages 687-697
Yungjue Bang | Éric Van D G Van Cutsem | Andrea Feyereislova | Hyuncheol Chung | Lin Shen | Akira Sawaki | Florian Lordick | Atsushi Ohtsu | Yasushi Omuro | Taroh Satoh | Giuseppe Aprile | Eugeny P. Kulikov | Julie Anne Hill | Michaela Lehle | Josef R. Rüschoff | Yoonkoo Kang
Background Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. Methods ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. Findings 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17·1 months (9-25) in the chemotherapy alone group. Median overall survival was 13·8 months (95 CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95 CI 0·60-0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197  vs chemotherapy alone, 184 ), vomiting (147  vs 134 ), and neutropenia (157  vs 165 ). Rates of overall grade 3 or 4 adverse events (201  vs 198 ) and cardiac adverse events (17  vs 18 ) did not differ between groups. Interpretaion Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Funding F Hoffmann-La Roche. © 2010 Elsevier Ltd.
Volume 376, Issue 9753, November 2010, Pages 1670-1681
Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15 (95 CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13 (95 CI 7-19; p<0·0001), in coronary revascularisation of 19 (95 CI 15-24; p<0·0001), and in ischaemic stroke of 16 (95 CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95 CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10 per 1·0 mmol/L LDL reduction (RR 0·90, 95 CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99 CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99 CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95 CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99 CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95 CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95 CI 0·96- 1·04; p=0·9), even at low LDL cholesterol concentrations. Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50. UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation. © 2010 Elsevier Ltd.
Volume 380, Issue 9859, December 2012, Pages 2095-2128
Rafael Lozano | Mohsen Naghavi | Kyle J. Foreman | Stephen Lim | Kenji Shibuya | Victor Aboyans | Jerry Puthenpurakal Abraham | Timothy Adair | Rakesh Aggarwal | Stephanie Y. Ahn | Miriam R. Alvarado | H. Ross Anderson | Laurie M. Anderson | Kathryn Gilman Andrews | Charles Atkinson | Larry M. Baddour | Suzanne Lyn Barker-Collo | David H. Bartels | Michelle Lee Bell | Emelia J. Benjamin | Derrick A. Bennett | Kavi S B Bhalla | Boris T. Bikbov | Aref Bin Abdulhak | Gretchen Lano Birbeck | Fiona M. Blyth | Ian W. Bolliger | Soufiane Boufous | Chiara Bucello | Michael Burch | Peter G J Burney | Jonathan Rhys Carapetis | Honglei Chen | David Chou | Sumeet S. Chugh | Luc Edgar Coffeng | Steven D. Colan | Samantha M. Colquhoun | K. Ellicott Colson | John R. Condon | Myles Dean Connor | Leslie Trumbull Cooper | Matthew A. Corriere | Monica Cortinovis | Karen Courville De Vaccaro | William G. Couser | Benjamin C. Cowie | Michael H. Criqui | Marita J. Cross | Kaustubh C. Dabhadkar | Nabila A. Dahodwala | Diego De Leo | Louisa Degenhardt | Allyne M. Delossantos | Julie O. Denenberg | Don Des Des Des Jarlais | Samath D. Dharmaratne | Earl Ray Dorsey | Tim Robert Driscoll | Herbert C. Duber | Beth E. Ebel | Patricia J. Erwin | Patricia Espindola | Majid Ezzati | Valery L. Feǐgin | Abraham D. Flaxman | Mohammad Hossein R Forouzanfar | Francis Gerald R Fowkes | Richard Charles Franklin | Marlene K. Fransen | Michael K. Freeman | Sherine E. Gabriel | Emmanuela E. Gakidou | Flavio Gaspari | Richard Frank Gillum | Diego Gonzalez-Medina | Yara A. Halasa | Diana Haring | James Edward Harrison | Rasmus Havmoeller | Roderick Hay | Bruno Hoen | Peter J. Hotez | D. G. Hoy | Kathryn H. Jacobsen | Spencer L. James | Rashmi Jasrasaria | Sudha P. Jayaraman | Nicole E. Johns | Ganesan Karthikeyan | Nicholas Kassebaum | André B. Keren | Jonpaul Khoo | Lisa Marie Knowlton | Olive Chifefe Kobusingye | Adofo Koranteng | Rita V. Krishnamurthi | Michael S. Lipnick | Steven Lipshultz | Summerlockett Ohno | Jacqueline R. Mabweijano | Michael F. MacIntyre | Leslie Mallinger | Lyn March | Guy Marks | Robin Marks | Akira Matsumori | Richard G. Matzopoulos | Bongani Mawethu Mayosi | John H. McAnulty | Mary McGrae McDermott | John Joseph McGrath | George A. Mensah | Tony R. Merriman | Catherine M. Michaud | Matthew Miller | Ted Olga Miller | Charles Mock | Ana Olga H Mocumbi | Ali H I Mokdad | Andrew E. Moran | Kim Mulholland | Mani Nathan Nair | Luigi Naldi | Kabayam M Venkat Narayan | Kiumarss Nasseri | Paul E. Norman | Martin J. O'Donnell | Saad Bin Omer | Katrina F. Ortblad | Richard H. Osborne | Doruk E. Ozgediz | Bishnu Pahari | Jeyaraj Durai Pandian | Andrea Panozo Rivero | Rogelio Pérez Padilla | Fernando Pérez-Ruiz | Norberto Perico | David E. Phillips | Kelsey R. Pierce | Christopher Arden Pope | Esteban L. Porrini | Farshad Pourmalek | Murugesan Raju | Dharani Ranganathan | Jürgen T. Rehm | David B. Rein | Giuseppe Remuzzi | Frederick Rodriguez Rivara | Thomas J. Roberts | Felipe Rodríguez De Leòn | Lisa C. Rosenfeld | Lesley Rushton | Ralph Sacco | Joshua A. Salomon | Uchechukwu K A Sampson | Ella Sanman | David C. Schwebel | María Seguí-Gómez | Donald S. Shepard | David K. Singh | Jessica Singleton | Karen S. Sliwa | Emma U R Smith | Andrew C. Steer | Jennifer A. Taylor | Bernadette A. Thomas | Imad M. Tleyjeh | Jeffrey A. Towbin | Thomas Clement Truelsen | Eduardo A. Undurraga | Narayanaswamy Venketasubramanian | Lakshmi Vijayakumar | Theo Vos | Gregory R. Wagner | Mengru Wang | Wenzhi Wang | Kerrianne Watt | Martin A. Weinstock | Robert G. Weintraub | James James D Wilkinson | Anthony D. Woolf | Sarah K. Wulf | Ponhsiu Yeh | Paul S F Yip | Azadeh Zabetian | Zhijie Zheng | Alan D. Lopez | Christopher JL L L Murray
Background Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs); 1separately by age and sex. Methods We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model; (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS); we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. Findings In 2010, there were 52 8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24 9% of deaths worldwide in 2010, down from 15 9 million (34 1%) of 46 5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2 5 to 1 4 million); 1lower respiratory infections (from 3 4 to 2 8 million); 1neonatal disorders; (from 3 1 to 2 2 million); 1measles; (from 0 63 to 0 13 million)l; 1and tetanus; (from 0 27 to 0 06 million). Deaths from HIV/AIDS increased from 0 30 million in 1990 to 1 5 million in 2010, reaching a peak of 1 7 million in 2006. Malaria mortality also rose by an estimated 19 9% since 1990 to 1 17 million deaths in 2010. Tuberculosis killed 1 2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34 5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1 5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12 9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1 3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5 1 million deaths) was marginally higher in 2010 (9 6%) compared with two decades earlier (8 8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1 3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD); 1lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality; (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub- Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular); 1but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Interpretation Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis.
Volume 380, Issue 9859, December 2012, Pages 2224-2260
Stephen Lim | Theo Vos | Abraham D. Flaxman | Goodarz Danaei | Kenji Shibuya | Heather Adair-Rohani | Markus Amann | H. Ross Anderson | Kathryn Gilman Andrews | Martin Aryee | Charles Atkinson | Loraine J. Bacchus | Adil N. Bahalim | Kalpana Balakrishnan | John R. Balmes | Suzanne Lyn Barker-Collo | Amanda J. Baxter | Michelle Lee Bell | Jed D. Blore | Fiona M. Blyth | Carissa Bonner | Guilherme Borges | Rupert Ra A Bourne | Michel Boussinesq | Michael Brauer | Peter M. Brooks | Nigel G. Bruce | Bert Brunekreef | Claire Bryan-Hancock | Chiara Bucello | Rachelle Buchbinder | Fiona C L Bull | Richard T. Burnett | Tim E. Byers | Bianca Calabria | Jonathan Rhys Carapetis | Emily Carnahan | Zoë A. Chafe | Fiona J. Charlson | Honglei Chen | Jianshen Chen | Andrew Cheng | Jennifer Christine Child | Aaron J. Cohen | K. Ellicott Colson | Benjamin C. Cowie | Sarah C. Darby | Susan Darling | Adrian B. Davis | Louisa Degenhardt | Frank J. Dentener | Don Des Des Des Jarlais | Karen M. Devries | Mukesh K. Dherani | Eric Ding | Earl Ray Dorsey | Tim Robert Driscoll | Karen M. Edmond | Suad Eltahir Ali | Rebecca E. Engell | Patricia J. Erwin | Saman Fahimi | Gail Falder | Farshad Farzadfar | Alize J. Ferrari | Mariel M. Finucane | Seth R. Flaxman | Francis Gerald R Fowkes | Greg D. Freedman | Michael K. Freeman | Emmanuela E. Gakidou | Santu Ghosh | Edward L. Giovannucci | Gerhard Gmel | Kathryn M. Graham | Rebecca Grainger | Bridget F. Grant | David J. Gunnell | Hialy R. Gutierrez | Wayne D. Hall | Hans Wijbrand Wijbrand Hoek | Anthony Hogan | Howard Dean Hosgood | D. G. Hoy | Howard Hu | Bryan J. Hubbell | Sally J. Hutchings | Sydney E. Ibeanusi | Gemma L. Jacklyn | Rashmi Jasrasaria | Jost Bruno Jonas | Haidong Kan | John Anthony Kanis | Nicholas Kassebaum | Norito Kawakami | Youngho Khang | Shahab Khatibzadeh | Jonpaul Khoo | Cindy Kok | Francine Laden | Ratilal Lalloo | Qing Lan | Tim Lathlean | Janet L. Leasher | James Leigh | Yang Li | Johnkent Lin | Steven Lipshultz | Stephanie J. London | Rafael Lozano | Yuan Lu | Joelle Mak | Reza Malekzadeh | Leslie Mallinger | Wagner Segura Marcenes | Lyn March | Robin Marks | Randall V. Martín | Paul McGale | John Joseph McGrath | Sumi C. Mehta | George A. Mensah | Tony R. Merriman | Renata Micha | Catherine M. Michaud | Vinod K. Mishra | Khayriyyah Mohd Hanafiah | Ali H I Mokdad | Lidia Morawska | Dariush Mozaffarian | Tasha J. Murphy | Mohsen Naghavi | Bruce Charles Neal | Paul K. Nelson | Joan Miquel Nolla | Rosana E. Norman | Casey Olives | Saad Bin Omer | Jessica Joan Oan Orchard | Richard H. Osborne | Bart D. Ostro | Andrew Nicholas Page | Kiran Dev Pandey | Charles D H Parry | Erin Passmore | Jayadeep Patra | Neil Perez Pearce | Pamela M. Pelizzari | Max Gustav Petzold | Michael Robert Phillips | Daniel P. Pope | Christopher Arden Pope | John W. Powles | Mayuree Rao | Homie A. Razavi | Eva Annette Rehfuess | Jürgen T. Rehm | Beate R. Ritz | Frederick Rodriguez Rivara | Thomas J. Roberts | Carolyn A. Robinson | José Adolfo Rodríguez Portales | Isabelle Romieu | Robin G W Room | Lisa C. Rosenfeld | Ananya Roy | Lesley Rushton | Joshua A. Salomon | Uchechukwu K A Sampson | Lídia Sànchez-Riera | Ella Sanman | Amir Sapkota | Soraya Seedat | Peilin Shi | Kevin D. Shield | Rupak Shivakoti | Gitanjali M. Singh | David A. Sleet | Emma U R Smith | Kirk R. Smith | Nicolas J C Stapelberg | Kyle N. Steenland | Heidi Stöckl | Lars Jacob Acob Stovner | Kurt Straif | Lahn D. Straney | George D. Thurston | Jimmy H. Tran | Rita Van Dingenen | Aaron Van Donkelaar | J. Lennert Veerman | Lakshmi Vijayakumar | Robert G. Weintraub | Myrna M. Weissman | Richard A. White | Harvey A M Whiteford | Steven Todd Wiersma | James James D Wilkinson | Hywel C G Williams | Warwick Williams | Nicholas M. Wilson | Anthony D. Woolf | Paul S F Yip | Jan M. Zieliński | Alan D. Lopez | Christopher JL L L Murray | Majid Ezzati
Background Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. Methods We estimated deaths and disability-adjusted life years; DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. Findings In 2010, the three leading risk factors for global disease burden were high blood pressure (7 0% [95% uncertainty interval 6 2-7 7] of global DALYs); tobacco smoking including second-hand smoke (6 3% [5 5-7 0]), and alcohol use (5 5% [5 0-5 9]). In 1990, the leading risks were childhood underweight (7 9% [6 8-9 4]), household air pollution from solid fuels; (HAP; 7 0% [5 6-8 3]), and tobacco smoking including second-hand smoke (6 1% [5 4-6 8]). Dietary risk factors and physical inactivity collectively accounted for 10 0% (95% UI 9 2-10 8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water ' and sanitation accounting for 0 9% (0 4-1 6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. Interpretation Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.
Volume 377, Issue 9765, February 2011, Pages 557-567
Mariel M. Finucane | Gretchen Anna Stevens | Melanie J. Cowan | Goodarz Danaei | Johnkent Lin | Christopher J. Paciorek | Gitanjali M. Singh | Hialy R. Gutierrez | Yuan Lu | Adil N. Bahalim | Farshad Farzadfar | Leanne M. Riley | Majid Ezzati
Excess bodyweight is a major public health concern. However, few worldwide comparative analyses of long-term trends of body-mass index (BMI) have been done, and none have used recent national health examination surveys. We estimated worldwide trends in population mean BMI. We estimated trends and their uncertainties of mean BMI for adults 20 years and older in 199 countries and territories. We obtained data from published and unpublished health examination surveys and epidemiological studies (960 country-years and 9·1 million participants). For each sex, we used a Bayesian hierarchical model to estimate mean BMI by age, country, and year, accounting for whether a study was nationally representative. Between 1980 and 2008, mean BMI worldwide increased by 0·4 kg/m 2 per decade (95 uncertainty interval 0·2-0·6, posterior probability of being a true increase >0·999) for men and 0·5 kg/m 2 per decade (0·3-0·7, posterior probability >0·999) for women. National BMI change for women ranged from non-significant decreases in 19 countries to increases of more than 2·0 kg/m 2 per decade (posterior probabilities >0·99) in nine countries in Oceania. Male BMI increased in all but eight countries, by more than 2 kg/m 2 per decade in Nauru and Cook Islands (posterior probabilities >0·999). Male and female BMIs in 2008 were highest in some Oceania countries, reaching 33·9 kg/m 2 (32·8-35·0) for men and 35·0 kg/m 2 (33·6-36·3) for women in Nauru. Female BMI was lowest in Bangladesh (20·5 kg/m 2, 19·8-21·3) and male BMI in Democratic Republic of the Congo 19·9 kg/m 2 (18·2-21·5), with BMI less than 21·5 kg/m 2 for both sexes in a few countries in sub-Saharan Africa, and east, south, and southeast Asia. The USA had the highest BMI of high-income countries. In 2008, an estimated 1·46 billion adults (1·41-1·51 billion) worldwide had BMI of 25 kg/m 2 or greater, of these 205 million men (193-217 million) and 297 million women (280-315 million) were obese. Globally, mean BMI has increased since 1980. The trends since 1980, and mean population BMI in 2008, varied substantially between nations. Interventions and policies that can curb or reverse the increase, and mitigate the health effects of high BMI by targeting its metabolic mediators, are needed in most countries. Bill Melinda Gates Foundation and WHO.
Volume 375, Issue 9730, May 2010, Pages 1969-1987
Robert Robert E Black | Simon Nicholas Cousens | Hope L. Johnson | Joy E. Lawn | Igor Rudan | Diego Garcia Bassani | Prabhat K S Jha | Harry Campbell | Christa Fischer Fischer Fischer Walker | Richard E. Cibulskis | Thomas P. Eisele | Li Liu | Colin Douglas Mathers
Background: Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in children younger than 5 years. Methods: We used multicause proportionate mortality models to estimate deaths in neonates aged 0-27 days and children aged 1-59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world. Findings: Of the estimated 8·795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5·970 million), with the largest percentages due to pneumonia (18%, 1·575 million, uncertainty range [UR] 1·046 million-1·874 million), diarrhoea (15%, 1·336 million, 0·822 million-2·004 million), and malaria (8%, 0·732 million, 0·601 million-0·851 million). 41% (3·575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1·033 million, UR 0·717 million-1·216 million), birth asphyxia (9%, 0·814 million, 0·563 million-0·997 million), sepsis (6%, 0·521 million, 0·356 million-0·735 million), and pneumonia (4%, 0·386 million, 0·264 million-0·545 million). 49% (4·294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China. Interpretation: These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions. Funding: WHO, UNICEF, and Bill & Melinda Gates Foundation. © 2010 Elsevier Ltd. All rights reserved.
Volume 375, Issue 9731, May 2010, Pages 2073-2081
Kunihiro Matsushita | Marije Van Der Velde | Brad C. Astor | Mark Woodward | Andrew S. Levey | Paul E. De Jong | Josef Coresh | Ron T. Gansevoort | Meguid A. El Nahas | Kai Uwe Eckardt | Bertram L. Kasiske | Marcello A. Tonelli | Brenda R. Hemmelgarn | Yaping Wang | Robert Charles Atkins | Kevan Roy Polkinghorne | Steven J. Chadban | Anoop Shankar | Ronald E. Klein | Barbara EK K Klein | Haiyan Wang | Fang Wang | Luxia Zhang | Lisheng Liu | Michael G. Shlipak | Mark J. Sarnak | Ronit Katz | Linda P. Fried | Tazeen Hasan Jafar | Muhammad Sadequl Islam | Juanita D. Hatcher | Neil R. Poulter | Nish Chaturvedi | Dietrich Rothenbacher | Hermann Hermann Brenner | Elke Raum | Wolfgang Koenig | Caroline S. Fox | Shihjen Hwang | James B. Meigs | Massimo Cirillo | Stein Ivar Hallan | Stian Lydersen | Jostein Holmen | Michael Shlipak | Mark J. Sarnak | Ronit Katz | Linda P. Fried | Paul J. Roderick | Dorothea D M Nitsch | Astrid Elizabeth Fletcher | Christopher John B Bulpitt | Takayoshi Ohkubo | Hirohito Metoki | Masaaki Nakayama | Masahiro Kikuya | Yutaka Imai | Simerjot Kaur Jassal | Elizabeth L. Barrett- Connor | Jaclyn N. Bergstrom | David Gene Warnock | Paul Muntner | Suzanne E. Judd | William Marvin McClellan | Mary Cushman | George Howard | Leslie A. McClure | Sunha Jee | Heejin Kimm | Jieun Yun | Chipang Wen | Sungfeng Wen | Chwenkeng Tsao | Minkuang Tsai | Johan Ärnlöv | Priscilla L. Auguste | Kasper Veldhuis | Laura Camarata | Beverly Gail Thomas | Tom Manley
Background: Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. Methods: In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. Findings: The analysis included 105 872 participants (730 577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1 128 310 participants (4 732 110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1·73 m2 and 105 mL/min/1·73 m2 and increased at lower eGFRs. Compared with eGFR 95 mL/min/1·73 m2, adjusted HRs for all-cause mortality were 1·18 (95% CI 1·05-1·32) for eGFR 60 mL/min/1·73 m2, 1·57 (1·39-1·78) for 45 mL/min/1·73 m2, and 3·14 (2·39-4·13) for 15 mL/min/1·73 m2. ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0·6 mg/mmol, adjusted HRs for all-cause mortality were 1·20 (1·15-1·26) for ACR 1·1 mg/mmol, 1·63 (1·50-1·77) for 3·4 mg/mmol, and 2·22 (1·97-2·51) for 33·9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. Interpretation: eGFR less than 60 mL/min/1·73 m2 and ACR 1·1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. Funding: Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation. © 2010 Elsevier Ltd. All rights reserved.
Volume 376, Issue 9756, December 2010, Pages 1903-1909
Murray David Esler | Henry Krum | Paul Andrew Sobotka | Markus Peter Schlaich | Roland Erich Schmieder | Michael P. Böhm | Felix Mahfoud | Horst Sievert | Nina C. Wunderlich | Lars Christian Hristian Rump | Oliver Vonend | Michael Uder | Melvin D. Lobo | Mark Caulfield | Andrejs Erglis | Michel Azizi | Marc R. Sapoval | Suku Thambar | Alexandre Persu | Jean P M Renkin | Heribert Schunkert | Joachim S. Weil | Uta C. Hoppe | Tony Walton | Dierk Scheinert | Thomas M C Binder | Andrzej A. Januszewicz | Adam Witkowski | Luís Miguel Ruilope | Robert J. Whitbourn | Heike Bruck | Mark O. Downes | Thomas Felix Lüscher | Alan G M Jardine | Mark Wi I Webster | Thomas Windecker Zeller | Jerzy Sadowski | Krzysztof Bartuś | Craig A. Straley | Neil C. Barman | David Lee | Ronald M. Witteles | Vivek Bhalla | Joseph M. Massaro
Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. 106 (56) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94) of 52 patients who underwent renal denervation and 51 (94) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients. Ardian. © 2010 Elsevier Ltd.
Volume 380, Issue 9859, December 2012, Pages 2197-2223
Christopher JL L L Murray | Theo Vos | Rafael Lozano | Mohsen Naghavi | Abraham D. Flaxman | Catherine M. Michaud | Majid Ezzati | Kenji Shibuya | Joshua A. Salomon | Safa I. Abdalla | Victor Aboyans | Jerry Puthenpurakal Abraham | Ilana N. Ackerman | Rakesh Aggarwal | Stephanie Y. Ahn | Mohammed K. Ali | Miriam R. Alvarado | H. Ross Anderson | Laurie M. Anderson | Kathryn Gilman Andrews | Charles Atkinson | Larry M. Baddour | Adil N. Bahalim | Suzanne Lyn Barker-Collo | Lope Hugo Barrero | David H. Bartels | María Gloria Basáñez | Amanda J. Baxter | Michelle Lee Bell | Emelia J. Benjamin | Derrick A. Bennett | Eduardo Martínez Bernabé | Kavi S B Bhalla | Bishal B. Bhandari | Boris T. Bikbov | Aref Bin Abdulhak | Gretchen Lano Birbeck | James A. Black | Hannah Blencowe | Jed D. Blore | Fiona M. Blyth | Ian W. Bolliger | Audrey Bonaventure | Soufiane Boufous | Rupert Ra A Bourne | Michel Boussinesq | Tasanee Braithwaite | Carol E G Brayne | Lisa A. Bridgett | Simon J. Brooker | Peter M. Brooks | Traolach S. Brugha | Claire Bryan-Hancock | Chiara Bucello | Rachelle Buchbinder | Geoffrey C. Buckle | Christine M. Budke | Michael Burch | Peter G J Burney | Roy Burstein | Bianca Calabria | Benjamin Campbell | Charles E. Canter | Hélène Carabin | Jonathan Rhys Carapetis | Loreto. Carmona | Claudia Cella | Fiona J. Charlson | Honglei Chen | Andrew Cheng | David Chou | Sumeet S. Chugh | Luc Edgar Coffeng | Steven D. Colan | Samantha M. Colquhoun | K. Ellicott Colson | John R. Condon | Myles Dean Connor | Leslie Trumbull Cooper | Matthew A. Corriere | Monica Cortinovis | Karen Courville De Vaccaro | William G. Couser | Benjamin C. Cowie | Michael H. Criqui | Marita J. Cross | Kaustubh C. Dabhadkar | Manu Dahiya | Nabila A. Dahodwala | James Damsere-Derry | Goodarz Danaei | Adrian B. Davis | Diego De Leo | Louisa Degenhardt | Robert Nicole D Dellavalle | Allyne M. Delossantos | Julie O. Denenberg | Sarah Derrett | Don Des Des Des Jarlais | Samath D. Dharmaratne | Mukesh K. Dherani | Cèsar Díaz-Torné | Helen M. Dolk | Earl Ray Dorsey | Tim Robert Driscoll | Herbert C. Duber | Beth E. Ebel | Karen M. Edmond | Alexis Elbaz | Suad Eltahir Ali | Holly E. Erskine | Patricia J. Erwin | Patricia Espindola | Stalin E. Ewoigbokhan | Farshad Farzadfar | Valery L. Feigin | David T. Felson | Alize J. Ferrari | Cleusa Pinheiro Ferri | Eric Maurice Fèvre | Mariel M. Finucane | Seth R. Flaxman | Louise S. Flood | Kyle J. Foreman | Mohammad Hossein R Forouzanfar | Francis Gerald R Fowkes | Marlene K. Fransen | Michael K. Freeman | Belinda Dip Clin Gabbe | Sherine E. Gabriel | Emmanuela E. Gakidou | Hammad Ashraf Ganatra | Bianca Garcia | Flavio Gaspari | Richard Frank Gillum | Gerhard Gmel | Diego Gonzalez-Medina | Richard Andre Gosselin | Rebecca Grainger | Bridget F. Grant | Justina L. Groeger | Francis Guillemin | David J. Gunnell | Ramyani P. Gupta | Juanita A. Haagsma | Holly C. Hagan | Yara A. Halasa | Wayne D. Hall | Diana Haring | Josep María Aria Haro | James Edward Harrison | Rasmus Havmoeller | Roderick Hay | Hideki Higashi | Catherine L. Hill | Bruno Hoen | Howard J. Hoffman | Peter J. Hotez | D. G. Hoy | John J. Huang | Sydney E. Ibeanusi | Kathryn H. Jacobsen | Spencer L. James | Deborah L. Jarvis | Rashmi Jasrasaria | Sudha P. Jayaraman | Nicole E. Johns | Jost Bruno Jonas | Ganesan Karthikeyan | Nicholas Kassebaum | Norito Kawakami | André B. Keren | Jonpaul Khoo | Charles H. King | Lisa Marie Knowlton | Olive Chifefe Kobusingye | Adofo Koranteng | Rita V. Krishnamurthi | Francine Laden | Ratilal Lalloo | Laura Louise Laslett | Tim Lathlean | Janet L. Leasher | Yong Yi Lee | James Leigh | Daphna Levinson | Stephen Lim | Elizabeth S. Limb | Johnkent Lin | Michael S. Lipnick | Steven Lipshultz | Wei Liu | Maria A. Loane | Summerlockett Ohno | Ronan Anthony Lyons | Jacqueline R. Mabweijano | Michael F. MacIntyre | Reza Malekzadeh | Leslie Mallinger | Sivabalan Manivannan | Wagner Segura Marcenes | Lyn March | David J. Margolis | Guy Marks | Robin Marks | Akira Matsumori | Richard G. Matzopoulos | Bongani Mawethu Mayosi | John H. McAnulty | Mary McGrae McDermott | Neil W. McGill | John Joseph McGrath | María Elena Lena Medina-Mora | Michele Meltzer | George A. Mensah | Tony R. Merriman | Ana Claire Lew Meyer | Valeria Miglioli | Matthew Miller | Ted Olga Miller | Philip Bowden Mitchell | Charles Mock | Ana Olga H Mocumbi | Terrie E. Moffitt | Ali H I Mokdad | Lorenzo Monasta | Marcella Montico | Maziar Moradi-Lakeh | Andrew E. Moran | Lidia Morawska | Rintaro Mori | Michele E. Murdoch | Michael K. Mwaniki | Kovin Shunmugan Naidoo | Mani Nathan Nair | Luigi Naldi | Kabayam M Venkat Narayan | Paul K. Nelson | Robert G. Nelson | Michael C. Nevitt | Charles Richard J C Newton | Sandra Nolte | Paul E. Norman | Rosana E. Norman | Martin J. O'Donnell | Simon J. O'Hanlon | Casey Olives | Saad Bin Omer | Katrina F. Ortblad | Richard H. Osborne | Doruk E. Ozgediz | Andrew Nicholas Page | Bishnu Pahari | Jeyaraj Durai Pandian | Andrea Panozo Rivero | Scott B. Patten | Neil Perez Pearce | Rogelio Pérez Padilla | Fernando Pérez-Ruiz | Norberto Perico | Konrad Pesudovs | David E. Phillips | Michael Robert Phillips | Kelsey R. Pierce | Sébastien Ds S Pion | Guilherme Vanoni Polanczyk | Suzanne Polinder | Christopher Arden Pope | Svetlana R. Popova | Esteban L. Porrini | Farshad Pourmalek | Martin J. Prince | Rachel L. Pullan | Kapa D. Ramaiah | Dharani Ranganathan | Homie A. Razavi | Mathilda C. Regan | Jürgen T. Rehm | David B. Rein | Giuseppe Remuzzi | Kathryn J. Richardson | Frederick Rodriguez Rivara | Thomas J. Roberts | Carolyn A. Robinson | Felipe Rodríguez De Leòn | Luca Ronfani | Robin G W Room | Lisa C. Rosenfeld | Lesley Rushton | Ralph Sacco | Sukanta Saha | Uchechukwu K A Sampson | Lídia Sànchez-Riera | Ella Sanman | David C. Schwebel | James Graham Scott | María Seguí-Gómez | Saeid Shahraz | Donald S. Shepard | Hwashin Hyun Shin | Rupak Shivakoti | David K. Singh | Gitanjali M. Singh | Jasvinder A. Singh | Jessica Singleton | David A. Sleet | Karen S. Sliwa | Emma U R Smith | Jennifer Lawson Smith | Nicolas J C Stapelberg | Andrew C. Steer | Timothy Joseph Steiner | Wilma A. Stolk | Lars Jacob Acob Stovner | Christopher R. Sudfeld | Sana Syed | Giorgio Tamburlini | Mohammad M. Tavakkoli | Hugh Ringland Taylor | Jennifer A. Taylor | William J. Taylor | Bernadette A. Thomas | W. M. Thomson | George D. Thurston | Imad M. Tleyjeh | Marcello A. Tonelli | Jeffrey A. Towbin | Thomas Clement Truelsen | Miltiadis K. Tsilimbaris | Clotilde Ubeda | Eduardo A. Undurraga | Marieke J. Van Der Werf | Jim J. Van Os | Monica S. Vavilala | Narayanaswamy Venketasubramanian | Mengru Wang | Wenzhi Wang | Kerrianne Watt | David J. Weatherall | Martin A. Weinstock | Robert G. Weintraub | Marc G. Weisskopf | Myrna M. Weissman | Richard A. White | Harvey A M Whiteford | Natasha Wiebe | Steven Todd Wiersma | James James D Wilkinson | Hywel C G Williams | Sean R M Williams | Emma Witt | Frederick J. Wolfe | Anthony D. Woolf | Sarah K. Wulf | Ponhsiu Yeh | Anita Km M Zaidi | Zhijie Zheng | David H. Zonies | Alan D. Lopez
Background Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. Methods We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. Findings Global DALYs remained stable from 1990 (2 503 billion) to 2010 (2 490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia); rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010; (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs); stroke; (fifth in 1990; 19% increase); diarrhoeal diseases; (second in 1990; 51% decrease); and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. Interpretation Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results.
Volume 376, Issue 9747, October 2010, Pages 1147-1154
Johann Sebastian De Bono | Stéphane Oudard | Mustafa Özgüroĝlu | Steinbjørn L. Hansen | Jean Pascal H MacHiels | Ivo Kocák | Gwenaëlle Gravis | István Bodrogi | Mary J. Mackenzie | Liji Shen | Martin R. Roessner | Sunil P. Gupta | Oliver Sartor
Background Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. Methods We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m2 mitoxantrone intravenously over 15-30 min or 25 mg/m2 cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079. Findings 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95 CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95 CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95 CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303  patients vs mitoxantrone, 215 ) and diarrhoea (23  vs one [<1]). 28 (8) patients in the cabazitaxel group and five (1) in the mitoxantrone group had febrile neutropenia. Interpretation Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. Funding Sanofi-Aventis. © 2010 Elsevier Ltd.
Volume 378, Issue 9785, July 2011, Pages 31-40
Goodarz Danaei | Mariel M. Finucane | Yuan Lu | Gitanjali M. Singh | Melanie J. Cowan | Christopher J. Paciorek | Johnkent Lin | Farshad Farzadfar | Youngho Khang | Gretchen Anna Stevens | Mayuree Rao | Mohammed K. Ali | Leanne M. Riley | Carolyn A. Robinson | Majid Ezzati
Data for trends in glycaemia and diabetes prevalence are needed to understand the effects of diet and lifestyle within populations, assess the performance of interventions, and plan health services. No consistent and comparable global analysis of trends has been done. We estimated trends and their uncertainties in mean fasting plasma glucose (FPG) and diabetes prevalence for adults aged 25 years and older in 199 countries and territories. We obtained data from health examination surveys and epidemiological studies (370 country-years and 2·7 million participants). We converted systematically between different glycaemic metrics. For each sex, we used a Bayesian hierarchical model to estimate mean FPG and its uncertainty by age, country, and year, accounting for whether a study was nationally, subnationally, or community representative. In 2008, global age-standardised mean FPG was 5·50 mmol/L (95 uncertainty interval 5·37-5·63) for men and 5·42 mmol/L (5·29-5·54) for women, having risen by 0·07 mmol/L and 0·09 mmol/L per decade, respectively. Age-standardised adult diabetes prevalence was 9·8 (8·6- 11·2) in men and 9·2 (8·0-10·5) in women in 2008, up from 8·3 (6·5-10·4) and 7·5 (5·8-9·6) in 1980. The number of people with diabetes increased from 153 (127-182) million in 1980, to 347 (314-382) million in 2008. We recorded almost no change in mean FPG in east and southeast Asia and central and eastern Europe. Oceania had the largest rise, and the highest mean FPG (6·09 mmol/L, 5·73-6·49 for men; 6·08 mmol/L, 5·72-6·46 for women) and diabetes prevalence (15·5, 11·6-20·1 for men; and 15·9, 12·1-20·5 for women) in 2008. Mean FPG and diabetes prevalence in 2008 were also high in south Asia, Latin America and the Caribbean, and central Asia, north Africa, and the Middle East. Mean FPG in 2008 was lowest in sub-Saharan Africa, east and southeast Asia, and high-income Asia-Pacific. In high-income subregions, western Europe had the smallest rise, 0·07 mmol/L per decade for men and 0·03 mmol/L per decade for women; North America had the largest rise, 0·18 mmol/L per decade for men and 0·14 mmol/L per decade for women. Glycaemia and diabetes are rising globally, driven both by population growth and ageing and by increasing age-specific prevalences. Effective preventive interventions are needed, and health systems should prepare to detect and manage diabetes and its sequelae. Bill & Melinda Gates Foundation and WHO. © 2011 Elsevier Ltd.
Volume 375, Issue 9726, April 2010, Pages 1609-1623
Margaret C. Hogan | Kyle J. Foreman | Mohsen Naghavi | Stephanie Y. Ahn | Mengru Wang | Susanna M. Makela | Alan D. Lopez | Rafael Lozano | Christopher JL L L Murray
Background: Maternal mortality remains a major challenge to health systems worldwide. Reliable information about the rates and trends in maternal mortality is essential for resource mobilisation, and for planning and assessment of progress towards Millennium Development Goal 5 (MDG 5), the target for which is a 75% reduction in the maternal mortality ratio (MMR) from 1990 to 2015. We assessed levels and trends in maternal mortality for 181 countries. Methods: We constructed a database of 2651 observations of maternal mortality for 181 countries for 1980-2008, from vital registration data, censuses, surveys, and verbal autopsy studies. We used robust analytical methods to generate estimates of maternal deaths and the MMR for each year between 1980 and 2008. We explored the sensitivity of our data to model specification and show the out-of-sample predictive validity of our methods. Findings: We estimated that there were 342 900 (uncertainty interval 302 100-394 300) maternal deaths worldwide in 2008, down from 526 300 (446 400-629 600) in 1980. The global MMR decreased from 422 (358-505) in 1980 to 320 (272-388) in 1990, and was 251 (221-289) per 100 000 livebirths in 2008. The yearly rate of decline of the global MMR since 1990 was 1·3% (1·0-1·5). During 1990-2008, rates of yearly decline in the MMR varied between countries, from 8·8% (8·7-14·1) in the Maldives to an increase of 5·5% (5·2-5·6) in Zimbabwe. More than 50% of all maternal deaths were in only six countries in 2008 (India, Nigeria, Pakistan, Afghanistan, Ethiopia, and the Democratic Republic of the Congo). In the absence of HIV, there would have been 281 500 (243 900-327 900) maternal deaths worldwide in 2008. Interpretation: Substantial, albeit varied, progress has been made towards MDG 5. Although only 23 countries are on track to achieve a 75% decrease in MMR by 2015, countries such as Egypt, China, Ecuador, and Bolivia have been achieving accelerated progress. Funding: Bill & Melinda Gates Foundation. © 2010 Elsevier Ltd. All rights reserved.
Volume 377, Issue 9784, June 2011, Pages 2181-2192
Colin N. Baigent | Martin J. Landray | Christina Reith | Jonathan Robert Emberson | David C. Wheeler | Charles Richard V Tomson | Christoph Wanner | Vera Krane | Alan Cass | Jonathan C. Craig | Bruce Charles Neal | Lixin Jiang | Lai Seong C Hooi | Adeera Levin | Lawrence Y C Agodoa | Michael J. Gaziano | Bertram L. Kasiske | Robert James Walker | Ziad A. Massy | Bo F. Feldt- Rasmussen | Udom Krairittichai | Vuddidhej Ophascharoensuk | Bengt C. Fellström | Hallvard Holdaas | Vladimír Tesař | Andrzej Wiȩcek | Diederick Egbertus Grobbee | Dick De Zeeuw | Carola Grönhagen-Riska | Tanaji Dasgupta | David A. Lewis | William Guy Herrington | Marion M. Mafham | William Majoni | Karl R. Wallendszus | Richard H. Grimm | Terje Rolf Pedersen | Jonathan A. Tobert | Jane M. Armitage | Alexander B. Baxter | Christopher J. Bray | Yiping Chen | Zhengming Chen | Michael R S Hill | Carol Knott | Sarah E. Parish | David J. Simpson | Peter J. Sleight | Allan H. Young | Rory E. Collins
Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17 proportional reduction in major atherosclerotic events (526 [11·3] simvastatin plus ezetimibe vs 619 [13·4] placebo; rate ratio [RR] 0·83, 95 CI 0·74-0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6] vs 230 [5·0]; RR 0·92, 95 CI 0·76-1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8] vs 174 [3·8]; RR 0·75, 95 CI 0·60-0·94; p=0·01) and arterial revascularisation procedures (284 [6·1] vs 352 [7·6]; RR 0·79, 95 CI 0·68-0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2] vs 5 [0·1]). There was no evidence of excess risks of hepatitis (21 [0·5] vs 18 [0·4]), gallstones (106 [2·3] vs 106 [2·3]), or cancer (438 [9·4] vs 439 [9·5], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4] vs 612 [13·2], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council. © 2011 Elsevier Ltd.
Volume 375, Issue 9727, May 2010, Pages 1695-1703
Kennedy R. Lees | Erich Bluhmki | Rüdiger D. Von Kummer | Thomas G. Brott | Danilo Toni | James C. Grotta | Gregory W. Albers | Markku Kaste | John R. Marler | Scott A. Hamilton | Barbara C. Tilley | Stephen M. Davis | Geoffrey A Donnan | Werner Hacke
Background: Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis. Methods: We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis. Findings: Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0·0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2·55 (95% CI 1·44-4·52) for 0-90 min, 1·64 (1·12-2·40) for 91-180 min, 1·34 (1·06-1·68) for 181-270 min, and 1·22 (0·92-1·61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5·2%) of 1850 patients assigned to alteplase and 18 (1·0%) of 1820 controls, with no clear relation to OTT (p=0·4140). Adjusted odds of mortality increased with OTT (p=0·0444) and were 0·78 (0·41-1·48) for 0-90 min, 1·13 (0·70-1·82) for 91-180 min, 1·22 (0·87-1·71) for 181-270 min, and 1·49 (1·00-2·21) for 271-360 min. Interpretation: Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4·5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4·5 h, risk might outweigh benefit. Funding: None. © 2010 Elsevier Ltd. All rights reserved.
Volume 375, Issue 9716, February 2010, Pages 735-742
Naveed A. Sattar | David J. Preiss | Heather M. Murray | Paul I. Welsh | Brendan M. Buckley | Anton Jm M De Craen | Sreenivasa Rao Kondapally Seshasai | John J V V McMurray | Dilys J. Freeman | Johan Wouter Outer Jukema | Peter W. MacFarlane | Chris J. Packard | David J. Stott | Rudi Gj J Westendorp | James Banks Shepherd . | Barry R. Davis | Sara L. Pressel | Roberto Marchioli | Rosa Maria Marfisi | Aldo Pietro Ietro Maggioni | Luigi Tavazzi | Gianni Tognoni | John K. Kjekshus | Terje Rolf Pedersen | Thomas Cook | Jr Gotto | Michael B. Clearfield | John R. Downs | Haruo Nakamura | Yasuo Ohashi | Kyoichi Mizuno | Kausik Kausik Ray | Ian Ford
Background: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. Methods: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I2 statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. Findings: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02-1·17), with little heterogeneity (I2=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. Interpretation: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. Funding: None. © 2010 Elsevier Ltd. All rights reserved.
Volume 375, Issue 9726, April 2010, Pages 1624-1633
Wendy S. Atkin | Robert P. Edwards | Ines Kralj-Hans | Kate M. Wooldrage | Andrew R. Hart | John MA A Northover | Donald Maxwell Parkin | Jane C R Wardle | Stephen William Duffy | Jack M. Cuzick
Background: Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. Methods: This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. Findings: 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11·2 years (IQR 10·7-11·9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0·77, 95% CI 0·70-0·84) and mortality by 31% (0·69, 0·59-0·82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0·67, 0·60-0·76) and mortality by 43% (0·57, 0·45-0·72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0·50, 0·42-0·59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. Interpretation: Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. Funding: Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed. © 2010 Elsevier Ltd. All rights reserved.
Volume 375, Issue 9709, January 2010, Pages 132-140
Background: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. Methods: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1·31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. Results: Log e CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log e CRP concentration (three-fold higher) were 1·63 (95% CI 1·51-1·76) when initially adjusted for age and sex only, and 1·37 (1·27-1·48) when adjusted further for conventional risk factors; 1·44 (1·32-1·57) and 1·27 (1·15-1·40) for ischaemic stroke; 1·71 (1·53-1·91) and 1·55 (1·37-1·76) for vascular mortality; and 1·55 (1·41-1·69) and 1·54 (1·40-1·68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1·23 (1·07-1·42) for coronary heart disease; 1·32 (1·18-1·49) for ischaemic stroke; 1·34 (1·18-1·52) for vascular mortality; and 1·34 (1·20-1·50) for non-vascular mortality. Interpretation: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. Funding: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline. © 2010 Elsevier Ltd. All rights reserved.
Volume 376, Issue 9756, December 2010, Pages 1923-1958
Julio J. Frenk | Lincoln Chen | Zulfiqar Ahmed Bhutta | Jordan John Cohen | Nigel G. Crisp | Timothy G. Evans | Harvey V. Fineberg | Patricía J. García | Yang Ke | Patrick W. Kelley | Barry Kistnasamy | Afaf Ibrahim Meleis | David H. Naylor | Ariel Pablos-Méndez | Srinath K. Reddy | Susan C M Scrimshaw | Jaime Sepúlveda | David M. Serwadda | Huda C. Zurayk
Background Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess eff ectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. Methods In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (?150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary eff ectiveness endpoint was change in seated offi ce-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. Findings 106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Offi ce-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0?0001), whereas they did not diff er from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0?77 systolic and p=0?83 diastolic). Between-group diff erences in blood pressure at 6 months were 33/11 mm Hg (p<0?0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0?0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not diff er between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. Interpretation Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatmentresistant hypertensive patients. Funding Ardian.
Volume 377, Issue 9768, March 2011, Pages 813-822
Karim S. Fizazi | Michael A. Carducci | Matthew R W Smith | Ronaldo Damião | Janet E. Brown | Lawrence I. Karsh | Piotr Milecki | Neal D. Shore | Michael Rader | Huei Wang | Qi Jiang | Sylvia Tadros | Roger Delemere Dansey | Carsten Goeßl
Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95 CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95 CI 0·71-0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97) on denosumab and 918 patients (97) on zoledronic acid, and serious adverse events were recorded in 594 patients (63) on denosumab and 568 patients (60) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 ) than in the zoledronic acid group (55 ; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22  vs 12 ; p=0·09). Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Amgen. © 2011 Elsevier Ltd.
Volume 376, Issue 9744, September 2010, Pages 875-885
Karl B. Swedberg | Michel Komajda | Michael P. Böhm | Jeffrey S. Borer | Ian Ford | Ariane Dubost-Brama | Guy Lerebours | Luigi Tavazzi
Background Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. Methods Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35 or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7·5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. Findings 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22·9 (IQR 18-28) months. 793 (24) patients in the ivabradine group and 937 (29) of those taking placebo had a primary endpoint event (HR 0·82, 95 CI 0·75-0·90, p<0·0001). The effects were driven mainly by hospital admissions for worsening heart failure (672  placebo vs 514  ivabradine; HR 0·74, 0·66-0·83; p<0·0001) and deaths due to heart failure (151  vs 113 ; HR 0·74, 0·58-0·94, p=0·014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0·025). 150 (5) of ivabradine patients had symptomatic bradycardia compared with 32 (1) of the placebo group (p<0·0001). Visual side-effects (phosphenes) were reported by 89 (3) of patients on ivabradine and 17 (1) on placebo (p<0·0001). Interpretation Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. Funding Servier, France. © 2010 Elsevier Ltd.
Volume 376, Issue 9735, June 2010, Pages 112-123
Martin J. O'Donnell | Xavier Denis | Lisheng Liu | Hongye Zhang | SiuLim Chin | Purnima Rao-Melacini | Sumathy Rangarajan | Shofiqul Islam | Prem S. Pais | Matthew J. McQueen | Charles Kiiza Mondo | Albertino A M Damasceno | Patricio López-Jaramillo | Graeme J. Hankey | Antonio L. Dans | Khalid Yusoff | Thomas Clement Truelsen | Hans Christoph W Diener | Ralph Sacco | Danuta Krystyna Ryglewicz | Anna Członkowska | Christian Weimar | Xingyu Wang | Salim M. Yusuf
Background The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. Methods We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. Findings In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2·64, 99% CI 2·26-3·08; PAR 34·6%, 99% CI 30·4-39·1); current smoking (2·09, 1·75-2·51; 18·9%, 15·3-23·1); waist-to-hip ratio (1·65, 1·36-1·99 for highest vs lowest tertile; 26·5%, 18·8-36·0); diet risk score (1·35, 1·11-1·64 for highest vs lowest tertile; 18·8%, 11·2-29·7); regular physical activity (0·69, 0·53-0·90; 28·5%, 14·5-48·5); diabetes mellitus (1·36, 1·10-1·68; 5·0%, 2·6-9·5); alcohol intake (1·51, 1·18-1·92 for more than 30 drinks per month or binge drinking; 3·8%, 0·9-14·4); psychosocial stress (1·30, 1·06- 1·60; 4·6%, 2·1-9·6) and depression (1·35, 1·10-1·66; 5·2%, 2·7-9·8); cardiac causes (2·38, 1·77-3·20; 6·7%, 4·8-9·1); and ratio of apolipoproteins B to A1 (1·89, 1·49-2·40 for highest vs lowest tertile; 24·9%, 15·7-37·1). Collectively, these risk factors accounted for 88·1% (99% CI 82·3-92·2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90·3% (85·3-93·7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. Interpretation Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.
Volume 379, Issue 9822, March 2012, Pages 1245-1255
Alejandro Forner | Josep María Llovet | Jordi Bruix
Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50 can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread not amenable to curative treatments, chemoembolisation can provide survival benefit. Findings of randomised trials of sorafenib have shown survival benefits for individuals with advanced hepatocellular carcinoma, suggesting that molecular-targeted therapies could be effective in this chemoresistant cancer. Research is active in the area of pathogenesis and treatment of hepatocellular carcinoma. © 2012 Elsevier Ltd.
Volume 380, Issue 9859, December 2012, Pages 2163-2196
Theo Vos | Abraham D. Flaxman | Mohsen Naghavi | Rafael Lozano | Catherine M. Michaud | Majid Ezzati | Kenji Shibuya | Joshua A. Salomon | Safa I. Abdalla | Victor Aboyans | Jerry Puthenpurakal Abraham | Ilana N. Ackerman | Rakesh Aggarwal | Stephanie Y. Ahn | Mohammed K. Ali | Miriam R. Alvarado | H. Ross Anderson | Laurie M. Anderson | Kathryn Gilman Andrews | Charles Atkinson | Larry M. Baddour | Adil N. Bahalim | Suzanne Lyn Barker-Collo | Lope Hugo Barrero | David H. Bartels | María Gloria Basáñez | Amanda J. Baxter | Michelle Lee Bell | Emelia J. Benjamin | Derrick A. Bennett | Eduardo Martínez Bernabé | Kavi S B Bhalla | Bishal B. Bhandari | Boris T. Bikbov | Aref Bin Abdulhak | Gretchen Lano Birbeck | James A. Black | Hannah Blencowe | Jed D. Blore | Fiona M. Blyth | Ian W. Bolliger | Audrey Bonaventure | Soufiane Boufous | Rupert Ra A Bourne | Michel Boussinesq | Tasanee Braithwaite | Carol E G Brayne | Lisa A. Bridgett | Simon J. Brooker | Peter M. Brooks | Traolach S. Brugha | Claire Bryan-Hancock | Chiara Bucello | Rachelle Buchbinder | Geoffrey C. Buckle | Christine M. Budke | Michael Burch | Peter G J Burney | Roy Burstein | Bianca Calabria | Benjamin Campbell | Charles E. Canter | Hélène Carabin | Jonathan Rhys Carapetis | Loreto. Carmona | Claudia Cella | Fiona J. Charlson | Honglei Chen | Andrew Cheng | David Chou | Sumeet S. Chugh | Luc Edgar Coffeng | Steven D. Colan | Samantha M. Colquhoun | K. Ellicott Colson | John R. Condon | Myles Dean Connor | Leslie Trumbull Cooper | Matthew A. Corriere | Monica Cortinovis | Karen Courville De Vaccaro | William G. Couser | Benjamin C. Cowie | Michael H. Criqui | Marita J. Cross | Kaustubh C. Dabhadkar | Manu Dahiya | Nabila A. Dahodwala | James Damsere-Derry | Goodarz Danaei | Adrian B. Davis | Diego De Leo | Louisa Degenhardt | Robert Nicole D Dellavalle | Allyne M. Delossantos | Julie O. Denenberg | Sarah Derrett | Don Des Des Des Jarlais | Samath D. Dharmaratne | Mukesh K. Dherani | Cèsar Díaz-Torné | Helen M. Dolk | Earl Ray Dorsey | Tim Robert Driscoll | Herbert C. Duber | Beth E. Ebel | Karen M. Edmond | Alexis Elbaz | Suad Eltahir Ali | Holly E. Erskine | Patricia J. Erwin | Patricia Espindola | Stalin E. Ewoigbokhan | Farshad Farzadfar | Valery L. Feǐgin | David T. Felson | Alize J. Ferrari | Cleusa Pinheiro Ferri | Eric Maurice Fèvre | Mariel M. Finucane | Seth R. Flaxman | Louise S. Flood | Kyle J. Foreman | Mohammad Hossein R Forouzanfar | Francis Gerald R Fowkes | Richard Charles Franklin | Marlene K. Fransen | Michael K. Freeman | Belinda Dip Clin Gabbe | Sherine E. Gabriel | Emmanuela E. Gakidou | Hammad Ashraf Ganatra | Bianca Garcia | Flavio Gaspari | Richard Frank Gillum | Gerhard Gmel | Dieg Gonzalez-Medina | Richard Andre Gosselin | Rebecca Grainger | Bridge Grant | Justina L. Groeger | Francis Guillemin | David J. Gunnell | Ramyani P. Gupta | Juanita A. Haagsma | Holly C. Hagan | Yara A. Halasa | Wayne D. Hall | Diana Haring | Josep María Aria Haro | James Edward Harrison | Rasmus Havmoeller | Roderick Hay | Hideki Higashi | Catherine L. Hill | Bruno Hoen | Howard J. Hoffman | Peter J. Hotez | D. G. Hoy | John J. Huang | Sydney E. Ibeanusi | Kathryn H. Jacobsen | Spencer L. James | Deborah L. Jarvis | Rashmi Jasrasaria | Sudha P. Jayaraman | Nicole E. Johns | Jost Bruno Jonas | Ganesan Karthikeyan | Nicholas Kassebaum | Norito Kawakami | André B. Keren | Jonpaul Khoo | Charles H. King | Lisa Marie Knowlton | Olive Chifefe Kobusingye | Adofo Koranteng | Rita V. Krishnamurthi | Francine Laden | Ratilal Lalloo | Laura Louise Laslett | Tim Lathlean | Janet L. Leasher | Yong Yi Lee | James Leigh | Daphn Levinson | Stephen Lim | Elizabeth S. Limb | Johnkent Lin | Michael S. Lipnick | Steven Lipshultz | Wei Liu | Maria A. Loane | Summerlockett Ohno | Ronan Anthony Lyons | Jixiang Ma | Jacqueline R. Mabweijano | Michael F. MacIntyre | Reza Malekzadeh | Leslie Mallinger | Sivabalan Manivannan | Wagner Segura Marcenes | Lyn March | David J. Margolis | Guy Marks | Robin Marks | Akira Matsumori | Richard G. Matzopoulos | Bongani Mawethu Mayosi | John H. McAnulty | Mary McGrae McDermott | Neil W. McGill | John Joseph McGrath | María Elena Lena Medina-Mora | Michele Meltzer | George A. Mensah | Tony R. Merriman | Ana Claire Lew Meyer | Valeria Miglioli | Matthew Miller | Ted Olga Miller | Philip Bowden Mitchell | Charles Mock | Ana Olga H Mocumbi | Terrie E. Moffitt | Ali H I Mokdad | Lorenzo Monasta | Marcella Montico | Andrew E. Moran | Lidia Morawska | Rintaro Mori | Michele E. Murdoch | Michael K. Mwaniki | Kovin Shunmugan Naidoo | Mani Nathan Nair | Luigi Naldi | Kabayam M Venkat Narayan | Paul K. Nelson | Robert G. Nelson | Michael C. Nevitt | Charles Richard J C Newton | Sandra Nolte | Paul E. Norman | Rosana E. Norman | Martin J. O'Donnell | Simon J. O'Hanlon | Casey Olives | Saad Bin Omer | Katrina F. Ortblad | Richard H. Osborne | Doruk E. Ozgediz | Andrew Nicholas Page | Bishnu Pahari | Jeyaraj Durai Pandian | Andrea Panozo Rivero | Scott B. Patten | Neil Perez Pearce | Rogelio Pérez Padilla | Fernando Pérez-Ruiz | Norberto Perico | Konrad Pesudovs | David E. Phillips | Michael Robert Phillips | Kelsey R. Pierce | Sébastien Ds S Pion | Guilherme Vanoni Polanczyk | Suzanne Polinder | Christopher Arden Pope | Svetlana R. Popova | Esteban L. Porrini | Farshad Pourmalek | Martin J. Prince | Rachel L. Pullan | Kapa D. Ramaiah | Dharani Ranganathan | Homie A. Razavi | Mathilda C. Regan | Jürgen T. Rehm | David B. Rein | Giuseppe Remuzzi | Kathryn J. Richardson | Frederick Rodriguez Rivara | Thomas J. Roberts | Carolyn A. Robinson | Felipe Rodríguez De Leòn | Luca Ronfani | Robin G W Room | Lisa C. Rosenfeld | Lesley Rushton | Ralph Sacco | Sukanta Saha | Uchechukwu K A Sampson | Lídia Sànchez-Riera | Ella Sanman | David C. Schwebel | James Graham Scott | María Seguí-Gómez | Saeid Shahraz | Donald S. Shepard | Hwashin Hyun Shin | Rupak Shivakoti | David K. Singh | Gitanjali M. Singh | Jasvinder A. Singh | Jessica Singleton | David A. Sleet | Karen S. Sliwa | Emma U R Smith | Jennifer Lawson Smith | Nicolas J C Stapelberg | Andrew C. Steer | Timothy Joseph Steiner | Wilma A. Stolk | Lars Jacob Acob Stovner | Christopher R. Sudfeld | Sana Syed | Giorgio Tamburlini | Mohammad M. Tavakkoli | Hugh Ringland Taylor | Jennifer A. Taylor | William J. Taylor | Bernadette A. Thomas | W. M. Thomson | George D. Thurston | Imad M. Tleyjeh | Marcello A. Tonelli | Jeffrey A. Towbin | Thomas Clement Truelsen | Miltiadis K. Tsilimbaris | Clotilde Ubeda | Eduardo A. Undurraga | Marieke J. Van Der Werf | Jim J. Van Os | Monica S. Vavilala | Narayanaswamy Venketasubramanian | Mengru Wang | Wenzhi Wang | Kerrianne Watt | David J. Weatherall | Martin A. Weinstock | Robert G. Weintraub | Marc G. Weisskopf | Myrna M. Weissman | Richard A. White | Harvey A M Whiteford | Natasha Wiebe | Steven Todd Wiersma | James James D Wilkinson | Hywel C G Williams | Sean R M Williams | Emma Witt | Frederick J. Wolfe | Anthony D. Woolf | Sarah K. Wulf | Ponhsiu Yeh | Anita Km M Zaidi | Zhijie Zheng | David H. Zonies | Alan D. Lopez | Christopher JL L L Murray | Maziar Moradi-Lakeh
Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality); or registration completeness models; (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0 37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world.
Volume 376, Issue 9737, July 2010, Pages 235-244
Andrew N J Tutt | Mark E. Robson | Judy Ellen Garber | Susan M. Domchek | M. William Audeh | Jeffrey Weitzel | Michael Leonard Eonard Friedlander | Banu K. Arun | Niklas Loman | Rita Katharina Schmutzler | Andrew M. Wardley | Gillian W Erle Mitchell | Helena M. Earl | Mark M. Wickens | James Carmichael
Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.
Volume 375, Issue 9719, March 2010, Pages 985-997
Jörg Ederle | Joanna E. Dobson | Roland L. Featherstone | Leo H. Bonati | Henk Bart Van Der Worp | Gert Jan An De Borst | T. Hauw Lo | Peter A. Gaines | Paul J. Dorman | Sumaira Macdonald | Philippe A. Lyrer | Johanna M H Hendriks | Charles N. McCollum | Paul J. Nederkoorn | Martin M. Brown | Ale Algra | John M. Bamford | Martin J. Bland | Werner Hacke | Jean Louís Mas. | Ali J. McGuire | Pushpinder Singh Sidhu | Andrew W. Bradbury | Rory E. Collins | Andrew J. Molyneux | Ross Naylor | Charles P. Warlow | Maurizio A. Ferro | Daffyd J. Thomas | R. F. Featherstone | H. Tindall | Dominick JH H McCabe | A. M. Wallis | Lucy J. Coward | Matthew J. Brooks | Brian R. Chambers | Albert Chan | P. Chu | David J. Clark | Helen M. Dewey | Geoffrey A Donnan | Gary Fell | M. Hoare | Maurice P. Molan | Andrew K. Roberts | Neil G. Roberts | Barry C. Beiles | Christopher F. Bladin | ChristineA Clifford | Michael J. Grigg | Gishel New | Roger C. Bell | Simon P C Bower | Winston Chong | Michael D. Holt | Alan C. Saunder | P. G. Than | S. S. Gett | David A C Leggett | Timothy J. McGahan | John M. Quinn | Mark Ray | Andrew Wong | Peter W H Woodruff | Robert K. Foreman | David W. Schultz | Rebecca Scroop | Brendan M. Stanley | Bernard Allard | Noel R. Atkinson | W. Cambell | Simon W V Davies | Peter L. Field | Peter Y. Milne | Peter J. Mitchell | Brian M. Tress | Bernard Yan | Anthony Beasley | David W. Dunbabin | David R. Starý | Stuart Robert Walker | Patrick Cras | Olivier C M D'Archambeau | Jeroen M H Hendriks | Paul E Y Van Schil | Marc Bosiers | Koen R. Deloose | E. Van Buggenhout | Jan A M De Letter | Virginie Devos | J. Ghekiere | Geert T O Vanhooren | Parla Astarci | Frank Dieter Hammer | Valérie H. Lacroix | André Philippe Peeters | Robert R. Verhelst | Luk DeJaegher | Anna Peeters | Jürgen Verbist | Jean François Blair | Joanna L. Caron | Nicole Daneault | Marie France Giroux | François Guilbert | Sylvain Lanthier | Louise Hélène Lebrun | Vincent L. Oliva | Jean Philippe Raymond | Daniel Roy | Gilles Soulez | Alain Weill | Michael R S Hill | William Hu | M. Hudion | William F. Morrish | Garnette Roy Sutherland | John Wong | Anders N. Albäck | H. Harno | Petra Ijäs | Markku Kaste | Mauri J A Lepäntalo | Satu M. Mustanoja | Tapio Paananen | Matti Porras | Jukka Putaala | Mikael J. Railo | Tiina R. Sairanen | Lauri Soinne | A. Vehmas | Pirkka Vikatmaa | Michael Wolfgang Goertler | Zuhir Halloul | Martin D. Skalej | Paul R. Brennan | Cathal J. Kelly | Austin L. Leahy | Joan T. Moroney | John M. Thornton | Mark J W Koelemay | Jim A A Reekers | Yvo Bwem W E M Roos | Joke M. Hendriks | Peter Jan Koudstaal | Peter Mt Th Pattynama | Aad Van Der Lugt | Lukas C. Van Dijk | M. Van Sambeek | Hero Van Urk | Hence Jm M P Verhagen | Cornelis Maria Adrianus Bruijninckx | Sebastiaan Ftm T M De Bruijn | Ruud W M Keunen | Bob Knippenberg | Arne Mosch | Frank E E Treurniet | Laurens J. Van Dijk | Hans Van Overhagen | Jan J. Wever | F. C. de Beer | Jan S P Peter Van Den Berg | Boudewijn A A M Van Hasselt | Dick J. Zeilstra | Jelis Boiten | Johan Coenraad Alexander De Mol Van Otterloo | Alexander C. De Vries | Geert J. Lycklama À Nijeholt | Bas F W Van Der Kallen | Jan D. Blankensteijn | Frank Erik De Leeuw | Leo J M D Schultze Kool | Johannes Adam Daan Van Der Vliet | Gérard A P De Kort | L. J. Kapelle | Tjoen H. Lo | Willem Pthm Th M M Mali | F. L. Moll | H. Verhagen | Philip A. Barber | R. Bourchier | Alan J. Hill | Annie Holden | James T. Stewart | Sören Jacob Bakke | Kirsten Krohg Krohg-Sørensen | Mona Skjelland | Bjørn Tennøe | Paweł Białek | Zbigniew Biejat | Wojciech Czepiel | Anna Członkowska | Anatol Dowzenko | Julia Jedrzejewska | Adam Kobayashi | M. Lelek | Jerzy A. Polański | Janez Kirbiš | Zoran V. Milošević | Bojana Žvan | Jordi Blasco | Ángel L. Chamorro | Juan M. MacHo | Víctor Obach | Vicente A. Riambau | Luís San Román | Jordi Branera | David Cánovas | Jordi Estela | Antonio Giménez Gaibar | Joan Perendreu | Katarina Björses | Anders Gottsäter | Krassi Ivancev | T. Maetzsch | Björn Sonesson | Bruce O. Berg | Martin Delle | Johan Formgren | Peter Gillgren | Tor Björn Käll | Peter I. Konrad | N. Nyman | Rabbe J. Takolander | Tommy B. Andersson | Jonas Malmstedt | Michael Söderman | Carl Magnus Wahlgren | Nils Gunnar Wahlgren | Stefano Binaghi | Lorenz Hirt | Patrik A. Michel | Patrick M. Ruchat | Stefan T. Engelter | Felix Fluri | Lorenz Guerke | Augustinus Ludwig Jacob | Eberhard C. Kirsch | Ernst Wilhelm Radüe | Peter Stierli | Morten G. Wasner | Stephan G. Wetzel | Christophe Bonvin | Afksendiyos Kalangos | Karl Olof Lövblad | Nicolas Mürith | Daniel A. Ruefenacht | Roman Felix Sztajzel | Nicholas J P Higgins | Peter John Kirkpatrick | Peter J. Martin | Donald J. Adam | Jocelyn L. Bell | Andrew W. Bradbury | Philip John Crowe | Mark Xavier Gannon | Michael John Henderson | David L. Sandler | Roger A. Shinton | J. M. Scriven | Teun B M Wilmink | Sean B. D'Souza | Anselm A. Egun | R. Guta | S. Punekar | Dare Mutiyu Seriki | George J L Thomson | John A. Brennan | Thyge Peter Enevoldson | G. I. Gilling-Smith | David A. Gould | Peter Lyon H Harris | Richard Gregory McWilliams | H. C. Nasser | Richard Patrick White | K. G. Prakash | Ferdinand Serracino-Inglott | Ganesh Mani Subramanian | J. V. Symth | Michael G. Walker | Mike J. Clarke | Mark A. Davis | Sanat A. Dixit | Philip J. Dorman | Alexander G. Dyker | Gary A. Ford | Armita Golkar | Ralph W. Jackson | Vijayam K. Jayakrishnan | David L. Lambert | Tim A. Lees | Stephen J. Louw | Alexander David Mendelow | Helen C. Rodgers | John D G Rose | Gerard Patrick Stansby | Michael Graham Wyatt | Tony H. Baker | N. J. Baldwin | Linda S. Jones | David Charles Mitchell | Euan N. Munro | Marianne Kathleen Thornton | Daryll M. Baker | Nicola G. Davis | George A. Hamilton | Daniel J H McCabe | Andrew D. Platts | Jonathan M. Tibballs | Jonathan D. Beard | Trevor J. Cleveland | Dominic P. Dodd | Peter A. Gaines | Robert J. Lonsdale | Rajesh U. Nair | Ahmad H. Nassef | Shah Nawaz | Graham S. Venables | Anna Maria Aria Belli | Andrew G. Clifton | Geoffrey Christopher Cloud | Alison W. Halliday | Hugh Stephen Markus | Robert J. McFarland | Robert Anthony Morgan | Anthony C G Pereira | Andrew G B Thompson | Jeremy Chataway | Nicholas J W Cheshire | Richard G J Gibbs | M. Hammady | Michael P. Jenkins | Iqbal S. Malik | John H N Wolfe | Mohan A. Adiseshiah | Christopher C R Bishop | Stefan Brew | Jocelyn A S Brookes | Rolf Hans Jäger | Neil D. Kitchen | Raymond Joel Ashleigh | Stephen Butterfield | Giles E. Gamble | Akhtar Nasim | Paul A. O'Neill | Julian C L Wong | Richard David Edwards | Kennedy R. Lees | Alison J. Mackay | Jonathan G. Moss | Paul N. Rogers
Background: Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods: The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings: The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4·0%) events of disabling stroke or death in the stenting group compared with 27 (3·2%) events in the endarterectomy group (hazard ratio [HR] 1·28, 95% CI 0·77-2·11). The incidence of stroke, death, or procedural myocardial infarction was 8·5% in the stenting group compared with 5·2% in the endarterectomy group (72 vs 44 events; HR 1·69, 1·16-2·45, p=0·006). Risks of any stroke (65 vs 35 events; HR 1·92, 1·27-2·89) and all-cause death (19 vs seven events; HR 2·76, 1·16-6·56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0·0197). Interpretation: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. Funding: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union. © 2010 Elsevier Ltd. All rights reserved.