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1. Cardiac arrhythmias and conduction abnormalities in patients with type 2 diabetes

Author

Araz Rawshani, Darren K. McGuire, Elmir Omerovic, Naveed Sattar, John J. V. McMurray, Ulf Smith, Bjorn Redfors, Lennart Bergfeldt, Bjorn Eliasson, Jan Borén, Deepak L. Bhatt, Goran Bergstrom, and Aidin Rawshani

Subjects
Medicine, Science
Abstract

Abstract The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D.

Published
2023
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2. Initiation of domiciliary care and nursing home admission following first hospitalization for heart failure, stroke, chronic obstructive pulmonary disease or cancer

Author

Rasmus Rørth, Marianne F. Clausen, Emil L. Fosbøl, Ulrik M. Mogensen, Kristian Kragholm, Pardeep S. Jhund, Mark C. Petrie, Christian Torp-Pedersen, Gunnar H. Gislason, John J. V. McMurray, Lars Køber, and Søren L. Kristensen

Subjects
Medicine, Science
Abstract

Background Patients with chronic diseases are at higher risk of requiring domiciliary and nursing home care, but how different chronic diseases compare in terms of risk is not known. We examined initiation of domiciliary care and nursing home admission among patients with heart failure (HF), stroke, COPD and cancer. Methods Patients with a first-time hospitalization for HF, stroke, COPD or cancer from 2008–2016 were identified. Patients were matched on age and sex and followed for five years. Results 111,144 patients, 27,786 with each disease, were identified. The median age was 69 years and two thirds of the patients were men. The 5-year risk of receiving domiciliary care was; HF 20.9%, stroke 25.2%, COPD 24.6% and cancer 19.3%. The corresponding adjusted hazard ratios (HRs), with HF patients used as reference, were: stroke 1.35[1.30–1.40]; COPD 1.29[1.25–1.34]; and cancer 1.19[1.14–1.23]. The five-year incidence of nursing home admission was 6.6% for stroke, and substantially lower in patients with HF(2.6%), COPD(2.6%) and cancer (1.5%). The adjusted HRs were (HF reference): stroke, 2.44 [2.23–2.68]; COPD 1.01 [0.91–1.13] and cancer 0.76 [0.67–0.86]. Living alone, older age, diabetes, chronic kidney disease, depression and dementia predicted a higher likelihood of both types of care. Conclusions In patients with HF, stroke, COPD or cancer 5-year risk of domiciliary care and nursing home admission, ranged from 19–25% and 1–7%, respectively. Patients with stroke had the highest rate of domiciliary care and were more than twice as likely to be admitted to a nursing home, compared to patients with the other conditions.

Published
2021

3. Diagnostic tests, drug prescriptions, and follow-up patterns after incident heart failure: A cohort study of 93,000 UK patients.

Author

Nathalie Conrad, Andrew Judge, Dexter Canoy, Jenny Tran, Johanna O'Donnell, Milad Nazarzadeh, Gholamreza Salimi-Khorshidi, F D Richard Hobbs, John G Cleland, John J V McMurray, and Kazem Rahimi

Subjects
Medicine
Abstract

BackgroundEffective management of heart failure is complex, and ensuring evidence-based practice presents a major challenge to health services worldwide. Over the past decade, the United Kingdom introduced a series of national initiatives to improve evidence-based heart failure management, including a landmark pay-for-performance scheme in primary care and a national audit in secondary care started in 2004 and 2007, respectively. Quality improvement efforts have been evaluated within individual clinical settings, but patterns of care across its continuum, although a critical component of chronic disease management, have not been studied. We have designed this study to investigate patients' trajectories of care around the time of diagnosis and their variation over time by age, sex, and socioeconomic status.Methods and findingsFor this retrospective population-based study, we used linked primary and secondary health records from a representative sample of the UK population provided by the Clinical Practice Research Datalink (CPRD). We identified 93,074 individuals newly diagnosed with heart failure between 2002 and 2014, with a mean age of 76.7 years and of which 49% were women. We examined five indicators of care: (i) diagnosis care setting (inpatient or outpatient), (ii) posthospitalisation follow-up in primary care, (iii) diagnostic investigations, (iv) prescription of essential drugs, and (v) drug treatment dose. We used Poisson and linear regression models to calculate category-specific risk ratios (RRs) or adjusted differences and 95% confidence intervals (CIs), adjusting for year of diagnosis, age, sex, region, and socioeconomic status. From 2002 to 2014, indicators of care presented diverging trends. Outpatient diagnoses and follow-up after hospital discharge in primary care declined substantially (ranging from 56% in 2002 to 36% in 2014, RR 0.64 [0.62, 0.67] and 20% to 14%, RR 0.73 [0.65, 0.82], respectively). Primary care referral for diagnostic investigations and appropriate initiation of beta blockers and angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) both increased significantly (37% versus 82%, RR 2.24 [2.15, 2.34] and 18% versus 63%, RR 3.48 [2.72, 4.43], respectively). Yet, the average daily dose prescribed remained below guideline recommendations (42% for ACE-Is or ARBs, 29% for beta blockers in 2014) and was largely unchanged beyond the first 30 days after diagnosis. Despite increasing rates of treatment initiation, the overall dose prescribed to patients in the 12 months following diagnosis improved little over the period of study (adjusted difference for the combined dose of beta blocker and ACE-I or ARB: +6% [+2%, +10%]). Women and patients aged over 75 years presented significant gaps across all five indicators of care. Our study was limited by the available clinical information, which did not include exact left ventricular ejection fraction values, investigations performed during hospital admissions, or information about follow-up in community heart failure clinics.ConclusionsManagement of heart failure patients in the UK presents important shortcomings that affect screening, continuity of care, and medication titration and disproportionally impact women and older people. National reporting and incentive schemes confined to individual clinical settings have been insufficient to identify these gaps and address patients' long-term care needs.

Published
2019
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4. Correction: Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-HF registry.

Author

Jasper Tromp, Wan Ting Tay, Wouter Ouwerkerk, Tiew-Hwa Katherine Teng, Jonathan Yap, Michael R MacDonald, Kirsten Leineweber, John J V McMurray, Michael R Zile, Inder S Anand, A Mark Richards, Carolyn S P Lam, and ASIAN-HF authors

Subjects
Medicine
Abstract

[This corrects the article DOI: 10.1371/journal.pmed.1002541.].

Published
2018
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5. Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-HF registry.

Author

Jasper Tromp, Wan Ting Tay, Wouter Ouwerkerk, Tiew-Hwa Katherine Teng, Jonathan Yap, Michael R MacDonald, Kirsten Leineweber, John J V McMurray, Michael R Zile, Inder S Anand, A Mark Richards, Carolyn S P Lam, and ASIAN-HF authors

Subjects
Medicine
Abstract

BackgroundComorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with patients' quality of life (QoL) and health outcomes.Methods and findingsWe used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all ConclusionsAmong Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients' QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity.Trial registrationClinicalTrials.gov NCT01633398.

Published
2018
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6. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis

Author

Ajay K, Singh, Kevin, Carroll, Vlado, Perkovic, Scott, Solomon, Vivekanand, Jha, Kirsten L, Johansen, Renato D, Lopes, Iain C, Macdougall, Gregorio T, Obrador, Sushrut S, Waikar, Christoph, Wanner, David C, Wheeler, Andrzej, Więcek, Allison, Blackorby, Borut, Cizman, Alexander R, Cobitz, Rich, Davies, Jo, Dole, Lata, Kler, Amy M, Meadowcroft, Xinyi, Zhu, John J V, McMurray, and Jorge, Posada

Subjects
Male, medicine.medical_specialty, Darbepoetin alfa, Anemia, medicine.medical_treatment, Glycine, Myocardial Infarction, Peritoneal dialysis, Hypoxia-Inducible Factor-Proline Dioxygenases, Hemoglobins, Renal Dialysis, Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, Dialysis, Aged, business.industry, Hazard ratio, Epoetin alfa, General Medicine, Middle Aged, medicine.disease, Intention to Treat Analysis, Epoetin Alfa, Stroke, Cardiovascular Diseases, Barbiturates, Hematinics, Female, Hemodialysis, business, Kidney disease, medicine.drug
Abstract

Background: \ud Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels.\ud \ud Methods: \ud In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, −0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25.\ud \ud Results: \ud A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups.\ud \ud Conclusions: \ud Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305. opens in new tab.).

Published
2021

7. Secreted Frizzled Related Protein 3 in Chronic Heart Failure: Analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

Author

Erik Tandberg Askevold, Lars Gullestad, Ståle Nymo, John Kjekshus, Arne Yndestad, Roberto Latini, John G F Cleland, John J V McMurray, Pål Aukrust, and Thor Ueland

Subjects
Medicine, Science
Abstract

We have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin.We evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.Kaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44-0.74], 0.55 [0.44-0.74] and 0.52 [0.39-0.69]; p

Published
2015
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8. Angiotensin receptor–neprilysin inhibition in acute myocardial infarction

Author

Marc A, Pfeffer, Brian, Claggett, Eldrin F, Lewis, Christopher B, Granger, Lars, Køber, Aldo P, Maggioni, Douglas L, Mann, John J V, McMurray, Jean-Lucien, Rouleau, Scott D, Solomon, Philippe G, Steg, Otavio, Berwanger, Maja, Cikes, Carmine G, De Pasquale, Cara, East, Alberto, Fernandez, Karola, Jering, Ulf, Landmesser, Roxana, Mehran, Béla, Merkely, Freny, Vaghaiwalla Mody, Mark C, Petrie, Ivo, Petrov, Morten, Schou, Michele, Senni, David, Sim, Peter, van der Meer, Martin, Lefkowitz, Yinong, Zhou, Jianjian, Gong, Eugene, Braunwald, M, Zughaib, Pfeffer, M, Claggett, B, Lewis, E, Granger, C, Kober, L, Maggioni, A, Mann, D, Mcmurray, J, Rouleau, J, Solomon, S, Steg, P, Berwanger, O, Cikes, M, De Pasquale, C, East, C, Fernandez, A, Jering, K, Landmesser, U, Mehran, R, Merkely, B, Mody, F, Petrie, M, Petrov, I, Schou, M, Senni, M, Sim, D, van der Meer, P, Lefkowitz, M, Zhou, Y, Gong, J, Braunwald, E, Department of Arts and Culture Studies, Cardiology, Erasmus MC other, Department of Technology and Operations Management, Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)

Subjects
Male, Ramipril, medicine.medical_specialty, alanine aminotransferase, Myocardial Infarction, heart failure, Angiotensin-Converting Enzyme Inhibitors, ramipril, Sacubitril, Angiotensin Receptor Antagonists, Ventricular Dysfunction, Left, Double-Blind Method, aspartate aminotransferase, Internal medicine, dipeptidyl carboxypeptidase inhibitor, medicine, Humans, Myocardial infarction, 610 Medicine & health, Aged, Proportional Hazards Models, sacubitril plus valsartan, Ejection fraction, business.industry, Aminobutyrates, potassium, Biphenyl Compounds, Hazard ratio, creatinine, mineralocorticoid antagonist, Stroke Volume, General Medicine, Middle Aged, angiotensin receptor, medicine.disease, Hospitalization, Drug Combinations, Valsartan, Cardiovascular Diseases, Heart failure, Cardiology, Myocardial infarction complications, Female, Hypotension, business, medicine.drug
Abstract

Sacubitril-Valsartan in Acute Myocardial Infarction In a randomized trial, 5661 patients with acute myocardial infarction and a reduced left ventricular ejection fraction, pulmonary congestion, or both were assigned to receive either sacubitril-valsartan or ramipril. At a median of 22 months, there was no significant difference between the two groups in the incidence of death from cardiovascular causes or incident heart failure. Background In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. Methods We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. Results A total of 5661 patients underwent randomization ; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90 ; 95% confidence interval [CI], 0.78 to 1.04 ; P=0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91 ; 95% CI, 0.78 to 1.07) ; death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87 ; 95% CI, 0.71 to 1.08) ; and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88 ; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. Conclusions Sacubitril- valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis ; PARADISE-MI ClinicalTrials.gov number, NCT02924727.)

Published
2021

9. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST):a multicentre, prospective, randomised, open-label, non-inferiority trial

Author

Isla S Mackenzie, Ian Ford, George Nuki, Jesper Hallas, Christopher J Hawkey, John Webster, Stuart H Ralston, Matthew Walters, Michele Robertson, Raffaele De Caterina, Evelyn Findlay, Fernando Perez-Ruiz, John J V McMurray, Thomas M MacDonald, J. Aziz, G. Dobson, A.S.F. Doney, R.W.V. Flynn, J. Furnace, J.W.K. Grieve, G. Guthrie, D. Jamieson, C.G. Jennings, S. Kean, L.C. Lund, A. McConnachie, F. Pigazzani, P.L. Riches, M. Rix Hanson, A Rogers, E.D.M. Rooke, J. Thomson, M. Warren, K. Wetherall, R. Wilson, C.P. Hall, A. Maseri, H.A. Bird, G. Murray, J.W. Dear, M. Petrie, M. MacDonald, P.S. Jhund, E. Connolly, D.J. Murphy, N. Paul, A. Olsson, P.T. Koskinen, A. Fuat, A. Foster, W. Saywood, R.J. Barr, L. McConnachie, L.F. Wilson, L. Larsen Rasmussen, A.R. McGinnis, H. Birrell, M. Keiller, I.S. Bremner, G.J. Forbes, J.S. Dumbleton, J. Rhodes, and T. Waller

Subjects
medicine.medical_specialty, business.industry, Allopurinol, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Gout, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, 030212 general & internal medicine, Febuxostat, Risk factor, business, Prospective cohort study, Adverse effect, medicine.drug
Abstract

Background:\ud Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.\ud \ud Methods:\ud We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (

Published
2020

10. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Author

Hiddo J L Heerspink, Hans-Henrik Parving, Dennis L Andress, George Bakris, Ricardo Correa-Rotter, Fan-Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John J V McMurray, Joel Z Melnick, Michael G Miller, Pablo E Pergola, Vlado Perkovic, Sheldon Tobe, Tingting Yi, Melissa Wigderson, Dick de Zeeuw, Alicia Elbert, Augusto Vallejos, Andres Alvarisqueta, Laura Maffei, Luis Juncos, Javier de Arteaga, Gustavo Greloni, Eduardo Farias, Alfredo Zucchini, Daniel Vogel, Ana Cusumano, Juan Santos, Margaret Fraenkel, Martin Gallagher, Tim Davis, Shamasunder Acharya, Duncan Cooke, Michael Suranyi, Simon Roger, Nigel Toussaint, Carol Pollock, Doris Chan, Stephen Stranks, Richard MacIsaac, Zoltan Endre, Alice Schmidt, Rudolf Prager, Gert Mayer, Xavier Warling, Michel Jadoul, Jean Hougardy, Chris Vercammen, Bruno Van Vlem, Pieter Gillard, Adriana Costa e Forti, Joao Lindolfo Borges, Luis Santos Canani, Freddy Eliaschewitz, Silmara Leite, Fadlo Fraige Filho, Raphael Paschoalin, Jose Andrade Moura Neto, Luciane Deboni, Irene de Lourdes Noronha, Cintia Cercato, Carlos Alberto Prompt, Maria Zanella, Nelson Rassi, Domingos D'Avila, Rosangela Milagres, Joao Felicio, Roberto Pecoits Filho, Miguel Carlos Riella, Joao Salles, Elizete Keitel, Sergio Draibe, Celso Amodeo, Joseph Youmbissi, Louise Roy, Serge Cournoyer, Shivinder Jolly, Vincent Pichette, Gihad Nesrallah, Harpreet Singh Bajaj, Hasnain Khandwala, Ronnie Aronson, Richard Goluch, Paul Tam, Christian Rabbat, Gordon Bailey, Stephen Chow, Alvaro Castillo, Alfredo Danin Vargas, Fernando Gonzalez, Rodrigo Munoz, Vicente Gutierrez, Gonzalo Godoy, Hongwen Zhao, Zhangsuo Liu, Minghui Zhao, Xiaohui Guo, Benli Su, Shuxia Fu, Yan Xu, Jinkui Yang, Bingyin Shi, Guanqing Xiao, Wei Shi, Chuanming Hao, Changying Xing, Fanfan Hou, Qun Luo, Yuxiu Li, Linong Ji, Li Zuo, Song Wang, Zhaohui Ni, Guohua Ding, Nan Chen, Jiajun Zhao, Weiping Jia, Shengqiang Yu, Jian Weng, Gang Xu, Ping Fu, Shiren Sun, Bicheng Liu, Xiaoqiang Ding, Ivan Rychlik, Alexandra Oplustilova, Dagmar Bartaskova, Vaclava Honova, Hana Chmelickova, Martin Petr, Petr Bucek, Vladimir Tesar, Emil Zahumensky, Johan Povlsen, Kenneth Egstrup, Anna Oczachowska-Kulik, Peter Rossing, Jorma Lahtela, Jorma Strand, Ilkka Kantola, Catherine Petit, Christian Combe, Philippe Zaoui, Vincent Esnault, Pablo Urena Torres, Jean-Michel Halimi, Bertrand Dussol, Tasso Bieler, Klemens Budde, Frank Dellanna, Thomas Segiet, Christine Kosch, Hans Schmidt-Guertler, Isabelle Schenkenberger, Volker Vielhauer, Frank Pistrosch, Mark Alscher, Christoph Hasslacher, Christian Hugo, Anja Muehlfeld, Christoph Wanner, Ploumis Passadakis, Theofanis Apostolou, Nikolaos Tentolouris, Ioannis Stefanidis, Konstantinos Mavromatidis, Vasilios Liakopoulos, Dimitrios Goumenos, Konstantinos Siamopoulos, Vincent Yeung, Risa Ozaki, Samuel Fung, Kathryn Tan, Sydney Tang, Sing Leung Lui, Siu Fai Cheung, Seamus Sreenan, Joseph Eustace, Donal O'Shea, Peter Lavin, Austin Stack, Yoram Yagil, Julio Wainstein, Hilla Knobler, Josef Cohen, Irina Kenis, Deeb Daoud, Yosefa Bar-Dayan, Victor Frajewicki, Faiad Adawi, Loreto Gesualdo, Domenico Santoro, Francesco Marino, Andrea Galfre, Chiara Brunati, Piero Ruggenenti, Giuseppe Rombola, Giuseppe Pugliese, Maura Ravera, Fabio Malberti, Giuseppe Pontoriero, Teresa Rampino, Salvatore De Cosmo, Ciro Esposito, Felice Nappi, Cataldo Abaterusso, Giuseppe Conte, Vincenzo Panichi, Davide Lauro, Giovambattista Capasso, Domenico Russo, Jiichi Anzai, Motoji Naka, Keita Ato, Tetsuro Tsujimoto, Toshinori Nimura, Eitaro Nakashima, Tetsuro Takeda, Shinya Fujii, Kunihisa Kobayashi, Hideaki Iwaoka, Koji Nagayama, Hiroyuki Harada, Hajime Maeda, Rui Kishimoto, Tadashi Iitsuka, Naoki Itabashi, Ryuichi Furuya, Yoshitaka Maeda, Daishiro Yamada, Nobuhiro Sasaki, Hiromitsu Sasaki, Shinichiro Ueda, Naoki Kashihara, Shuichi Watanabe, Takehiro Nakamura, Hidetoshi Kanai, Yuichiro Makita, Keiko Ono, Noriyuki Iehara, Daisuke Goto, Keiichiro Kosuge, Kenichi Tsuchida, Toshiaki Sato, Takashi Sekikawa, Hideki Okamoto, Tsuyoshi Tanaka, Naoko Ikeda, Takenobu Tadika, Koji Mukasa, Takeshi Osonoi, Fuminori Hirano, Motonobu Nishimura, Yuko Yambe, Yukio Tanaka, Makoto Ujihara, Takashi Sakai, Mitsuo Imura, Yutaka Umayahara, Shinya Makino, Jun Nakazawa, Yukinari Yamaguchi, Susumu Kashine, Hiroaki Miyaoka, Katsunori Suzuki, Toshihiko Inoue, Sou Nagai, Nobuyuki Sato, Masahiro Yamamoto, Noriyasu Taya, Akira Fujita, Akira Matsutani, Yugo Shibagaki, Yuichi Sato, Akira Yamauchi, Masahiro Tsutsui, Tamayo Ishiko, Shizuka Kaneko, Nobuyuki Azuma, Hirofumi Matsuda, Yasuhiro Hashiguchi, Yukiko Onishi, Mikiya Tokui, Munehide Matsuhisa, Arihiro Kiyosue, Junji Shinoda, Kazuo Ishikawa, Ghazali Ahmad, Shalini Vijayasingham, Nor Azizah Aziz, Zanariah Hussein, Yin Khet Fung, Wan Hasnul Halimi Wan Hassan, Hin Seng Wong, Bak Leong Goh, Norhaliza Mohd Ali, Nor Shaffinaz Yusuf Azmi Merican, Indralingam Vaithilingam, Nik Nur Fatnoon Nik Ahmad, Noor Adam, Norlela Sukor, V Paranthaman P Vengadasalam, Khalid Abdul Kadir, Mafauzy Mohamed, Karina Renoirte Lopez, Aniceto Leguizamo-Dimas, Alfredo Chew Wong, Jose Chevaile-Ramos, Jose Gonzalez Gonzalez, Raul Rico Hernandez, Jose Nino-Cruz, Leobardo Sauque Reyna, Guillermo Gonzalez-Galvez, Magdalena Madero Rovalo, Tomasso Bochicchio-Ricardelli, Jorge Aldrete, Jaime Carranza-Madrigal, Liffert Vogt, Peter Smak Gregoor, JNM Barendregt, Peter Luik, Ronald Gansevoort, Gozewijn Laverman, Helen Pilmore, Helen Lunt, John Baker, Steven Miller, Kannaiyan Rabindranath, Luis Zapata-Rincon, Rolando Vargas-Gonzales, Jorge Calderon Ticona, Augusto Dextre Espinoza, Jose Burga Nunez, Carlos Antonio Zea-Nunez, Benjamin Herrada Orue, Boris Medina-Santander, Cesar Delgado-Butron, Julio Farfan-Aspilcueta, Stanislaw Mazur, Miroslaw Necki, Michal Wruk, Katarzyna Klodawska, Grazyna Popenda, Ewa Skokowska, Malgorzata Arciszewska, Andrzej Wiecek, Kazimierz Ciechanowski, Michal Nowicki, Rita Birne, Antonio Cabrita, Aura Ramos, Manuel Anibal Antunes Ferreira, Evelyn Matta Fontanet, Altagracia Aurora Alcantara-Gonzalez, Angel Comulada-Rivera, Eugenia Galindo Ramos, Jose Cangiano, Luis Quesada-Suarez, Ricardo Calderon Ortiz, Jose Vazquez-Tanus, Rafael Burgos-Calderon, Carlos Rosado, Nicolae Hancu, Ella Pintilei, Cristina Mistodie, Gabriel Bako, Lavinia Ionutiu, Ligia Petrica, Romulus Timar, Liliana Tuta, Livia Duma, Adriana Tutescu, Svetlana Ivanova, Ashot Essaian, Konstantin Zrazhevskiy, Natalia Tomilina, Elena Smolyarchuk, Anatoly Kuzin, Olga Lantseva, Irina Karpova, Minara Shamkhalova, Natalia Liberanskaya, Andrey Yavdosyuk, Yuri Shvarts, Tatiana Bardymova, Olga Blagoveshchenskaya, Oleg Solovev, Elena Rechkova, Natalia Pikalova, Maria Pavlova, Elena Kolmakova, Rustam Sayfutdinov, Svetlana Villevalde, Natalya Koziolova, Vladimir Martynenko, Vyacheslav Marasaev, Adelya Maksudova, Olga Sigitova, Viktor Mordovin, Vadim Klimontov, Yulia Samoylova, Tatiana Karonova, Lee Ying Yeoh, Boon Wee Teo, Marjorie Wai Yin Foo, Adrian Liew, Ivan Tkac, Aniko Oroszova, Jozef Fekete, Jaroslav Rosenberger, Ida Obetkova, Alla Fulopova, Eva Kolesarova, Katarina Raslova, Peter Smolko, Adrian Oksa, Larry Distiller, Julien Trokis, Luthando Adams, Hemant Makan, Padaruth Ramlachan, Essack Mitha, Kathleen Coetzee, Zelda Punt, Qasim Bhorat, Puvenesvari Naiker, Graham Ellis, Louis Van Zyl, Kwan Woo Lee, Min Seon Kim, Soon-Jib Yoo, Kun Ho Yoon, Yong-Wook Cho, Tae-Sun Park, Sang Yong Kim, Moon-Gi Choi, Tae Keun Oh, Kang-Wook Lee, Ho Sang Shon, Sung Hwan Suh, Byung-Joon Kim, Kim Doo-Man, Joo Hark Yi, Sang Ah Lee, Ho Chan Cho, Sin-Gon Kim, Dae-Ryong Cha, Ji A Seo, Kyung Mook Choi, Jeong-Taek Woo, Kyu Jeung Ahn, Jae Hyuk Lee, In-Joo Kim, Moon-Kyu Lee, Hak Chul Jang, Kyong-Soo Park, Beom Seok Kim, Ji Oh Mok, Mijung Shin, Sun Ae Yoon, Il-Seong Nam-Goong, Choon Hee Chung, Tae Yang Yu, Hyoung Woo Lee, Alfonso Soto Gonzalez, Jaume Almirall, Jesus Egido, Francesca Calero Gonzalez, Gema Fernandez Fresnedo, Ildefonso Valera Cortes, Manuel Praga Terente, Isabel Garcia Mendez, Juan Navarro Gonzalez, Jose Herrero Calvo, Secundino Cigarran Guldris, Mario Prieto Velasco, Jose Ignacio Minguela Pesquera, Antonio Galan, Julio Pascual, Maria Marques Vidas, Judith Martins Munoz, Jose Rodriguez-Perez, Cristina Castro-Alonso, Josep Bonet Sol, Daniel Seron, Elvira Fernandez Giraldez, Javier Arrieta Lezama, Nuria Montero, Julio Hernandez-Jaras, Rafael Santamaria Olmo, Jose Ramon Molas Coten, Olof Hellberg, Bengt Fellstrom, Andreas Bock, Dee Pei, Ching-Ling Lin, Kai-Jen Tien, Ching-Chu Chen, Chien-Ning Huang, Ju-Ying Jiang, Du-An Wu, Chih-Hsun Chu, Shih-Ting Tseng, Jung-Fu Chen, Cho-Tsan Bau, Wayne Sheu, Mai-Szu Wu, Ramazan Sari, Siren Sezer, Alaattin Yildiz, Ilhan Satman, Betul Kalender, Borys Mankovskyy, Ivan Fushtey, Mykola Stanislavchuk, Mykola Kolenyk, Iryna Dudar, Viktoriia Zolotaikina, Orest Abrahamovych, Tetyana Kostynenko, Olena Petrosyan, Petro Kuskalo, Olga Galushchak, Oleg Legun, Ivan Topchii, Liliya Martynyuk, Vasyl Stryzhak, Svitlana Panina, Sergii Tkach, Vadym Korpachev, Peter Maxwell, Luigi Gnudi, Sui Phin Kon, Hilary Tindall, Phillip Kalra, Patrick Mark, Dipesh Patel, Mohamed El-Shahawy, Liqun Bai, Romanita Nica, Yeong-Hau Lien, Judson Menefee, Robert Busch, Alan Miller, Azazuddin Ahmed, Ahmed Arif, Joseph Lee, Sachin Desai, Shweta Bansal, Marie Bentsianov, Mario Belledonne, Charles Jere, Raul Gaona, Gregory Greenwood, Osvaldo Brusco, Mark Boiskin, Diogo Belo, Raffi Minasian, Naveen Atray, Mary Lawrence, John Taliercio, Pablo Pergola, David Scott, German Alvarez, Bradley Marder, Thomas Powell, Wa'el Bakdash, George Stoica, Christopher McFadden, Marc Rendell, Jonathan Wise, Audrey Jones, Michael Jardula, Ivy-Joan Madu, Freemu Varghese, Brian Tulloch, Ziauddin Ahmed, Melanie Hames, Imran Nazeer, Newman Shahid, Rekha John, Manuel Montero, David Fitz-Patrick, Lawrence Phillips, Antonio Guasch, Elena Christofides, Aijaz Gundroo, Mohammad Amin, Cynthia Bowman-Stroud, Michael Link, Laura Mulloy, Michael Nammour, Tarik Lalwani, Lenita Hanson, Adam Whaley-Connell, Lee Herman, Rupi Chatha, Sayed Osama, Kenneth Liss, Zeid Kayali, Anuj Bhargava, Ezra Israel, Alfredo Peguero-Rivera, Michael Fang, Judith Slover, Elena Barengolts, Jose Flores, Rosemary Muoneke, Virginia Savin, Stella Awua-Larbi, Andrew Levine, George Newman, Laden Golestaneh, Guillermo Bohm, Efrain Reisin, Lucita Cruz, Robert Weiss, Franklin Zieve, Edward Horwitz, Peale Chuang, James Mersey, John Manley, Ronald Graf, Fadi Bedros, Sudhir Joshi, Juan Frias, Ali Assefi, Andrew O'Shaughnessy, Roman Brantley, Todd Minga, David Tietjen, Samuel Kantor, Aamir Jamal, Ramon Guadiz, Kenneth Hershon, Peter Bressler, Nelson Kopyt, Harold Cathcart, Scott Bloom, Ronald Reichel, Samer Nakhle, Emily Dulude, Joshua Tarkan, Penelope Baker, Steven Zeig, Jaynier Moya Hechevarria, Armando Ropero-Cartier, Gilda De la Calle, Ankur Doshi, Fadi Saba, Teresa Sligh, Sylvia Shaw, Jayant Kumar, Harold Szerlip, George Bayliss, Alan Perlman, Lakhi Sakhrani, Steven Gouge, Georges Argoud, Idalia Acosta, John Elder, Sucharit Joshi, John Sensenbrenner, Steven Vicks, Roberto Mangoo-Karim, Claude Galphin, Carlos Leon-Forero, John Gilbert, Eric Brown, Adeel Ijaz, Salman Butt, Mariana Markell, Carlos Arauz-Pacheco, Lance Sloan, Odilon Alvarado, Serge Jabbour, Eric Simon, Anjay Rastogi, Sam James, Karen Hall, John Melish, Brad Dixon, Allen Adolphe, Csaba Kovesdy, Srinivasan Beddhu, Richard Solomon, Ronald Fernando, Ellis Levin, Charuhas Thakar, Brooks Robey, David Goldfarb, Linda Fried, Geetha Maddukuri, Stephen Thomson, Andrew Annand, Saeed Kronfli, Paramjit Kalirao, Rebecca Schmidt, Neera Dahl, Samuel Blumenthal, Debra Weinstein, Ove Ostergaard, Talia Weinstein, Yasuhiro Ono, Murat Yalcin, Shahana Karim, APH - Health Behaviors & Chronic Diseases, Nephrology, ACS - Amsterdam Cardiovascular Sciences, ACS - Microcirculation, Biomedical Signals and Systems, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Heerspink, H. J. L., Parving, H. -H., Andress, D. L., Bakris, G., Correa-Rotter, R., Hou, F. -F., Kitzman, D. W., Kohan, D., Makino, H., Mcmurray, J. J. V., Melnick, J. Z., Miller, M. G., Pergola, P. E., Perkovic, V., Tobe, S., Yi, T., Wigderson, M., de Zeeuw, D., Elbert, A., Vallejos, A., Alvarisqueta, A., Maffei, L., Juncos, L., de Arteaga, J., Greloni, G., Farias, E., Zucchini, A., Vogel, D., Cusumano, A., Santos, J., Fraenkel, M., Gallagher, M., Davis, T., Acharya, S., Cooke, D., Suranyi, M., Roger, S., Toussaint, N., Pollock, C., Chan, D., Stranks, S., Macisaac, R., Endre, Z., Schmidt, A., Prager, R., Mayer, G., Warling, X., Jadoul, M., Hougardy, J., Vercammen, C., Van Vlem, B., Gillard, P., Costa e Forti, A., Borges, J. L., Santos Canani, L., Eliaschewitz, F., Leite, S., Fraige Filho, F., Paschoalin, R., Moura Neto, J. A., Deboni, L., de Lourdes Noronha, I., Cercato, C., Prompt, C. A., Zanella, M., Rassi, N., D'Avila, D., Milagres, R., Felicio, J., Pecoits Filho, R., Riella, M. C., Salles, J., Keitel, E., Draibe, S., Amodeo, C., Youmbissi, J., Roy, L., Cournoyer, S., Jolly, S., Pichette, V., Nesrallah, G., Bajaj, H. S., Khandwala, H., Aronson, R., Goluch, R., Tam, P., Rabbat, C., Bailey, G., Chow, S., Castillo, A., Danin Vargas, A., Gonzalez, F., Munoz, R., Gutierrez, V., Godoy, G., Zhao, H., Liu, Z., Zhao, M., Guo, X., Su, B., Fu, S., Xu, Y., Yang, J., Shi, B., Xiao, G., Shi, W., Hao, C., Xing, C., Hou, F., Luo, Q., Li, Y., Ji, L., Zuo, L., Wang, S., Ni, Z., Ding, G., Chen, N., Zhao, J., Jia, W., Yu, S., Weng, J., Xu, G., Fu, P., Sun, S., Liu, B., Ding, X., Rychlik, I., Oplustilova, A., Bartaskova, D., Honova, V., Chmelickova, H., Petr, M., Bucek, P., Tesar, V., Zahumensky, E., Povlsen, J., Egstrup, K., Oczachowska-Kulik, A., Rossing, P., Lahtela, J., Strand, J., Kantola, I., Petit, C., Combe, C., Zaoui, P., Esnault, V., Urena Torres, P., Halimi, J. -M., Dussol, B., Bieler, T., Budde, K., Dellanna, F., Segiet, T., Kosch, C., Schmidt-Guertler, H., Schenkenberger, I., Vielhauer, V., Pistrosch, F., Alscher, M., Hasslacher, C., Hugo, C., Muehlfeld, A., Wanner, C., Passadakis, P., Apostolou, T., Tentolouris, N., Stefanidis, I., Mavromatidis, K., Liakopoulos, V., Goumenos, D., Siamopoulos, K., Yeung, V., Ozaki, R., Fung, S., Tan, K., Tang, S., Lui, S. L., Cheung, S. F., Sreenan, S., Eustace, J., O'Shea, D., Lavin, P., Stack, A., Yagil, Y., Wainstein, J., Knobler, H., Cohen, J., Kenis, I., Daoud, D., Bar-Dayan, Y., Frajewicki, V., Adawi, F., Gesualdo, L., Santoro, D., Marino, F., Galfre, A., Brunati, C., Ruggenenti, P., Rombola, G., Pugliese, G., Ravera, M., Malberti, F., Pontoriero, G., Rampino, T., De Cosmo, S., Esposito, C., Nappi, F., Abaterusso, C., Conte, G., Panichi, V., Lauro, D., Capasso, G., Russo, D., Anzai, J., Naka, M., Ato, K., Tsujimoto, T., Nimura, T., Nakashima, E., Takeda, T., Fujii, S., Kobayashi, K., Iwaoka, H., Nagayama, K., Harada, H., Maeda, H., Kishimoto, R., Iitsuka, T., Itabashi, N., Furuya, R., Maeda, Y., Yamada, D., Sasaki, N., Sasaki, H., Ueda, S., Kashihara, N., Watanabe, S., Nakamura, T., Kanai, H., Makita, Y., Ono, K., Iehara, N., Goto, D., Kosuge, K., Tsuchida, K., Sato, T., Sekikawa, T., Okamoto, H., Tanaka, T., Ikeda, N., Tadika, T., Mukasa, K., Osonoi, T., Hirano, F., Nishimura, M., Yambe, Y., Tanaka, Y., Ujihara, M., Sakai, T., Imura, M., Umayahara, Y., Makino, S., Nakazawa, J., Yamaguchi, Y., Kashine, S., Miyaoka, H., Suzuki, K., Inoue, T., Nagai, S., Sato, N., Yamamoto, M., Taya, N., Fujita, A., Matsutani, A., Shibagaki, Y., Sato, Y., Yamauchi, A., Tsutsui, M., Ishiko, T., Kaneko, S., Azuma, N., Matsuda, H., Hashiguchi, Y., Onishi, Y., Tokui, M., Matsuhisa, M., Kiyosue, A., Shinoda, J., Ishikawa, K., Ahmad, G., Vijayasingham, S., Aziz, N. A., Hussein, Z., Fung, Y. K., Hassan, W. H. H. W., Wong, H. S., Goh, B. L., Ali, N. M., Merican, N. S. Y. A., Vaithilingam, I., Nik Ahmad, N. N. F., Adam, N., Sukor, N., Vengadasalam, V. P. P., Abdul Kadir, K., Mohamed, M., Renoirte Lopez, K., Leguizamo-Dimas, A., Chew Wong, A., Chevaile-Ramos, J., Gonzalez Gonzalez, J., Rico Hernandez, R., Nino-Cruz, J., Sauque Reyna, L., Gonzalez-Galvez, G., Madero Rovalo, M., Bochicchio-Ricardelli, T., Aldrete, J., Carranza-Madrigal, J., Vogt, L., Smak Gregoor, P., Barendregt, J. N. M., Luik, P., Gansevoort, R., Laverman, G., Pilmore, H., Lunt, H., Baker, J., Miller, S., Rabindranath, K., Zapata-Rincon, L., Vargas-Gonzales, R., Calderon Ticona, J., Dextre Espinoza, A., Burga Nunez, J., Zea-Nunez, C. A., Herrada Orue, B., Medina-Santander, B., Delgado-Butron, C., Farfan-Aspilcueta, J., Mazur, S., Necki, M., Wruk, M., Klodawska, K., Popenda, G., Skokowska, E., Arciszewska, M., Wiecek, A., Ciechanowski, K., Nowicki, M., Birne, R., Cabrita, A., Ramos, A., Antunes Ferreira, M. A., Matta Fontanet, E., Alcantara-Gonzalez, A. A., Comulada-Rivera, A., Galindo Ramos, E., Cangiano, J., Quesada-Suarez, L., Calderon Ortiz, R., Vazquez-Tanus, J., Burgos-Calderon, R., Rosado, C., Hancu, N., Pintilei, E., Mistodie, C., Bako, G., Ionutiu, L., Petrica, L., Timar, R., Tuta, L., Duma, L., Tutescu, A., Ivanova, S., Essaian, A., Zrazhevskiy, K., Tomilina, N., Smolyarchuk, E., Kuzin, A., Lantseva, O., Karpova, I., Shamkhalova, M., Liberanskaya, N., Yavdosyuk, A., Shvarts, Y., Bardymova, T., Blagoveshchenskaya, O., Solovev, O., Rechkova, E., Pikalova, N., Pavlova, M., Kolmakova, E., Sayfutdinov, R., Villevalde, S., Koziolova, N., Martynenko, V., Marasaev, V., Maksudova, A., Sigitova, O., Mordovin, V., Klimontov, V., Samoylova, Y., Karonova, T., Yeoh, L. Y., Teo, B. W., Foo, M. W. Y., Liew, A., Tkac, I., Oroszova, A., Fekete, J., Rosenberger, J., Obetkova, I., Fulopova, A., Kolesarova, E., Raslova, K., Smolko, P., Oksa, A., Distiller, L., Trokis, J., Adams, L., Makan, H., Ramlachan, P., Mitha, E., Coetzee, K., Punt, Z., Bhorat, Q., Naiker, P., Ellis, G., Van Zyl, L., Lee, K. W., Kim, M. S., Yoo, S. -J., Yoon, K. H., Cho, Y. -W., Park, T. -S., Kim, S. Y., Choi, M. -G., Oh, T. K., Lee, K. -W., Shon, H. S., Suh, S. H., Kim, B. -J., Doo-Man, K., Yi, J. H., Lee, S. A., Cho, H. C., Kim, S. -G., Cha, D. -R., Seo, J. A., Choi, K. M., Woo, J. -T., Ahn, K. J., Lee, J. H., Kim, I. -J., Lee, M. -K., Jang, H. C., Park, K. -S., Kim, B. S., Mok, J. O., Shin, M., Yoon, S. A., Nam-Goong, I. -S., Chung, C. H., Yu, T. Y., Lee, H. W., Soto Gonzalez, A., Almirall, J., Egido, J., Calero Gonzalez, F., Fernandez Fresnedo, G., Valera Cortes, I., Praga Terente, M., Garcia Mendez, I., Navarro Gonzalez, J., Herrero Calvo, J., Cigarran Guldris, S., Prieto Velasco, M., Minguela Pesquera, J. I., Galan, A., Pascual, J., Marques Vidas, M., Martins Munoz, J., Rodriguez-Perez, J., Castro-Alonso, C., Bonet Sol, J., Seron, D., Fernandez Giraldez, E., Arrieta Lezama, J., Montero, N., Hernandez-Jaras, J., Santamaria Olmo, R., Molas Coten, J. R., Hellberg, O., Fellstrom, B., Bock, A., Pei, D., Lin, C. -L., Tien, K. -J., Chen, C. -C., Huang, C. -N., Jiang, J. -Y., Wu, D. -A., Chu, C. -H., Tseng, S. -T., Chen, J. -F., Bau, C. -T., Sheu, W., Wu, M. -S., Sari, R., Sezer, S., Yildiz, A., Satman, I., Kalender, B., Mankovskyy, B., Fushtey, I., Stanislavchuk, M., Kolenyk, M., Dudar, I., Zolotaikina, V., Abrahamovych, O., Kostynenko, T., Petrosyan, O., Kuskalo, P., Galushchak, O., Legun, O., Topchii, I., Martynyuk, L., Stryzhak, V., Panina, S., Tkach, S., Korpachev, V., Maxwell, P., Gnudi, L., Kon, S. P., Tindall, H., Kalra, P., Mark, P., Patel, D., El-Shahawy, M., Bai, L., Nica, R., Lien, Y. -H., Menefee, J., Busch, R., Miller, A., Ahmed, A., Arif, A., Lee, J., Desai, S., Bansal, S., Bentsianov, M., Belledonne, M., Jere, C., Gaona, R., Greenwood, G., Brusco, O., Boiskin, M., Belo, D., Minasian, R., Atray, N., Lawrence, M., Taliercio, J., Pergola, P., Scott, D., Alvarez, G., Marder, B., Powell, T., Bakdash, W., Stoica, G., Mcfadden, C., Rendell, M., Wise, J., Jones, A., Jardula, M., Madu, I. -J., Varghese, F., Tulloch, B., Ahmed, Z., Hames, M., Nazeer, I., Shahid, N., John, R., Montero, M., Fitz-Patrick, D., Phillips, L., Guasch, A., Christofides, E., Gundroo, A., Amin, M., Bowman-Stroud, C., Link, M., Mulloy, L., Nammour, M., Lalwani, T., Hanson, L., Whaley-Connell, A., Herman, L., Chatha, R., Osama, S., Liss, K., Kayali, Z., Bhargava, A., Israel, E., Peguero-Rivera, A., Fang, M., Slover, J., Barengolts, E., Flores, J., Muoneke, R., Savin, V., Awua-Larbi, S., Levine, A., Newman, G., Golestaneh, L., Bohm, G., Reisin, E., Cruz, L., Weiss, R., Zieve, F., Horwitz, E., Chuang, P., Mersey, J., Manley, J., Graf, R., Bedros, F., Joshi, S., Frias, J., Assefi, A., O'Shaughnessy, A., Brantley, R., Minga, T., Tietjen, D., Kantor, S., Jamal, A., Guadiz, R., Hershon, K., Bressler, P., Kopyt, N., Cathcart, H., Bloom, S., Reichel, R., Nakhle, S., Dulude, E., Tarkan, J., Baker, P., Zeig, S., Moya Hechevarria, J., Ropero-Cartier, A., De la Calle, G., Doshi, A., Saba, F., Sligh, T., Shaw, S., Kumar, J., Szerlip, H., Bayliss, G., Perlman, A., Sakhrani, L., Gouge, S., Argoud, G., Acosta, I., Elder, J., Sensenbrenner, J., Vicks, S., Mangoo-Karim, R., Galphin, C., Leon-Forero, C., Gilbert, J., Brown, E., Ijaz, A., Butt, S., Markell, M., Arauz-Pacheco, C., Sloan, L., Alvarado, O., Jabbour, S., Simon, E., Rastogi, A., James, S., Hall, K., Melish, J., Dixon, B., Adolphe, A., Kovesdy, C., Beddhu, S., Solomon, R., Fernando, R., Levin, E., Thakar, C., Robey, B., Goldfarb, D., Fried, L., Maddukuri, G., Thomson, S., Annand, A., Kronfli, S., Kalirao, P., Schmidt, R., Dahl, N., Blumenthal, S., Weinstein, D., Ostergaard, O., Weinstein, T., Ono, Y., Yalcin, M., Karim, S., Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Diabetes Clinic

Subjects
Male, endothelin, albuminuria, nephropathy, inhibition, Diabetes Mellitus, Type 2/drug therapy, Endocrinology, Diabetes and Metabolism, Placebo-controlled study, Administration, Oral, 030204 cardiovascular system & hematology, Settore MED/13 - Endocrinologia, chemistry.chemical_compound, 0302 clinical medicine, ENDOTHELIN, 80 and over, Diabetic Nephropathies, 030212 general & internal medicine, Renal Insufficiency, Chronic, Aged, 80 and over, Diabetic Nephropathies/blood, General Medicine, Middle Aged, Atrasentan/administration & dosage, Editorial Commentary, Treatment Outcome, Nephrology, Creatinine, Administration, young adult, Female, medicine.symptom, Glomerular filtration rate, Type 2, Endothelin A Receptor Antagonists/administration & dosage, medicine.drug, Glomerular Filtration Rate, Human, Oral, Adult, medicine.medical_specialty, ALBUMINURIA, Endothelin A Receptor Antagonists, NEPHROPATHY, Urology, INHIBITION, Renal function, Serum Albumin, Human, Placebo, Nephropathy, 03 medical and health sciences, Young Adult, Double-Blind Method, Atresentan, diabetes, chronic kidney disease, medicine, Diabetes Mellitus, Aged, Atrasentan, Diabetes Mellitus, Type 2, Humans, Renal Insufficiency, Chronic, Serum Albumin, business.industry, Creatinine/blood, medicine.disease, Serum Albumin, Human/urine, n/a OA procedure, chemistry, Albuminuria, Renal Insufficiency, Chronic/blood, business, aged, 80 and over, Kidney disease
Abstract

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Published
2019

11. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Author

Adrian F Hernandez, Jennifer B Green, Salim Janmohamed, Ralph B D'Agostino, Christopher B Granger, Nigel P Jones, Lawrence A Leiter, Anne E Rosenberg, Kristina N Sigmon, Matthew C Somerville, Karl M Thorpe, John J V McMurray, Stefano Del Prato, John J.V. McMurray, Ralph B. D'Agostino, Christopher B. Granger, Adrian F. Hernandez, Lawrence A. Leiter, Robert M Califf, Rury Holman, David DeMets, Matthew Riddle, Shaun Goodman, Darren McGuire, Karen Alexander, Adam Devore, Chiara Melloni, Chetan Patel, David Kong, Gerald Bloomfield, Matthew Roe, Pierluigi Tricoci, Rob Harrison, Renato Lopes, Robin Mathews, Rajendra Mehta, William Schuyler Jones, Sreekanth Vemulapalli, Thomas Povsic, Zubin Eapen, Keith Dombrowski, Brad Kolls, Dedrick Jordan, Andrew Ambrosy, Stephen Greene, Aditya Mandawat, Jay Shavadia, Lauren Cooper, Abhinav Sharma, Patricia Guimaraes, Daniel Friedman, Matt Wilson, Patricia Endsley, Tracy Gentry, Jeannie Collier, Kathleen Perez, Kourtnei James, Jennifer Roush, Connie Pope, Christina Howell, Megan Johnson, Matt Bailey, Joanna Cole, Teresa Akers, Beth Vandyne, Betsy Thomas, Jenny Rich, Susan Bartone, Gail Beaulieu, Kim Brown, Tuan Chau, Tamra Christian, Rebecca Coker, Deb Greene, Trevorlyn Haddock, Wendy Jenkins, Ghazala Haque, Marsha Marquess, Jean Pesarchick, Renee Rethaford, Allegra Stone, Firas Al Kawas, Michelle Anderson, Robert Enns, Isaac Sinay, Chantal Mathieu, Victor Yordanov, Irene Hramiak, Martin Haluzik, Søren Galatius, Bruno Guerci, Michael Nauck, Ilias Migdalis, Choon Beng Kathryn Tan, Gyozo Kocsis, Andrea Giaccari, Moon Kyu Lee, Ernesto German Cardona Muñoz, Jan Cornel, Kare Birkeland, Miguel Pinto, Louie Tirador, Martyna Olesinska-Mader, Marina Shestakova, Larry Distiller, Jose Lopez-Sendon, Bjorn Eliasson, Chern-En Chiang, Suphot Srimahachota, Boris Mankovsky, M Angelyn Bethel, Kathleen Dungan, Mikhail Kosiborod, Andres Alvarisqueta, Jorge Baldovino, Diego Besada, Pedro Calella, Maria Cecilia Cantero, Patricia Castaño, Alejandro Chertkoff, Jesus Cuadrado, Luis De Loredo, Andrea Dominguez, Maria Vanesa Español, Hernan Finkelstein, Gustavo Frechtel, Jose Fretes, Natalia Garrido Santos, Joaquin Gonzalez, Marcos Litvak, Juan Loureyro, Laura Maffei, Natacha Maldonado, Diego Mohr Gasparini, Silvia Orio, Federico Perez Manghi, Nelson Rodriguez Papini, Jorgelina Sala, Pablo Schygiel, Georgina Sposetti, Maria Ulla, Fernando Verra, Silvina Zabalua, Cesar Zaidman, Laurent Crenier, Corinne Debroye, Francis Duyck, André Scheen, Luc Van Gaal, Chris Vercammen, Velichka Damyanova, Stefan Dimitrov, Snezhina Kovacheva, Lachezar Lozanov, Viktor Margaritov, Rositsa Mihaylova-Shumkova, Antoaneta Nikolaeva, Zhasmina Stoyanova, Ronald Akhras, Yves Beaudry, Jacques Bedard, Joseph Berlingieri, Raja Chehayeb, Stephen Cheung, James Conway, Jean Cusson, Anthony Della Siega, Richard Dumas, Peter Dzongowski, Murdo Ferguson, Daniel Gaudet, Francois Grondin, Anil Gupta, Milan Gupta, Frank Halperin, Pierre-Alain Houle, Michael Jones, Simon Kouz, Christopher Kovacs, Daniel Landry, Eva Lonn, William O'Mahony, Sean Peterson, Dennis Reich, Alan Rosenbloom, Francois St-Maurice, Barna Tugwell, Saul Vizel, Vincent Woo, Tomas Brychta, Vladimir Cech, Eva Dvorakova, Tomas Edelsberger, Katarina Halciakova, Jarmila Krizova, Jiri Lastuvka, Martin Piperek, Vera Prymkova, Lea Raclavska, Elena Silhova, Robin Urbanek, Jan Vrkoc, Ulla Andersen, Jens Brønnum-Schou, Jens Hove, Jan Skov Jensen, Lars Kober, Ole Peter Kristiansen, Per Lund, Thomas Melchior, Ole Nyvad, Morten Schou, Alain Boye, Didier Cadinot, Didier Gouet, Patrick Henry, Laurence Kessler, Jean-Daniel Lalau, Catherine Petit, Jean-Francois Thuan, Christel Voinot, Julien Vouillarmet, Christoph Axthelm, Dirk Berger, Tasso Bieler, Andreas Birkenfeld, Jochen Bott, Klaus Busch, Karel Caca, Julia Chevts, Torsten Donaubauer, Rudolf Erlinger, Klaus Funke, Josef Grosskopf, Andreas Hagenow, Monika Hamann, Manfred Hartard, Peter Heymer, Wolfgang Huppertz, Gabriele Illies, Stephan Jacob, Thomas Jung, Gerd Kahrmann, Petra Kast, Monika Kellerer, Hans-Peter Kempe, Andrei Khariouzov, Gerhard Klausmann, Christiane Klein, Uwe Kleinecke-Pohl, Klaus Kleinertz, Thorsten Koch, Christine Kosch, Babette Lorra, Joerg Luedemann, Matthias Luttermann, Stephan Maxeiner, Karsten Milek, Andrea Moelle, Gerhard Neumann, Ruth Nischik, Edith Oehrig-Pohl, Georg Plassmann, Lars Pohlmeier, Felix Proepper, Stefan Regner, Werner Rieker, Ludger Rose, Holger Samer, Joachim Sauter, Frank Schaper, Clemens Schiffer, Juergen Schmidt, Bernd-M. Scholz, Joerg Schulze, Alexander Segner, Jochen Seufert, Helena Sigal, Joerg Steindorf, Juergen Stockhausen, Petra Stuebler, Heidrun Taeschner, Dietrich Tews, Diethelm Tschoepe, Karl Wilhelm, Helga Zeller-Stefan, Iakovos Avramidis, Stavros Bousboulas, Magdalini Bristianou, Georgios Dimitriadis, Moses Elisaf, Kalliopi Kotsa, Andreas Melidonis, Asimina Mitrakou, Emmanouil Pagkalos, Nikolaos Papanas, Angelos Pappas, Christos Sampanis, Nikolaos Tentolouris, Apostolos Tsapas, Glykeria Tzatzagou, Risa Ozaki, Csaba Hajdú, Eleonóra Harcsa, Laszlo Konyves, János Mucsi, Zsolt Pauker, Gizella Petró, Zsolt Plés, Katalin Revesz, Vangel Sándor, Viktor Vass, Angelo Avogaro, Massimo Boemi, Riccardo Bonadonna, Agostino Consoli, Salvatore De Cosmo, Paolo Di Bartolo, Francesco Dotta, Simona Frontoni, Marianna Galetta, Alessandra Gambineri, Carmine Gazzaruso, Francesco Giorgino, Davide Lauro, Emanuela Orsi, Giuseppe Paolisso, Gabriele Perriello, Piermarco Piatti, Antonio Pontiroli, Paola Ponzani, Angela Albarosa Rivellese, Giorgio Sesti, Giancarlo Tonolo, Roberto Trevisan, Chul Woo Ahn, Sei-Hyun Baik, Bong-Soo Cha, Choon-Hee Chung, Hak Chul Jang, Chong-Jin Kim, Hye Soon Kim, In Joo Kim, Eun Young Lee, Hyoung Woo Lee, Kwan-Woo Lee, Keon-Woong Moon, June Namgung, Kyong Soo Park, Soon Jib Yoo, Jaemyung Yu, Edmundo-Alfredo Bayram Llamas, Jose-Luis Cervantes-Escárcega, Luis Fernando Flota-Cervera, José Gerardo González-González, Sara Pascoe-Gonzalez, Emilia Susana Pelayo-Orozco, Santiago-Paulino Ramirez-Diaz, Arturo Saldana-Mendoza, Carlos Sánchez Jerjes-Díaz, Jose Juan Torres-Colores, Maricela Vidrio-Velázquez, Juan Villagordoa-Mesa, Hugo Peter Beijerbacht, Reginald G.E.J. Groutars, Boudewijn A Hoek, Pieter A.M. Hoogslag, Adriaan Kooy, Johannes A. Kragten, Aloysius G. Lieverse, Hendrik P. Swart, Eric P. Viergever, Jørn Ahlqvist, John Cooper, Hanne Gulseth, Gaute Guttormsen, Cecilie Wium, Hugo Arbañil, Jorge Calderon, Luis Camacho, Augusto Dextre Espinoza, Elizabeth Garrido, Alejandro Luna, Helard Manrique, Frederick Massucco Revoredo, Rolando Vargas Gonzales, Luis Zapata Rincon, Carlos Zubiate, Geraldine Ebo, Ellen Morales-Palomares, Malgorzata Arciszewska, Marek Banach, Renata Bijata-Bronisz, Tadeusz Derezinski, Waldemar Gadzinski, Jacek Gajek, Katarzyna Klodawska, Ewa Krzyzagorska, Andrzej Madej, Pawel Miekus, Jaroslaw Opiela, Piotr Romanczuk, Anna Siegel, Ewa Skokowska, Andrzej Stankiewicz, Teresa Stasinska, Iwona Trznadel-Morawska, Robert Witek, Sergey Aksentyev, Irina Bondar, Irina Demidova, Alexander Dreval, Olga Ershova, Gagik Galstyan, Alla Garganeeva, Nadezhda Izmozherova, Victoria Karetnikova, Marina Kharakhulakh, Aleksandr Khokhlov, Zhanna Kobalava, Olga Koshelskaya, Elena Kosmacheva, Vladimir Kostin, Natalia Koziolova, Anatoly Kuzin, Victor Lesnov, Tatyana Lysenko, Valentin Markov, Alexander Mayorov, Sergey Moiseev, Svetlana Myasoedova, Nina Petunina, Andrey Rebrov, Ludmila Ruyatkina, Julia Samoylova, Olga Sazonova, Natalia Shilkina, Nadezhda Sokolova, Olga Vasilevskaya, Nelli Verbovaya, Elena Vishneva, Sergey Vorobyev, Natalya Vorokhobina, Olga Zanozina, Elena Zhdanova, Tatyana Zykova, Lesley Burgess, Kathleen Coetzee, Saleem Dawood, Landman Lombard, Ellen Makotoko, Rajendran Moodley, Wessels Oosthuysen, Mohamed Sarvan, Carlos Calvo Gómez, Isidoro Cano Rodríguez, Almudena Castro Conde, Angel Cequier Fillat, Guillem Cuatrecasas Cambra, Fernando de Álvaro Moreno, Luis De Teresa Parreño, Javier Delgado Lista, José Ramón Domínguez Escribano, Santiago Durán García, Javier Elvira González, José María Fernández Rodríguez, Alberto Goday Arno, Ricardo Gomez Huelgas, José Ramón González Juanatey, Antonio Hernandez Mijares, Víctor Alfonso Jiménez Díaz, Esteban Jodar Gimeno, Tomás Lucas Morante, Monica Marazuela, Nieves Martell Claros, Didac Mauricio Puente, Elena Mena Ribas, Juan Francisco Merino Torres, Pedro Mezquita Raya, Andreu Nubiola Calonge, Xavier Ordoñez Sánchez, Jose Maria Pascual Izuel, Verónica Perea Castilla, Antonio Pérez Pérez, Isabel Perez Soto, Miguel Quesada Charneco, Angustias Quesada Simón, Josep Redón Mas, Antonia Rego Iraeta, Maria Rodriguez Alvarez, Irene Rodríguez Rodríguez, José Sabán Ruiz, Alfonso Soto González, Francisco Tinahones Madueno, Carlos Trescoli Serrano, Angels Ulied Armiñana, Erasmus Bachus, Katarina Berndtsson Blom, Ken Eliasson, Pekka Koskinen, Hans Larnefeldt, Cornelia Lif-Tiberg, Carina Linderfalk, Gustav Lund, Pia Lundman, Linda Moris, Åke Olsson, Staffan Salmonsson, Johan Sanmartin Berglund, Folke Sjöberg, Stefan Söderberg, Ingemar Torstensson, Jung-Fu Chen, Kai Jen Tien, Shih-Ting Tseng, Shih-Te Tu, Chih-Yuan Wang, Ji-Hung Wang, Arintaya Phrommintikul, Sukit Yamwong, Woravut Jintapakorn, Pisit Hutayanon, Nakarin Sansanayudh, Larysa Bazhan, Ivan Fushtey, Mariya Grachova, Vitaliy Katerenchuk, Vadym Korpachev, Nonna Kravchun, Oleksandr Larin, Galyna Mykhalchyshyn, Halyna Myshanych, Olga Oleksyk, Valeriia Orlenko, Nataliia Pashkovska, Nataliia Pertseva, Olena Petrosyan, Ivan Smirnov, Maryna Vlasenko, Tetiana Zlova, Myint Aye, Arun Baksi, Mathangi Balasubramani, Ronnie Beboso, Mark Blagden, Charles Bundy, Tobias Cookson, Allan Copland, Alistair Emslie-Smith, Fiona Green, Anthony Gunstone, Basil Issa, Ewart Jackson-Voyzey, Andrew Johnson, Malcolm Maclean, John McKnight, Solomon Muzulu, Ian O'Connell, Babatunde Oyesile, Catherine Patterson, Ewan Pearson, Sam Philip, Paul Smith, Usha Sukumaran, Jalal Abbas, Gaurav Aggarwala, Faiq Akhter, James Andersen, Moise Anglade, Georges Argoud, Mehrdad Ariani, Reswan Ashdji, Ladan Bakhtari, Subhash Banerjee, Andrew Bartlett, Howard Baum, Harold Bays, Richard Beasley, Renata Belfort de Aguiar, Sabrina Benjamin, Ravi Bhagwat, Anuj Bhargava, Bruce Bode, Christina Bratcher, Toby Briskin, Andrew Brockmyre, Raymond Broughton, Judith Brown, Madhusudan Budhraja, Kevin Cannon, Jewell Carr, Harold Cathcart, Arvind Cavale, Louis Chaykin, Deanna Cheung, Richard Childress, Allan Cohen, Jonathan Condit, Erin Cooksey, George Mitchell Cornett, Ira Dauber, William Davila, Luis De Armas, Julius Dean, Robert Detweiler, Ernesto Diaz, Michael Di Giovanna, Isaac Dor, Waymon Drummond, Donald Eagerton, John Earl, Charles Eaton, Howard Ellison, Neil Farris, Thomas Fiel, Anthony Firek, Brian First, Les Forgosh, William French, Winston Gandy, Ronald Garcia, Santosh Gill, Murray Gordon, Michael Guice, Siva Gummadi, Jonathan Hackenyos, Kristen Hairston, Lenita Hanson, Lindsay Harrison, Israel Hartman, John Heitner, Srini Hejeebu, Paul Hermany, Carlos Hernandez-Cassis, Horacio Hidalgo, Alexander Higgins, Hassan Ibrahim, Shahram Jacobs, David Johnson, Parag Joshi, Steven Kaster, Daniel Kellum, Christopher Kim, Ellen Kim, William Kirby, Albert Knouse, Steven Kulback, Mariananda Kumar, Tulsidas Kuruvanka, Ajay Labroo, William Lasswell, John Lentz, Thomas Lenzmeier, David Lewis, Zhaoping Li, Michael Lillestol, Raymond Little, Richard Lorraine, Cecilia McKeown-Biagas, Robert McNeill, Anand Mehta, Alan Miller, Joseph Moran, Emily Morawski, Venkatesh Nadar, Thomas O'Connor, Alberto Odio, Reginald Parker, Rajesh Patel, Lawrence Phillips, George Raad, Aref Rahman, Marina Raikhel, Ajit Raisinghani, Raj Rajan, Neda Rasouli, Frank Rauzi, Kathryn Rohr, Hal Roseman, Sergio Rovner, Fadi Saba, Richard Sachson, Alex Schabauer, Ricky Schneider, Timothy Schuchard, John Sensenbrenner, Yshay Shlesinger, Narendra Singh, Kanagaratnam Sivalingam, Larry Stonesifer, Daniel Storey, David Suh, Mohammed Tahir, Anjanette Tan, Marilyn Tan, Alain Taylon, Maitreya Thakkar, Devjit Tripathy, Gabriel Uwaifo, Amarnath Vedere, Chandra Venugopal, Anthony Vo, Michelle Welch, James Welker, Alexander White, John Willis, Alan Wynne, Shahram Yazdani, Anne Rosenberg, Lauren Price, Kristina Sigmon, Yuliya Lokhngina, Weibing Xing, Robert Overton, Murray Stewart, Janet Stead, Alistair Lindsay, Vickas Patel, Jorge Ross, Joseph Soffer, Shruti Daga, Margaret Sowell, Prashant Patel, Louisa Garvey, Jessica Ackert, Sybil Abraham, Mary Beth Sabol, Desma Altobelli, JuYoung Ha, Mangesh Kulkarni, Matthew Somerville, Drusilla Noronha, Ed Casson, Eddie Zang, Chamandeep Sandhu, Rakesh Kumar, David Chen, Lin Taft, Rajivkumar Patel, June Ye, Jennifer Shannon, Tim Wilson, Charleen Babi, Diane Miller, Karl Thorpe, Rachael Russell, Georgina Bull, Belinda Hereghty, Eva Fernandez-Salazar, Troy Longley, Jill Donaldson, Marie Jarosz, Karen Murphy, Patricia Adams, Peter Smith, Rachel James, Jackie Richards, Sangeeta Sedani, Denise Althouse, David Watson, Jamie Lorimer, Steven Lauder, Ron Schultheis, Terese Womer, Ella Wraight, Wenyan Li, Emma Price-Olsen, Anthony Watson, Aoife Kelly, Patricia McLaughlin, John Fleming, Jessica Schubert, Debra Schleiden, Tara Harris, Rahul Prakash, Jody Breneman, Sameer Deshpande, Aarti Saswadkar, Aditi Kumari, Aditi Shitut, Amruta Raorane, Anisha Karmalkar, Ankita Mhambrey, Archana Bhosale, Ashok Vaphare, Ashwini P Patil, Chaitali Khandelwal, Fayaz Shaik, Madhumitha Nadar, Mounika Karka, Neha Kadgaonkar, Nikita Gupta, Nutan Aher, Omkar Potnis, Pallavi Naicker, Rakesh Shinde, Richa Sharma, Rupali Godse, Sheetal Solanki, Shruti Sahu, Snehal Dumbre, Somesh Kumar, Suradnya Patil, Trisha Mandal, Hernandez, Adrian F, Green, Jennifer B, Janmohamed, Salim, D'Agostino, Ralph B, Granger, Christopher B, Jones, Nigel P, Leiter, Lawrence A, Rosenberg, Anne E, Sigmon, Kristina N, Somerville, Matthew C, Thorpe, Karl M, Mcmurray, John J V, Del Prato, Stefano, Mcmurray, John J. V., D'Agostino, Ralph B., Granger, Christopher B., Hernandez, Adrian F., Leiter, Lawrence A., Califf, Robert M, Holman, Rury, Demets, David, Riddle, Matthew, Goodman, Shaun, Mcguire, Darren, Alexander, Karen, Devore, Adam, Melloni, Chiara, Patel, Chetan, Kong, David, Bloomfield, Gerald, Roe, Matthew, Tricoci, Pierluigi, Harrison, Rob, Lopes, Renato, Mathews, Robin, Mehta, Rajendra, Schuyler Jones, William, Vemulapalli, Sreekanth, Povsic, Thoma, Eapen, Zubin, Dombrowski, Keith, Kolls, Brad, Jordan, Dedrick, Ambrosy, Andrew, Greene, Stephen, Mandawat, Aditya, Shavadia, Jay, Cooper, Lauren, Sharma, Abhinav, Guimaraes, Patricia, Friedman, Daniel, Wilson, Matt, Endsley, Patricia, Gentry, Tracy, Collier, Jeannie, Perez, Kathleen, James, Kourtnei, Roush, Jennifer, Pope, Connie, Howell, Christina, Johnson, Megan, Bailey, Matt, Cole, Joanna, Akers, Teresa, Vandyne, Beth, Thomas, Betsy, Rich, Jenny, Bartone, Susan, Beaulieu, Gail, Brown, Kim, Chau, Tuan, Christian, Tamra, Coker, Rebecca, Greene, Deb, Haddock, Trevorlyn, Jenkins, Wendy, Haque, Ghazala, Marquess, Marsha, Pesarchick, Jean, Rethaford, Renee, Stone, Allegra, Al Kawas, Fira, Anderson, Michelle, Enns, Robert, Sinay, Isaac, Mathieu, Chantal, Yordanov, Victor, Hramiak, Irene, Haluzik, Martin, Galatius, Søren, Guerci, Bruno, Nauck, Michael, Migdalis, Ilia, Tan, Choon Beng Kathryn, Kocsis, Gyozo, Giaccari, Andrea, Lee, Moon Kyu, Muñoz, Ernesto German Cardona, Cornel, Jan, Birkeland, Kare, Pinto, Miguel, Tirador, Louie, Olesinska-Mader, Martyna, Shestakova, Marina, Distiller, Larry, Lopez-Sendon, Jose, Eliasson, Bjorn, Chiang, Chern-En, Srimahachota, Suphot, Mankovsky, Bori, Bethel, M Angelyn, Dungan, Kathleen, Kosiborod, Mikhail, Alvarisqueta, Andre, Baldovino, Jorge, Besada, Diego, Calella, Pedro, Cantero, Maria Cecilia, Castaño, Patricia, Chertkoff, Alejandro, Cuadrado, Jesu, De Loredo, Lui, Dominguez, Andrea, Español, Maria Vanesa, Finkelstein, Hernan, Frechtel, Gustavo, Fretes, Jose, Garrido Santos, Natalia, Gonzalez, Joaquin, Litvak, Marco, Loureyro, Juan, Maffei, Laura, Maldonado, Natacha, Mohr Gasparini, Diego, Orio, Silvia, Perez Manghi, Federico, Rodriguez Papini, Nelson, Sala, Jorgelina, Schygiel, Pablo, Sposetti, Georgina, Ulla, Maria, Verra, Fernando, Zabalua, Silvina, Zaidman, Cesar, Crenier, Laurent, Debroye, Corinne, Duyck, Franci, Scheen, André, Van Gaal, Luc, Vercammen, Chri, Damyanova, Velichka, Dimitrov, Stefan, Kovacheva, Snezhina, Lozanov, Lachezar, Margaritov, Viktor, Mihaylova-Shumkova, Rositsa, Nikolaeva, Antoaneta, Stoyanova, Zhasmina, Akhras, Ronald, Beaudry, Yve, Bedard, Jacque, Berlingieri, Joseph, Chehayeb, Raja, Cheung, Stephen, Conway, Jame, Cusson, Jean, Della Siega, Anthony, Dumas, Richard, Dzongowski, Peter, Ferguson, Murdo, Gaudet, Daniel, Grondin, Francoi, Gupta, Anil, Gupta, Milan, Halperin, Frank, Houle, Pierre-Alain, Jones, Michael, Kouz, Simon, Kovacs, Christopher, Landry, Daniel, Lonn, Eva, O'Mahony, William, Peterson, Sean, Reich, Denni, Rosenbloom, Alan, St-Maurice, Francoi, Tugwell, Barna, Vizel, Saul, Woo, Vincent, Brychta, Toma, Cech, Vladimir, Dvorakova, Eva, Edelsberger, Toma, Halciakova, Katarina, Krizova, Jarmila, Lastuvka, Jiri, Piperek, Martin, Prymkova, Vera, Raclavska, Lea, Silhova, Elena, Urbanek, Robin, Vrkoc, Jan, Andersen, Ulla, Brønnum-Schou, Jen, Hove, Jen, Jensen, Jan Skov, Kober, Lar, Kristiansen, Ole Peter, Lund, Per, Melchior, Thoma, Nyvad, Ole, Schou, Morten, Boye, Alain, Cadinot, Didier, Gouet, Didier, Henry, Patrick, Kessler, Laurence, Lalau, Jean-Daniel, Petit, Catherine, Thuan, Jean-Francoi, Voinot, Christel, Vouillarmet, Julien, Axthelm, Christoph, Berger, Dirk, Bieler, Tasso, Birkenfeld, Andrea, Bott, Jochen, Busch, Klau, Caca, Karel, Chevts, Julia, Donaubauer, Torsten, Erlinger, Rudolf, Funke, Klau, Grosskopf, Josef, Hagenow, Andrea, Hamann, Monika, Hartard, Manfred, Heymer, Peter, Huppertz, Wolfgang, Illies, Gabriele, Jacob, Stephan, Jung, Thoma, Kahrmann, Gerd, Kast, Petra, Kellerer, Monika, Kempe, Hans-Peter, Khariouzov, Andrei, Klausmann, Gerhard, Klein, Christiane, Kleinecke-Pohl, Uwe, Kleinertz, Klau, Koch, Thorsten, Kosch, Christine, Lorra, Babette, Luedemann, Joerg, Luttermann, Matthia, Maxeiner, Stephan, Milek, Karsten, Moelle, Andrea, Neumann, Gerhard, Nischik, Ruth, Oehrig-Pohl, Edith, Plassmann, Georg, Pohlmeier, Lar, Proepper, Felix, Regner, Stefan, Rieker, Werner, Rose, Ludger, Samer, Holger, Sauter, Joachim, Schaper, Frank, Schiffer, Clemen, Schmidt, Juergen, Scholz, Bernd-M., Schulze, Joerg, Segner, Alexander, Seufert, Jochen, Sigal, Helena, Steindorf, Joerg, Stockhausen, Juergen, Stuebler, Petra, Taeschner, Heidrun, Tews, Dietrich, Tschoepe, Diethelm, Wilhelm, Karl, Zeller-Stefan, Helga, Avramidis, Iakovo, Bousboulas, Stavro, Bristianou, Magdalini, Dimitriadis, Georgio, Elisaf, Mose, Kotsa, Kalliopi, Melidonis, Andrea, Mitrakou, Asimina, Pagkalos, Emmanouil, Papanas, Nikolao, Pappas, Angelo, Sampanis, Christo, Tentolouris, Nikolao, Tsapas, Apostolo, Tzatzagou, Glykeria, Ozaki, Risa, Hajdú, Csaba, Harcsa, Eleonóra, Konyves, Laszlo, Mucsi, Jáno, Pauker, Zsolt, Petró, Gizella, Plés, Zsolt, Revesz, Katalin, Sándor, Vangel, Vass, Viktor, Avogaro, Angelo, Boemi, Massimo, Bonadonna, Riccardo, Consoli, Agostino, De Cosmo, Salvatore, Di Bartolo, Paolo, Dotta, Francesco, Frontoni, Simona, Galetta, Marianna, Gambineri, Alessandra, Gazzaruso, Carmine, Giorgino, Francesco, Lauro, Davide, Orsi, Emanuela, Paolisso, Giuseppe, Perriello, Gabriele, Piatti, Piermarco, Pontiroli, Antonio, Ponzani, Paola, Rivellese, Angela Albarosa, Sesti, Giorgio, Tonolo, Giancarlo, Trevisan, Roberto, Ahn, Chul Woo, Baik, Sei-Hyun, Cha, Bong-Soo, Chung, Choon-Hee, Jang, Hak Chul, Kim, Chong-Jin, Kim, Hye Soon, Kim, In Joo, Lee, Eun Young, Lee, Hyoung Woo, Lee, Kwan-Woo, Moon, Keon-Woong, Namgung, June, Park, Kyong Soo, Yoo, Soon Jib, Yu, Jaemyung, Llamas, Edmundo-Alfredo Bayram, Cervantes-Escárcega, Jose-Lui, Flota-Cervera, Luis Fernando, González-González, José Gerardo, Pascoe-Gonzalez, Sara, Pelayo-Orozco, Emilia Susana, Ramirez-Diaz, Santiago-Paulino, Saldana-Mendoza, Arturo, Jerjes-Díaz, Carlos Sánchez, Torres-Colores, Jose Juan, Vidrio-Velázquez, Maricela, Villagordoa-Mesa, Juan, Beijerbacht, Hugo Peter, Groutars, Reginald G. E. J., Hoek, Boudewijn A, Hoogslag, Pieter A. M., Kooy, Adriaan, Kragten, Johannes A., Lieverse, Aloysius G., Swart, Hendrik P., Viergever, Eric P., Ahlqvist, Jørn, Cooper, John, Gulseth, Hanne, Guttormsen, Gaute, Wium, Cecilie, Arbañil, Hugo, Calderon, Jorge, Camacho, Lui, Espinoza, Augusto Dextre, Garrido, Elizabeth, Luna, Alejandro, Manrique, Helard, Revoredo, Frederick Massucco, Gonzales, Rolando Varga, Rincon, Luis Zapata, Zubiate, Carlo, Ebo, Geraldine, Morales-Palomares, Ellen, Arciszewska, Malgorzata, Banach, Marek, Bijata-Bronisz, Renata, Derezinski, Tadeusz, Gadzinski, Waldemar, Gajek, Jacek, Klodawska, Katarzyna, Krzyzagorska, Ewa, Madej, Andrzej, Miekus, Pawel, Opiela, Jaroslaw, Romanczuk, Piotr, Siegel, Anna, Skokowska, Ewa, Stankiewicz, Andrzej, Stasinska, Teresa, Trznadel-Morawska, Iwona, Witek, Robert, Aksentyev, Sergey, Bondar, Irina, Demidova, Irina, Dreval, Alexander, Ershova, Olga, Galstyan, Gagik, Garganeeva, Alla, Izmozherova, Nadezhda, Karetnikova, Victoria, Kharakhulakh, Marina, Khokhlov, Aleksandr, Kobalava, Zhanna, Koshelskaya, Olga, Kosmacheva, Elena, Kostin, Vladimir, Koziolova, Natalia, Kuzin, Anatoly, Lesnov, Victor, Lysenko, Tatyana, Markov, Valentin, Mayorov, Alexander, Moiseev, Sergey, Myasoedova, Svetlana, Petunina, Nina, Rebrov, Andrey, Ruyatkina, Ludmila, Samoylova, Julia, Sazonova, Olga, Shilkina, Natalia, Sokolova, Nadezhda, Vasilevskaya, Olga, Verbovaya, Nelli, Vishneva, Elena, Vorobyev, Sergey, Vorokhobina, Natalya, Zanozina, Olga, Zhdanova, Elena, Zykova, Tatyana, Burgess, Lesley, Coetzee, Kathleen, Dawood, Saleem, Lombard, Landman, Makotoko, Ellen, Moodley, Rajendran, Oosthuysen, Wessel, Sarvan, Mohamed, Calvo Gómez, Carlo, Cano Rodríguez, Isidoro, Castro Conde, Almudena, Cequier Fillat, Angel, Cuatrecasas Cambra, Guillem, de Álvaro Moreno, Fernando, De Teresa Parreño, Lui, Delgado Lista, Javier, Domínguez Escribano, José Ramón, Durán García, Santiago, Elvira González, Javier, Fernández Rodríguez, José María, Goday Arno, Alberto, Gomez Huelgas, Ricardo, González Juanatey, José Ramón, Hernandez Mijares, Antonio, Jiménez Díaz, Víctor Alfonso, Jodar Gimeno, Esteban, Lucas Morante, Tomá, Marazuela, Monica, Martell Claros, Nieve, Mauricio Puente, Didac, Mena Ribas, Elena, Merino Torres, Juan Francisco, Mezquita Raya, Pedro, Nubiola Calonge, Andreu, Ordoñez Sánchez, Xavier, Pascual Izuel, Jose Maria, Perea Castilla, Verónica, Pérez Pérez, Antonio, Perez Soto, Isabel, Quesada Charneco, Miguel, Quesada Simón, Angustia, Redón Mas, Josep, Rego Iraeta, Antonia, Rodriguez Alvarez, Maria, Rodríguez Rodríguez, Irene, Sabán Ruiz, José, Soto González, Alfonso, Tinahones Madueno, Francisco, Trescoli Serrano, Carlo, Ulied Armiñana, Angel, Bachus, Erasmu, Berndtsson Blom, Katarina, Eliasson, Ken, Koskinen, Pekka, Larnefeldt, Han, Lif-Tiberg, Cornelia, Linderfalk, Carina, Lund, Gustav, Lundman, Pia, Moris, Linda, Olsson, Åke, Salmonsson, Staffan, Sanmartin Berglund, Johan, Sjöberg, Folke, Söderberg, Stefan, Torstensson, Ingemar, Chen, Jung-Fu, Tien, Kai Jen, Tseng, Shih-Ting, Tu, Shih-Te, Wang, Chih-Yuan, Wang, Ji-Hung, Phrommintikul, Arintaya, Yamwong, Sukit, Jintapakorn, Woravut, Hutayanon, Pisit, Sansanayudh, Nakarin, Bazhan, Larysa, Fushtey, Ivan, Grachova, Mariya, Katerenchuk, Vitaliy, Korpachev, Vadym, Kravchun, Nonna, Larin, Oleksandr, Mykhalchyshyn, Galyna, Myshanych, Halyna, Oleksyk, Olga, Orlenko, Valeriia, Pashkovska, Nataliia, Pertseva, Nataliia, Petrosyan, Olena, Smirnov, Ivan, Vlasenko, Maryna, Zlova, Tetiana, Aye, Myint, Baksi, Arun, Balasubramani, Mathangi, Beboso, Ronnie, Blagden, Mark, Bundy, Charle, Cookson, Tobia, Copland, Allan, Emslie-Smith, Alistair, Green, Fiona, Gunstone, Anthony, Issa, Basil, Jackson-Voyzey, Ewart, Johnson, Andrew, Maclean, Malcolm, Mcknight, John, Muzulu, Solomon, O'Connell, Ian, Oyesile, Babatunde, Patterson, Catherine, Pearson, Ewan, Philip, Sam, Smith, Paul, Sukumaran, Usha, Abbas, Jalal, Aggarwala, Gaurav, Akhter, Faiq, Andersen, Jame, Anglade, Moise, Argoud, George, Ariani, Mehrdad, Ashdji, Reswan, Bakhtari, Ladan, Banerjee, Subhash, Bartlett, Andrew, Baum, Howard, Bays, Harold, Beasley, Richard, Belfort de Aguiar, Renata, Benjamin, Sabrina, Bhagwat, Ravi, Bhargava, Anuj, Bode, Bruce, Bratcher, Christina, Briskin, Toby, Brockmyre, Andrew, Broughton, Raymond, Brown, Judith, Budhraja, Madhusudan, Cannon, Kevin, Carr, Jewell, Cathcart, Harold, Cavale, Arvind, Chaykin, Loui, Cheung, Deanna, Childress, Richard, Cohen, Allan, Condit, Jonathan, Cooksey, Erin, Cornett, George Mitchell, Dauber, Ira, Davila, William, De Armas, Lui, Dean, Juliu, Detweiler, Robert, Diaz, Ernesto, Di Giovanna, Michael, Dor, Isaac, Drummond, Waymon, Eagerton, Donald, Earl, John, Eaton, Charle, Ellison, Howard, Farris, Neil, Fiel, Thoma, Firek, Anthony, First, Brian, Forgosh, Le, French, William, Gandy, Winston, Garcia, Ronald, Gill, Santosh, Gordon, Murray, Guice, Michael, Gummadi, Siva, Hackenyos, Jonathan, Hairston, Kristen, Hanson, Lenita, Harrison, Lindsay, Hartman, Israel, Heitner, John, Hejeebu, Srini, Hermany, Paul, Hernandez-Cassis, Carlo, Hidalgo, Horacio, Higgins, Alexander, Ibrahim, Hassan, Jacobs, Shahram, Johnson, David, Joshi, Parag, Kaster, Steven, Kellum, Daniel, Kim, Christopher, Kim, Ellen, Kirby, William, Knouse, Albert, Kulback, Steven, Kumar, Mariananda, Kuruvanka, Tulsida, Labroo, Ajay, Lasswell, William, Lentz, John, Lenzmeier, Thoma, Lewis, David, Li, Zhaoping, Lillestol, Michael, Little, Raymond, Lorraine, Richard, McKeown-Biagas, Cecilia, Mcneill, Robert, Mehta, Anand, Miller, Alan, Moran, Joseph, Morawski, Emily, Nadar, Venkatesh, O'Connor, Thoma, Odio, Alberto, Parker, Reginald, Patel, Rajesh, Phillips, Lawrence, Raad, George, Rahman, Aref, Raikhel, Marina, Raisinghani, Ajit, Rajan, Raj, Rasouli, Neda, Rauzi, Frank, Rohr, Kathryn, Roseman, Hal, Rovner, Sergio, Saba, Fadi, Sachson, Richard, Schabauer, Alex, Schneider, Ricky, Schuchard, Timothy, Sensenbrenner, John, Shlesinger, Yshay, Singh, Narendra, Sivalingam, Kanagaratnam, Stonesifer, Larry, Storey, Daniel, Suh, David, Tahir, Mohammed, Tan, Anjanette, Tan, Marilyn, Taylon, Alain, Thakkar, Maitreya, Tripathy, Devjit, Uwaifo, Gabriel, Vedere, Amarnath, Venugopal, Chandra, Vo, Anthony, Welch, Michelle, Welker, Jame, White, Alexander, Willis, John, Wynne, Alan, Yazdani, Shahram, Rosenberg, Anne, Price, Lauren, Sigmon, Kristina, Lokhngina, Yuliya, Xing, Weibing, Overton, Robert, Stewart, Murray, Stead, Janet, Lindsay, Alistair, Patel, Vicka, Ross, Jorge, Soffer, Joseph, Daga, Shruti, Sowell, Margaret, Patel, Prashant, Garvey, Louisa, Ackert, Jessica, Abraham, Sybil, Sabol, Mary Beth, Altobelli, Desma, Ha, Juyoung, Kulkarni, Mangesh, Somerville, Matthew, Noronha, Drusilla, Casson, Ed, Zang, Eddie, Sandhu, Chamandeep, Kumar, Rakesh, Chen, David, Taft, Lin, Patel, Rajivkumar, Ye, June, Shannon, Jennifer, Wilson, Tim, Babi, Charleen, Miller, Diane, Thorpe, Karl, Russell, Rachael, Bull, Georgina, Hereghty, Belinda, Fernandez-Salazar, Eva, Longley, Troy, Donaldson, Jill, Jarosz, Marie, Murphy, Karen, Adams, Patricia, Smith, Peter, James, Rachel, Richards, Jackie, Sedani, Sangeeta, Althouse, Denise, Watson, David, Lorimer, Jamie, Lauder, Steven, Schultheis, Ron, Womer, Terese, Wraight, Ella, Li, Wenyan, Price-Olsen, Emma, Watson, Anthony, Kelly, Aoife, Mclaughlin, Patricia, Fleming, John, Schubert, Jessica, Schleiden, Debra, Harris, Tara, Prakash, Rahul, Breneman, Jody, Deshpande, Sameer, Saswadkar, Aarti, Kumari, Aditi, Shitut, Aditi, Raorane, Amruta, Karmalkar, Anisha, Mhambrey, Ankita, Bhosale, Archana, Vaphare, Ashok, Patil, Ashwini P, Khandelwal, Chaitali, Shaik, Fayaz, Nadar, Madhumitha, Karka, Mounika, Kadgaonkar, Neha, Gupta, Nikita, Aher, Nutan, Potnis, Omkar, Naicker, Pallavi, Shinde, Rakesh, Sharma, Richa, Godse, Rupali, Solanki, Sheetal, Sahu, Shruti, Dumbre, Snehal, Kumar, Somesh, Patil, Suradnya, Mandal, Trisha, McMurray, John J V, McMurray, John J.V., DeMets, David, McGuire, Darren, Groutars, Reginald G.E.J., Hoogslag, Pieter A.M., McKnight, John, McNeill, Robert, Ha, JuYoung, McLaughlin, Patricia, Hernandez, A. F., Green, J. B., Janmohamed, S., D'Agostino, R. B., Granger, C. B., Jones, N. P., Leiter, L. A., Rosenberg, A. E., Sigmon, K. N., Somerville, M. C., Thorpe, K. M., Mcmurray, J. J. V., Del Prato, S., Califf, R. M., Holman, R., Demets, D., Riddle, M., Goodman, S., Mcguire, D., Alexander, K., Devore, A., Melloni, C., Patel, C., Kong, D., Bloomfield, G., Roe, M., Tricoci, P., Harrison, R., Lopes, R., Mathews, R., Mehta, R., Schuyler Jones, W., Vemulapalli, S., Povsic, T., Eapen, Z., Dombrowski, K., Kolls, B., Jordan, D., Ambrosy, A., Greene, S., Mandawat, A., Shavadia, J., Cooper, L., Sharma, A., Guimaraes, P., Friedman, D., Wilson, M., Endsley, P., Gentry, T., Collier, J., Perez, K., James, K., Roush, J., Pope, C., Howell, C., Johnson, M., Bailey, M., Cole, J., Akers, T., Vandyne, B., Thomas, B., Rich, J., Bartone, S., Beaulieu, G., Brown, K., Chau, T., Christian, T., Coker, R., Greene, D., Haddock, T., Jenkins, W., Haque, G., Marquess, M., Pesarchick, J., Rethaford, R., Stone, A., Al Kawas, F., Anderson, M., Enns, R., Sinay, I., Mathieu, C., Yordanov, V., Hramiak, I., Haluzik, M., Galatius, S., Guerci, B., Nauck, M., Migdalis, I., Tan, C. B. K., Kocsis, G., Giaccari, A., Lee, M. K., Munoz, E. G. C., Cornel, J., Birkeland, K., Pinto, M., Tirador, L., Olesinska-Mader, M., Shestakova, M., Distiller, L., Lopez-Sendon, J., Eliasson, B., Chiang, C. -E., Srimahachota, S., Mankovsky, B., Bethel, M. A., Dungan, K., Kosiborod, M., Alvarisqueta, A., Baldovino, J., Besada, D., Calella, P., Cantero, M. C., Castano, P., Chertkoff, A., Cuadrado, J., De Loredo, L., Dominguez, A., Espanol, M. V., Finkelstein, H., Frechtel, G., Fretes, J., Garrido Santos, N., Gonzalez, J., Litvak, M., Loureyro, J., Maffei, L., Maldonado, N., Mohr Gasparini, D., Orio, S., Perez Manghi, F., Rodriguez Papini, N., Sala, J., Schygiel, P., Sposetti, G., Ulla, M., Verra, F., Zabalua, S., Zaidman, C., Crenier, L., Debroye, C., Duyck, F., Scheen, A., Van Gaal, L., Vercammen, C., Damyanova, V., Dimitrov, S., Kovacheva, S., Lozanov, L., Margaritov, V., Mihaylova-Shumkova, R., Nikolaeva, A., Stoyanova, Z., Akhras, R., Beaudry, Y., Bedard, J., Berlingieri, J., Chehayeb, R., Cheung, S., Conway, J., Cusson, J., Della Siega, A., Dumas, R., Dzongowski, P., Ferguson, M., Gaudet, D., Grondin, F., Gupta, A., Gupta, M., Halperin, F., Houle, P. -A., Jones, M., Kouz, S., Kovacs, C., Landry, D., Lonn, E., O'Mahony, W., Peterson, S., Reich, D., Rosenbloom, A., St-Maurice, F., Tugwell, B., Vizel, S., Woo, V., Brychta, T., Cech, V., Dvorakova, E., Edelsberger, T., Halciakova, K., Krizova, J., Lastuvka, J., Piperek, M., Prymkova, V., Raclavska, L., Silhova, E., Urbanek, R., Vrkoc, J., Andersen, U., Bronnum-Schou, J., Hove, J., Jensen, J. 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R., Duran Garcia, S., Elvira Gonzalez, J., Fernandez Rodriguez, J. M., Goday Arno, A., Gomez Huelgas, R., Gonzalez Juanatey, J. R., Hernandez Mijares, A., Jimenez Diaz, V. A., Jodar Gimeno, E., Lucas Morante, T., Marazuela, M., Martell Claros, N., Mauricio Puente, D., Mena Ribas, E., Merino Torres, J. F., Mezquita Raya, P., Nubiola Calonge, A., Ordonez Sanchez, X., Pascual Izuel, J. M., Perea Castilla, V., Perez Perez, A., Perez Soto, I., Quesada Charneco, M., Quesada Simon, A., Redon Mas, J., Rego Iraeta, A., Rodriguez Alvarez, M., Rodriguez Rodriguez, I., Saban Ruiz, J., Soto Gonzalez, A., Tinahones Madueno, F., Trescoli Serrano, C., Ulied Arminana, A., Bachus, E., Berndtsson Blom, K., Eliasson, K., Koskinen, P., Larnefeldt, H., Lif-Tiberg, C., Linderfalk, C., Lund, G., Lundman, P., Moris, L., Olsson, A., Salmonsson, S., Sanmartin Berglund, J., Sjoberg, F., Soderberg, S., Torstensson, I., Chen, J. -F., Tien, K. J., Tseng, S. -T., Tu, S. -T., Wang, C. -Y., Wang, J. -H., Phrommintikul, A., Yamwong, S., Jintapakorn, W., Hutayanon, P., Sansanayudh, N., Bazhan, L., Fushtey, I., Grachova, M., Katerenchuk, V., Korpachev, V., Kravchun, N., Larin, O., Mykhalchyshyn, G., Myshanych, H., Oleksyk, O., Orlenko, V., Pashkovska, N., Pertseva, N., Petrosyan, O., Smirnov, I., Vlasenko, M., Zlova, T., Aye, M., Baksi, A., Balasubramani, M., Beboso, R., Blagden, M., Bundy, C., Cookson, T., Copland, A., Emslie-Smith, A., Green, F., Gunstone, A., Issa, B., Jackson-Voyzey, E., Johnson, A., Maclean, M., Mcknight, J., Muzulu, S., O'Connell, I., Oyesile, B., Patterson, C., Pearson, E., Philip, S., Smith, P., Sukumaran, U., Abbas, J., Aggarwala, G., Akhter, F., Andersen, J., Anglade, M., Argoud, G., Ariani, M., Ashdji, R., Bakhtari, L., Banerjee, S., Bartlett, A., Baum, H., Bays, H., Beasley, R., Belfort de Aguiar, R., Benjamin, S., Bhagwat, R., Bhargava, A., Bode, B., Bratcher, C., Briskin, T., Brockmyre, A., Broughton, R., Brown, J., Budhraja, M., Cannon, K., Carr, J., Cathcart, H., Cavale, A., Chaykin, L., Cheung, D., Childress, R., Cohen, A., Condit, J., Cooksey, E., Cornett, G. 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Escribano, J, Duran Garcia, S, Elvira Gonzalez, J, Fernandez Rodriguez, J, Goday Arno, A, Gomez Huelgas, R, Gonzalez Juanatey, J, Hernandez Mijares, A, Jimenez Diaz, V, Jodar Gimeno, E, Lucas Morante, T, Marazuela, M, Martell Claros, N, Mauricio Puente, D, Mena Ribas, E, Merino Torres, J, Mezquita Raya, P, Nubiola Calonge, A, Ordonez Sanchez, X, Pascual Izuel, J, Perea Castilla, V, Perez Perez, A, Perez Soto, I, Quesada Charneco, M, Quesada Simon, A, Redon Mas, J, Rego Iraeta, A, Rodriguez Alvarez, M, Rodriguez Rodriguez, I, Saban Ruiz, J, Soto Gonzalez, A, Tinahones Madueno, F, Trescoli Serrano, C, Ulied Arminana, A, Bachus, E, Berndtsson Blom, K, Eliasson, K, Koskinen, P, Larnefeldt, H, Lif-Tiberg, C, Linderfalk, C, Lund, G, Lundman, P, Moris, L, Olsson, A, Salmonsson, S, Sanmartin Berglund, J, Sjoberg, F, Soderberg, S, Torstensson, I, Chen, J, Tien, K, Tseng, S, Tu, S, Wang, C, Wang, J, Phrommintikul, A, Yamwong, S, Jintapakorn, W, Hutayanon, P, Sansanayudh, N, Bazhan, L, Fushtey, I, Grachova, M, Katerenchuk, V, Korpachev, V, Kravchun, N, Larin, O, Mykhalchyshyn, G, Myshanych, H, Oleksyk, O, Orlenko, V, Pashkovska, N, Pertseva, N, Petrosyan, O, Smirnov, I, Vlasenko, M, Zlova, T, Aye, M, Baksi, A, Balasubramani, M, Beboso, R, Blagden, M, Bundy, C, Cookson, T, Copland, A, Emslie-Smith, A, Green, F, Gunstone, A, Issa, B, Jackson-Voyzey, E, Johnson, A, Maclean, M, Mcknight, J, Muzulu, S, O'Connell, I, Oyesile, B, Patterson, C, Pearson, E, Philip, S, Smith, P, Sukumaran, U, Abbas, J, Aggarwala, G, Akhter, F, Andersen, J, Anglade, M, Argoud, G, Ariani, M, Ashdji, R, Bakhtari, L, Banerjee, S, Bartlett, A, Baum, H, Bays, H, Beasley, R, Belfort de Aguiar, R, Benjamin, S, Bhagwat, R, Bhargava, A, Bode, B, Bratcher, C, Briskin, T, Brockmyre, A, Broughton, R, Brown, J, Budhraja, M, Cannon, K, Carr, J, Cathcart, H, Cavale, A, Chaykin, L, Cheung, D, Childress, R, Cohen, A, Condit, J, Cooksey, E, Cornett, G, Dauber, I, Davila, W, De Armas, L, Dean, J, Detweiler, R, Diaz, E, Di Giovanna, M, Dor, I, Drummond, W, Eagerton, D, Earl, J, Eaton, C, Ellison, H, Farris, N, Fiel, T, Firek, A, First, B, Forgosh, L, French, W, Gandy, W, Garcia, R, Gill, S, Gordon, M, Guice, M, Gummadi, S, Hackenyos, J, Hairston, K, Hanson, L, Harrison, L, Hartman, I, Heitner, J, Hejeebu, S, Hermany, P, Hernandez-Cassis, C, Hidalgo, H, Higgins, A, Ibrahim, H, Jacobs, S, Johnson, D, Joshi, P, Kaster, S, Kellum, D, Kim, E, Kirby, W, Knouse, A, Kulback, S, Kumar, M, Kuruvanka, T, Labroo, A, Lasswell, W, Lentz, J, Lenzmeier, T, Lewis, D, Li, Z, Lillestol, M, Little, R, Lorraine, R, McKeown-Biagas, C, Mcneill, R, Mehta, A, Miller, A, Moran, J, Morawski, E, Nadar, V, O'Connor, T, Odio, A, Parker, R, Patel, R, Phillips, L, Raad, G, Rahman, A, Raikhel, M, Raisinghani, A, Rajan, R, Rasouli, N, Rauzi, F, Rohr, K, Roseman, H, Rovner, S, Saba, F, Sachson, R, Schabauer, A, Schneider, R, Schuchard, T, Sensenbrenner, J, Shlesinger, Y, Singh, N, Sivalingam, K, Stonesifer, L, Storey, D, Suh, D, Tahir, M, Tan, A, Tan, M, Taylon, A, Thakkar, M, Tripathy, D, Uwaifo, G, Vedere, A, Venugopal, C, Vo, A, Welch, M, Welker, J, White, A, Willis, J, Wynne, A, Yazdani, S, Price, L, Lokhngina, Y, Xing, W, Overton, R, Stewart, M, Stead, J, Lindsay, A, Patel, V, Ross, J, Soffer, J, Daga, S, Sowell, M, Patel, P, Garvey, L, Ackert, J, Abraham, S, Sabol, M, Altobelli, D, Ha, J, Kulkarni, M, Noronha, D, Casson, E, Zang, E, Sandhu, C, Kumar, R, Chen, D, Taft, L, Ye, J, Shannon, J, Wilson, T, Babi, C, Miller, D, Russell, R, Bull, G, Hereghty, B, Fernandez-Salazar, E, Longley, T, Donaldson, J, Jarosz, M, Murphy, K, Adams, P, James, R, Richards, J, Sedani, S, Althouse, D, Watson, D, Lorimer, J, Lauder, S, Schultheis, R, Womer, T, Wraight, E, Li, W, Price-Olsen, E, Watson, A, Kelly, A, Mclaughlin, P, Fleming, J, Schubert, J, Schleiden, D, Harris, T, Prakash, R, Breneman, J, Deshpande, S, Saswadkar, A, Kumari, A, Shitut, A, Raorane, A, Karmalkar, A, Mhambrey, A, Bhosale, A, Vaphare, A, Patil, A, Khandelwal, C, Shaik, F, Nadar, M, Karka, M, Kadgaonkar, N, Gupta, N, Aher, N, Potnis, O, Naicker, P, Shinde, R, Sharma, R, Godse, R, Solanki, S, Sahu, S, Dumbre, S, Kumar, S, Patil, S, and Mandal, T

Subjects
Male, Placebo-controlled study, Myocardial Infarction, alanine aminotransferase, albiglutide, bilirubin, placebo, antidiabetic agent, glucagon like peptide 1, rGLP-1 protein, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Glucagon-Like Peptide 1, Cardiovascular Disease, Medicine(all), education.field_of_study, Subcutaneous, Medicine (all), albigutide, Hazard ratio, General Medicine, Middle Aged, Albiglutide, Stroke, Treatment Outcome, Tolerability, Cardiovascular Diseases, Female, type 2 diabetes, Type 2, Human, Adult, medicine.medical_specialty, Injections, Subcutaneous, Population, 030209 endocrinology & metabolism, Placebo, Injections, Subcutaneou, Drug Administration Schedule, Injections, 03 medical and health sciences, Double-Blind Method, Internal medicine, Diabetes Mellitus, medicine, Humans, Hypoglycemic Agents, education, Aged, Diabetes Mellitus, Type 2, Hypoglycemic Agent, business.industry, Semaglutide, Settore MED/13 - ENDOCRINOLOGIA, Harmony, business
Abstract

Background: \ud Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.\ud \ud Methods: \ud We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.\ud \ud Findings: \ud Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p

Published
2018

12. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure

Author

Karl Swedberg, James B. Young, Inder S. Anand, Sunfa Cheng, Akshay S. Desai, Rafael Diaz, Aldo P. Maggioni, John J. V. McMurray, Christopher O'Connor, Marc A. Pfeffer, Scott D. Solomon, Yan Sun, Michal Tendera, Dirk J. van Veldhuisen, Young J, Grinfeld L, Krum H, Vanhaecke J, Olivera Clausell N, Goudev A, Howlett J, Corbalan R, Hradec J, Kober L, Eha J, Cohen Solal A, Anker SD, Chopra V, Lewis B, Erglis A, Sakalyte G, Cardona Munoz E, Dunselman P, Dickstein K, Ponikowski P, Seabra Gomes R, Apetrei E, Mareev V, Murin J, Dalby A, Lopez Sendon J, Willenheimer R, Cleland J, Adams K, Anand I, Butler J, Dunlap M, Felker M, Ghali J, Levy W, Carson P, Cohn J, Drexler H, Pocock S, Ryden L, Poole Wilson P, Fishbane S, Ivanovich P, Nissenson A, Katz S, Barkoudah E, Campbell P, Desai A, Finn PV, Hartley L, Kasabov R, Odutayo KA, Rajesh V, Solomon S, Weinrauch LA, Albizem M, Cheng S, Chou W, Deegenaars M, Dougherty M, Fouqueray B, Froissart M, Froment A, Gadd S, Ghosh S, Grazette L, Guillet S, Gulabani D, Haddock B, Harris C, Jaffer A, Kerns C, Kim J, Knussel B, Law H, Mather R, Mix C, Moore L, Moyes R, Polu K, Rossert J, Scarlata D, Smirnakis K, Smith L, Snyder W, Sun Y, Trotman ML, Wasserman S, Watkins A, Wong M, Zhang Y, Amuchastegui M, Belziti C, Bluguermann J, Caccavo M, Cartasegna L, Colque R, Cuneo C, Fernandez A, Gabito A, Goicochea R, Gonzalez M, Gorosito V, Hominal M, Kevorkian R, Litvak Bruno M, Llanos J, Mackinnon I, Manuale O, Marzetti E, Nul D, Perna E, Riccitelli M, Sanchez A, Santos D, Schygiel P, Toblli J, Vogel D, Aggarwal A, Amerena J, De Looze F, Fletcher P, Hare D, Ireland M, Lattimore J, Marwick T, Sindone A, Thompson P, Waites J, Altenberger J, Ebner C, Lenz K, Pacher R, Poelzl G, Charlier F, de Ceuninck M, De Keulenaer G, Dendale P, Maréchal P, Mullens W, Thoeng J, Vanderheyden M, Weytjens C, Wollaert B, Albuquerque D, Almeida D, Aspe y. Rosas J, Bocchi E, Bordignon S, Clausell N, Kaiser S, Leaes P, Martins Alves S, Montera M, Moura L, Pereira de Castro R, Rassi S, Reis A, Saraiva J, Simões M, Souza Neto J, Teixeira M, Benov H, Chompalova B, Donova T, Georgiev P, Gotchev D, Grigorov M, Guenova D, Hergeldjieva V, Ivanov D, Kostova E, Manolova A, Marchev S, Nikolov F, Popov A, Raev D, Tzekova M, Czarnecki W, Giannetti N, Haddad H, Heath J, Huynh T, Lepage S, Liu P, Lonn E, Ma P, Manyari D, Moe G, Parker J, Pesant Y, Rajda M, Ricci J, Roth S, Sestier F, Sluzar V, Sussex B, Vizel S, Antezana G, Bugueno C, Castro P, Conejeros C, Manriquez L, Martinez D, Potthoff S, Stockins B, Vukasovic J, Gregor P, Herold M, Jerabek O, Jirmar R, Kuchar R, Linhart A, Podzemska B, Soucek M, Spac J, Spacek R, Vodnansky P, Bronnum Schou J, Clemmensen K, Egstrup K, Jensen G, Kjoller Hansen L, Markenvard J, Rokkedal J, Skagen K, Torp Pedersen C, Tuxen C, Videbak L, Laks T, Vahula V, Harjola V, Kettunen R, Kotila M, Bauer F, Coisne D, Davy J, De Groote P, Dos Santos P, Funck F, Galinier M, Gibelin P, Isnard R, Neuder Y, Roul G, Sabatier R, Trochu J, Denny S, Dreykluft T, Flesch M, Genth Zotz S, Hambrecht R, Hein J, Jeserich M, John M, Kreider Stempfle H, Laufs U, Muellerleile K, Natour M, Sandri M, Schäufele T, von Hodenberg E, Weyland K, Winkelmann B, Tse H, Yan B, Barsi B, Csikasz J, Dezsi C, Edes I, Forster T, Karpati P, Kerekes C, Kis E, Kosa I, Lupkovics G, Nagy A, Preda I, Ronaszeki A, Tomcsanyi J, Zamolyi K, Agarwal D, Bahl V, Bordoloi A, Chockalingam K, Chopda M, Dugal J, Ghaisas N, Grant P, Hiremath S, Iyengar S, Jagadeesa Subramania B, Jain P, Joshi A, Khan A, Mullasari A, Naik S, Oomman A, Pai V, Pareppally Gopal R, Parikh K, Patel T, Prakash V, Sastry B, Sathe S, Sinha N, Srikanthan V, Subburamakrishnan P, Thacker H, Wander G, Admon D, Katz A, Klainman E, Marmor A, Moriel M, Mosseri M, Shotan A, Weinstein J, Zimlichman R, Agostoni P, Albanese M, Alunni G, Bini R, Boccanelli A, Bolognese L, Campana C, Carbonieri E, Carpino C, Checco L, Cosmi F, Angelo GD, De Cristofaro M, Floresta A, Fucili A, Galvani M, Ivleva A, Marra S, Musca G, Peccerillo N, Picchio E, Russo T, Scelsi L, Senni M, Tavazzi L, Jasinkevica I, Kakurina N, Veze I, Volans E, Bagdonas A, Berukstis E, Celutkiene J, Dambrauskaite A, Jarasuniene D, Luksiene D, Rudys A, Sliaziene S, Aguilar Romero R, Cardona Muñoz E, Castro Jimenez J, Chavez Herrera J, Chuquiure Valenzuela E, De la Pena G, Herrera E, Leiva Pons J, Lopez Alvarado A, Mendez Machado G, Ramos Lopez G, Basart D, Buijs E, Cornel J, de Leeuw M, Dijkgraaf R, Freericks M, Hamraoui K, Lenderlink T, Linssen G, Lodewick P, Lodewijks C, Lok D, Nierop P, Ronner E, Somsen A, van Dantzig J, van der Burgh P, van Kempen L, van Vlies B, Voors A, Wardeh A, Willems F, Gundersen T, Hole T, Thalamus J, Westheim A, Dabrowski M, Gorski J, Korewicki J, Kuc K, Miekus P, Musial W, Niegowska J, Piotrowski W, Podolec P, Polonski L, Rynkiewicz A, Szelemej R, Trusz Gluza M, Ujda M, Wojciechowski D, Wysokinski A, Camacho A, Fonseca C, Monteiro P, Bruckner I, Carasca E, Coman I, Datcu M, Dragulescu S, Ionescu P, Iordachescu Petica D, Manitiu I, Popa V, Pop Moldovan A, Radoi M, Stamate S, Tomescu M, Vita I, Aroutiounov G, Ballyuzek M, Bart B, Churina S, Glezer M, Goloshchekin B, Kobalava Z, Kostenko V, Lopatin Y, Martynov A, Orlov V, Semernin E, Shogenov Z, Sidorenko B, Skvortsov A, Storzhakov G, Sulimov V, Talibov O, Tereshenko S, Tsyrline V, Zadionchenko V, Zateyshchikov D, Dzupina A, Hranai M, Kmec J, Micko K, Pella D, Sojka G, Spisak V, Vahala P, Vinanska D, Badat A, Bayat J, Dawood S, Delport E, Ellis G, Garda R, Klug E, Mabin T, Naidoo D, Pretorius M, Ranjith N, Van Zyl L, Weich H, Anguita M, Berrazueta J, Bruguera i. 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Brien T, Oellerich W, Oren R, Pamboukian S, Pereira N, Pitt W, Porter C, Prabhu S, Promisloff S, Ratkovec R, Richardson R, Ross A, Saleh N, Saltzberg M, Sarkar S, Schmedtje J, Schneider R, Schuyler G, Shanes J, Sharma A, Siegel C, Siegel R, Silber D, Singh N, Singh J, Singh V, Sklar J, Small R, Smith A, Smith E, Smull D, Sotolongo R, Staniloae C, Stapleton D, Steele P, Stehlik J, Stein M, Tang W, Thadani U, Torre Amoine G, Trichon B, Tsai C, Tummala R, Van Bakel A, Vicari R, Vijay N, Vijayaraghavan K, Vittorio T, Vossler M, Wagoner L, Wallis D, Ward N, Widmer M, Wight J, Wilkins C, Williams C, Williams G, Winchester M, Winkel E, Wittmer B, Wood D, Wormer D, Wright R, Xu Z, Yasin M, Zolty R., PERRONE FILARDI, PASQUALE, Karl, Swedberg, James B., Young, Inder S., Anand, Sunfa, Cheng, Akshay S., Desai, Rafael, Diaz, Aldo P., Maggioni, John J. V., Mcmurray, Christopher, O'Connor, Marc A., Pfeffer, Scott D., Solomon, Yan, Sun, Michal, Tendera, Dirk J., van Veldhuisen, Young, J, Grinfeld, L, Krum, H, Vanhaecke, J, Olivera Clausell, N, Goudev, A, Howlett, J, Corbalan, R, Hradec, J, Kober, L, Eha, J, Cohen Solal, A, Anker, Sd, Chopra, V, Lewis, B, Erglis, A, Sakalyte, G, Cardona Munoz, E, Dunselman, P, Dickstein, K, Ponikowski, P, Seabra Gomes, R, Apetrei, E, Mareev, V, Murin, J, Dalby, A, Lopez Sendon, J, Willenheimer, R, Cleland, J, Adams, K, Anand, I, Butler, J, Dunlap, M, Felker, M, Ghali, J, Levy, W, Carson, P, Cohn, J, Drexler, H, Pocock, S, Ryden, L, Poole Wilson, P, Fishbane, S, Ivanovich, P, Nissenson, A, Katz, S, Barkoudah, E, Campbell, P, Desai, A, Finn, Pv, Hartley, L, Kasabov, R, Odutayo, Ka, Rajesh, V, Solomon, S, Weinrauch, La, Albizem, M, Cheng, S, Chou, W, Deegenaars, M, Dougherty, M, Fouqueray, B, Froissart, M, Froment, A, Gadd, S, Ghosh, S, Grazette, L, Guillet, S, Gulabani, D, Haddock, B, Harris, C, Jaffer, A, Kerns, C, Kim, J, Knussel, B, Law, H, Mather, R, Mix, C, Moore, L, Moyes, R, Polu, K, Rossert, J, Scarlata, D, Smirnakis, K, Smith, L, Snyder, W, Sun, Y, Trotman, Ml, Wasserman, S, Watkins, A, Wong, M, Zhang, Y, Amuchastegui, M, Belziti, C, Bluguermann, J, Caccavo, M, Cartasegna, L, Colque, R, Cuneo, C, Fernandez, A, Gabito, A, Goicochea, R, Gonzalez, M, Gorosito, V, Hominal, M, Kevorkian, R, Litvak Bruno, M, Llanos, J, Mackinnon, I, Manuale, O, Marzetti, E, Nul, D, Perna, E, Riccitelli, M, Sanchez, A, Santos, D, Schygiel, P, Toblli, J, Vogel, D, Aggarwal, A, Amerena, J, De Looze, F, Fletcher, P, Hare, D, Ireland, M, Lattimore, J, Marwick, T, Sindone, A, Thompson, P, Waites, J, Altenberger, J, Ebner, C, Lenz, K, Pacher, R, Poelzl, G, Charlier, F, de Ceuninck, M, De Keulenaer, G, Dendale, P, Maréchal, P, Mullens, W, Thoeng, J, Vanderheyden, M, Weytjens, C, Wollaert, B, Albuquerque, D, Almeida, D, Aspe y., Rosas J, Bocchi, E, Bordignon, S, Clausell, N, Kaiser, S, Leaes, P, Martins Alves, S, Montera, M, Moura, L, Pereira de Castro, R, Rassi, S, Reis, A, Saraiva, J, Simões, M, Souza Neto, J, Teixeira, M, Benov, H, Chompalova, B, Donova, T, Georgiev, P, Gotchev, D, Grigorov, M, Guenova, D, Hergeldjieva, V, Ivanov, D, Kostova, E, Manolova, A, Marchev, S, Nikolov, F, Popov, A, Raev, D, Tzekova, M, Czarnecki, W, Giannetti, N, Haddad, H, Heath, J, Huynh, T, Lepage, S, Liu, P, Lonn, E, Ma, P, Manyari, D, Moe, G, Parker, J, Pesant, Y, Rajda, M, Ricci, J, Roth, S, Sestier, F, Sluzar, V, Sussex, B, Vizel, S, Antezana, G, Bugueno, C, Castro, P, Conejeros, C, Manriquez, L, Martinez, D, Potthoff, S, Stockins, B, Vukasovic, J, Gregor, P, Herold, M, Jerabek, O, Jirmar, R, Kuchar, R, Linhart, A, Podzemska, B, Soucek, M, Spac, J, Spacek, R, Vodnansky, P, Bronnum Schou, J, Clemmensen, K, Egstrup, K, Jensen, G, Kjoller Hansen, L, Markenvard, J, Rokkedal, J, Skagen, K, Torp Pedersen, C, Tuxen, C, Videbak, L, Laks, T, Vahula, V, Harjola, V, Kettunen, R, Kotila, M, Bauer, F, Coisne, D, Davy, J, De Groote, P, Dos Santos, P, Funck, F, Galinier, M, Gibelin, P, Isnard, R, Neuder, Y, Roul, G, Sabatier, R, Trochu, J, Denny, S, Dreykluft, T, Flesch, M, Genth Zotz, S, Hambrecht, R, Hein, J, Jeserich, M, John, M, Kreider Stempfle, H, Laufs, U, Muellerleile, K, Natour, M, Sandri, M, Schäufele, T, von Hodenberg, E, Weyland, K, Winkelmann, B, Tse, H, Yan, B, Barsi, B, Csikasz, J, Dezsi, C, Edes, I, Forster, T, Karpati, P, Kerekes, C, Kis, E, Kosa, I, Lupkovics, G, Nagy, A, Preda, I, Ronaszeki, A, Tomcsanyi, J, Zamolyi, K, Agarwal, D, Bahl, V, Bordoloi, A, Chockalingam, K, Chopda, M, Dugal, J, Ghaisas, N, Grant, P, Hiremath, S, Iyengar, S, Jagadeesa Subramania, B, Jain, P, Joshi, A, Khan, A, Mullasari, A, Naik, S, Oomman, A, Pai, V, Pareppally Gopal, R, Parikh, K, Patel, T, Prakash, V, Sastry, B, Sathe, S, Sinha, N, Srikanthan, V, Subburamakrishnan, P, Thacker, H, Wander, G, Admon, D, Katz, A, Klainman, E, Marmor, A, Moriel, M, Mosseri, M, Shotan, A, Weinstein, J, Zimlichman, R, Agostoni, P, Albanese, M, Alunni, G, Bini, R, Boccanelli, A, Bolognese, L, Campana, C, Carbonieri, E, Carpino, C, Checco, L, Cosmi, F, Angelo, Gd, De Cristofaro, M, Floresta, A, Fucili, A, Galvani, M, Ivleva, A, Marra, S, Musca, G, Peccerillo, N, PERRONE FILARDI, Pasquale, Picchio, E, Russo, T, Scelsi, L, Senni, M, Tavazzi, L, Jasinkevica, I, Kakurina, N, Veze, I, Volans, E, Bagdonas, A, Berukstis, E, Celutkiene, J, Dambrauskaite, A, Jarasuniene, D, Luksiene, D, Rudys, A, Sliaziene, S, Aguilar Romero, R, Cardona Muñoz, E, Castro Jimenez, J, Chavez Herrera, J, Chuquiure Valenzuela, E, De la Pena, G, Herrera, E, Leiva Pons, J, Lopez Alvarado, A, Mendez Machado, G, Ramos Lopez, G, Basart, D, Buijs, E, Cornel, J, de Leeuw, M, Dijkgraaf, R, Freericks, M, Hamraoui, K, Lenderlink, T, Linssen, G, Lodewick, P, Lodewijks, C, Lok, D, Nierop, P, Ronner, E, Somsen, A, van Dantzig, J, van der Burgh, P, van Kempen, L, van Vlies, B, Voors, A, Wardeh, A, Willems, F, Gundersen, T, Hole, T, Thalamus, J, Westheim, A, Dabrowski, M, Gorski, J, Korewicki, J, Kuc, K, Miekus, P, Musial, W, Niegowska, J, Piotrowski, W, Podolec, P, Polonski, L, Rynkiewicz, A, Szelemej, R, Trusz Gluza, M, Ujda, M, Wojciechowski, D, Wysokinski, A, Camacho, A, Fonseca, C, Monteiro, P, Bruckner, I, Carasca, E, Coman, I, Datcu, M, Dragulescu, S, Ionescu, P, Iordachescu Petica, D, Manitiu, I, Popa, V, Pop Moldovan, A, Radoi, M, Stamate, S, Tomescu, M, Vita, I, Aroutiounov, G, Ballyuzek, M, Bart, B, Churina, S, Glezer, M, Goloshchekin, B, Kobalava, Z, Kostenko, V, Lopatin, Y, Martynov, A, Orlov, V, Semernin, E, Shogenov, Z, Sidorenko, B, Skvortsov, A, Storzhakov, G, Sulimov, V, Talibov, O, Tereshenko, S, Tsyrline, V, Zadionchenko, V, Zateyshchikov, D, Dzupina, A, Hranai, M, Kmec, J, Micko, K, Pella, D, Sojka, G, Spisak, V, Vahala, P, Vinanska, D, Badat, A, Bayat, J, Dawood, S, Delport, E, Ellis, G, Garda, R, Klug, E, Mabin, T, Naidoo, D, Pretorius, M, Ranjith, N, Van Zyl, L, Weich, H, Anguita, M, Berrazueta, J, Bruguera i., Cortada J, de Teresa, E, Gómez Sánchez, M, González Juanatey, J, Gonzalez Maqueda, I, Jordana, R, Lupon, J, Manzano, L, Pascual Figal, D, Pulpón, L, Recio, J, Ridocci Soriano, F, Rodríguez Lambert, J, Roig Minguell, E, Romero, J, Valdovinos, P, Klintberg, L, Kronvall, T, Lycksell, M, Morner, S, Rydberg, E, Swedberg, K, Timberg, I, Wikstrom, G, Moccetti, T, Ashok, J, Banerjee, P, Carr White, G, Connolly, E, Francis, M, Greenbaum, R, Kadr, H, Lindsay, S, Mcmurray, J, Megarry, S, Memon, A, Murdoch, D, Senior, R, Squire, I, Tan, L, Witte, K, Adamson, P, Adler, A, Altschul, L, Altschuller, A, Amirani, H, Andreou, C, Ansari, M, Antonishen, M, Banchs, H, Banerjee, S, Banish, D, Bank, A, Barbagelata, A, Barnard, D, Bellinger, R, Benn, A, Berk, M, Berry, B, Bethala, V, Bilazarian, S, Bisognano, J, Bleyer, F, Blum, M, Boehmer, J, Bouchard, A, Boyle, A, Bozkurt, B, Brown, C, Burlew, B, Burnham, K, Call, J, Cambier, P, Cappola, T, Carlson, R, Chandler, B, Chandra, R, Chandraratna, P, Chernick, R, Colan, D, Colfer, H, Colucci, W, Connelly, T, Costantini, O, Dadkhah, S, Dauber, I, Davis, J, Davis, S, Denning, S, Drazner, M, Dunlap, S, Egbujiobi, L, Elkayam, U, Elliott, J, El Shahawy, M, Essandoh, L, Ewald, G, Fang, J, Farhoud, H, Felker, G, Fernandez, J, Festin, R, Fishbein, G, Florea, V, Flores, E, Floro, J, Gabris, M, Garg, M, Gatewood, R, Geller, M, Ghumman, W, Gibbs, G, Gillespie, E, Gilmore, R, Gogia, H, Goldberg, L, Gradus Pizlo, I, Grainger, T, Gudmundsson, G, Gunawardena, D, Gupta, D, Hack, T, Hall, S, Hamroff, G, Hankins, S, Hanna, M, Hargrove, J, Haught, W, Hauptman, P, Hazelrigg, M, Herzog, C, Heywood, J, Hill, T, Hilton, T, Hirsch, H, Hunter, J, Ibrahim, H, Imburgia, M, Iteld, B, Jackson, B, Jaffrani, N, Jain, D, Jain, A, James, M, Jimenez, J, Johnson, E, Kale, P, Kaneshige, A, Kapadia, S, Karia, D, Karlsberg, R, Katholi, R, Kerut, E, Khoury, W, Kipperman, R, Klapholz, M, Kosinski, E, Kozinn, M, Kraus, D, Krueger, S, Kumar, S, Lader, E, Lee, C, Lewis, E, Light McGroary, K, Loh, I, Lombardi, W, Machado, C, Maislos, F, Mancini, D, Markus, T, Mather, P, Mccants, K, Mcgrew, F, Mclaurin, B, Mcmillan, E, Mcnamara, D, Meyer, T, Meymandi, S, Miller, A, Minami, E, Modi, M, Mody, F, Mohanty, P, Moscoso, R, Moskowitz, R, Moustafa, M, Mullen, M, Naz, T, Noonan, T, O., Brien T, Oellerich, W, Oren, R, Pamboukian, S, Pereira, N, Pitt, W, Porter, C, Prabhu, S, Promisloff, S, Ratkovec, R, Richardson, R, Ross, A, Saleh, N, Saltzberg, M, Sarkar, S, Schmedtje, J, Schneider, R, Schuyler, G, Shanes, J, Sharma, A, Siegel, C, Siegel, R, Silber, D, Singh, N, Singh, J, Singh, V, Sklar, J, Small, R, Smith, A, Smith, E, Smull, D, Sotolongo, R, Staniloae, C, Stapleton, D, Steele, P, Stehlik, J, Stein, M, Tang, W, Thadani, U, Torre Amoine, G, Trichon, B, Tsai, C, Tummala, R, Van Bakel, A, Vicari, R, Vijay, N, Vijayaraghavan, K, Vittorio, T, Vossler, M, Wagoner, L, Wallis, D, Ward, N, Widmer, M, Wight, J, Wilkins, C, Williams, C, Williams, G, Winchester, M, Winkel, E, Wittmer, B, Wood, D, Wormer, D, Wright, R, Xu, Z, Yasin, M, Zolty, R., Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
Male, CHRONIC KIDNEY-DISEASE, Darbepoetin alfa, Ciencias de la Salud, Kaplan-Meier Estimate, law.invention, Hemoglobins, DOUBLE-BLIND, Randomized controlled trial, law, hemic and lymphatic diseases, Treatment Failure, Hazard ratio, Ética Médica, Anemia, General Medicine, Middle Aged, Shock, Septic, Stroke, purl.org/becyt/ford/3 [https], Female, medicine.drug, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Placebo, CONTROLLED-TRIAL, purl.org/becyt/ford/3.3 [https], MORBIDITY, Double-Blind Method, Darbepoetin, Internal medicine, Thromboembolism, parasitic diseases, medicine, Humans, Adverse effect, Erythropoietin, Aged, Proportional Hazards Models, CITY CARDIOMYOPATHY QUESTIONNAIRE, business.industry, Proportional hazards model, MORTALITY, equipment and supplies, medicine.disease, Surgery, REDUCTION, EPOETIN, Heart failure, Hematinics, business, Systolic heart failure, Heart Failure, Systolic
Abstract

BACKGROUND: Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia. METHODS: In this randomized, double-blind trial, we assigned 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to receive either darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure. RESULTS: The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin alfa group and 565 of 1142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P=0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P=0.01). Cancer-related adverse events were similar in the two study groups. CONCLUSIONS: Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Our findings do not support the use of darbepoetin alfa in these patients. (Funded by Amgen; RED-HF ClinicalTrials.gov number, NCT00358215.). Fil: Swedberg, Karl. University of Gothenburg; Suecia Fil: Young, James B.. Cleveland Clinic; Estados Unidos Fil: Anand, Inder S.. University of Minnesota; Estados Unidos Fil: Cheng, Sunfa. Amgen; Estados Unidos Fil: Desai, Akshay S.. Brigham and Women’s Hospital; Estados Unidos Fil: Diaz, Rafael. Estudios Clínicos Latinoamérica; Argentina Fil: Maggioni, Aldo P.. Italian Association of Hospital Cardiologists Research Center; Italia Fil: McMurray, John J.V.. University of Glasgow; Reino Unido Fil: O’Connor, Christopher. University of Duke; Estados Unidos Fil: Pfeffer, Marc A.. Brigham and Women’s Hospital; Estados Unidos Fil: Solomon, Scott D.. Brigham and Women’s Hospital; Estados Unidos Fil: Sun, Yan. Amgen; Estados Unidos Fil: Tendera, Michal. Medical University of Silesia; Polonia Fil: van Veldhuisen, Dirk J.. University of Groningen; Países Bajos Fil: Toblli, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2013

13. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

Author

John J V, McMurray, Stamatis, Adamopoulos, Stefan D, Anker, Angelo, Auricchio, Michael, Böhm, Kenneth, Dickstein, Volkmar, Falk, Gerasimos, Filippatos, Cândida, Fonseca, Miguel Angel, Gomez-Sanchez, Tiny, Jaarsma, Lars, Køber, Gregory Y H, Lip, Aldo Pietro, Maggioni, Alexander, Parkhomenko, Burkert M, Pieske, Bogdan A, Popescu, Per K, Rønnevik, Frans H, Rutten, Juerg, Schwitter, Petar, Seferovic, Janina, Stepinska, Pedro T, Trindade, Adriaan A, Voors, Faiez, Zannad, Andreas, Zeiher, and Bernard, Lung

Subjects
medicine.medical_treatment, Comorbidity, Cardiotonic Agents, Cardiac Resynchronization Therapy, Electrocardiography, Ventricular Dysfunction, Left, Diuretics, reproductive and urinary physiology, Ejection fraction, medicine.diagnostic_test, Therapies, Investigational, Prognosis, Defibrillators, Implantable, Drug Combinations, Acute Disease, embryonic structures, Cardiology, biological phenomena, cell phenomena, and immunity, Cardiology and Cardiovascular Medicine, Anti-Arrhythmia Agents, Algorithms, medicine.medical_specialty, Cardiac resynchronization therapy, behavioral disciplines and activities, Serelaxin, Terminology as Topic, Thromboembolism, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, Genetic Testing, Natriuretic Peptides, Intensive care medicine, Heart Failure, Clinical Laboratory Techniques, urogenital system, business.industry, Arrhythmias, Cardiac, Stroke Volume, medicine.disease, Transplantation, Cardiac Imaging Techniques, Heart failure, Chronic Disease, Exercise Test, business
Abstract

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 : The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

Published
2012

14. An economic evaluation of rosuvastatin treatment in systolic heart failure

Author

Paula K, Lorgelly, Andrew H, Briggs, Hans, Wedel, Peter, Dunselman, Ake, Hjalmarson, John, Kjekshus, Finn, Waagstein, John, Wikstrand, András, Jánosi, Dirk J, van Veldhuisen, Vivencio, Barrios, Cândida, Fonseca, John J V, McMurray, Karl, Swedberg, Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
Male, medicine.medical_specialty, Statin, Cost effectiveness, medicine.drug_class, Cost-Benefit Analysis, medicine.medical_treatment, Heart failure, ALONGSIDE, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Humans, Rosuvastatin, Hospital Mortality, Prospective Studies, Rosuvastatin Calcium, Prospective cohort study, health care economics and organizations, Aged, Heart transplantation, Sulfonamides, Cardiopulmonary Bypass, business.industry, Statins, nutritional and metabolic diseases, Multinational trial, Middle Aged, medicine.disease, Surgery, LIFETIME RISK, Fluorobenzenes, Hospitalization, Pyrimidines, Costs and Cost Analysis, Cardiology, Heart Transplantation, Female, Cost-effectiveness, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, COSTS, medicine.drug
Abstract

To estimate the cost-effectiveness of 10 mg rosuvastatin daily for older patients with systolic heart failure in the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial.This within trial analysis of CORONA used major cardiovascular (CV) events as the outcome measure. Resource use was valued and the costs of hospitalizations, procedures, and statin use compared. Cost-effectiveness was estimated as cost per major CV event avoided. There were significantly fewer major CV events in the rosuvastatin group compared with the placebo group (1.04 vs. 1.20 per patient; difference 0.164; 95% CI: 0.075-0.254, P This economic analysis showed that a significant reduction in major CV events with rosuvastatin led to significantly reduced costs of CV hospitalizations and procedures. The reduction in associated costs for major CV events was found to offset partially (by 44%) the cost of rosuvastatin treatment in patients with systolic heart failure.

Published
2010

15. Design of the Reduction of Events with Darbepoetin alfa in Heart Failure (RED‐HF): a Phase III, anaemia correction, morbidity–mortality trial

Author

John J V, McMurray, Inder S, Anand, Rafael, Diaz, Aldo P, Maggioni, Christopher, O'Connor, Marc A, Pfeffer, Krishna R, Polu, Scott D, Solomon, Yan, Sun, Karl, Swedberg, Michal, Tendera, Dirk J, van Veldhuisen, Scott M, Wasserman, James B, Young, A, Swan, Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
Adult, Male, CHRONIC KIDNEY-DISEASE, SUBCUTANEOUS ERYTHROPOIETIN, RENAL-FUNCTION, medicine.medical_specialty, New York Heart Association Class, Darbepoetin alfa, Renal function, Heart failure, Anaemia, PROGRESSION, Placebo, Ventricular Function, Left, DOUBLE-BLIND, Double-Blind Method, Quality of life, Surveys and Questionnaires, Internal medicine, medicine, Clinical endpoint, Humans, Erythropoietin, Aged, Aged, 80 and over, Ejection fraction, business.industry, BLUNTED ERYTHROPOIETIN PRODUCTION, Anemia, Stroke Volume, Middle Aged, medicine.disease, CANCER, Surgery, EPOETIN, Research Design, CLINICAL-PRACTICE, INTRAVENOUS IRON, Hematinics, Female, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Patients with heart failure (HF) and anaemia have greater functional impairment, worse symptoms, increased rates of hospital admission, and a higher risk of death, compared with non-anaemic HF patients. Whether correcting anaemia can improve outcomes is unknown.The Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF; Clinical Trials.gov NCT 003 58215) was designed to evaluate the effect of the long-acting erythropoietin-stimulating agent darbepoetin alfa on mortality and morbidity (and quality of life) in patients with HF and anaemia.Approximately 2600 patients with New York Heart Association class II-IV, an ejection fraction = 9.0 g/dL will be enrolled. Patients are randomized 1:1 to double-blind subcutaneous administration of darbepoetin alfa or placebo. Investigators are also blinded to Hb measurements and darbepoetin alfa is dosed to achieve an Hb concentration of 13.0 g/dL (but not exceeding 14.5 g/dL) with sham adjustments of the dose of placebo. The primary endpoint is the time to death from any cause or first hospital admission for worsening HF, whichever occurs first. The study will complete when similar to 1150 subjects experience a primary endpoint.

Published
2009

16. Awareness and perception of heart failure among European cardiologists, internists, geriatricians, and primary care physicians

Author

Willem J, Remme, John J V, McMurray, F D Richard, Hobbs, Alain, Cohen-Solal, José, Lopez-Sendon, Alessandro, Boccanelli, Faiez, Zannad, Bernhard, Rauch, Karen, Keukelaar, Cezar, Macarie, Witold, Ruzyllo, Charles, Cline, and J, McMurray

Subjects
medicine.medical_specialty, Heart disease, Attitude of Health Personnel, health care facilities, manpower, and services, Adrenergic beta-Antagonists, education, Diagnostic Techniques, Cardiovascular, MEDLINE, Angiotensin-Converting Enzyme Inhibitors, Primary care, β blockade, health services administration, Humans, Medicine, Intensive care medicine, Ace inhibition, health care economics and organizations, Heart Failure, Primary Health Care, business.industry, medicine.disease, Drug Utilization, Europe, Chronic disease, Health Care Surveys, Family medicine, Heart failure, Chronic Disease, Practice Guidelines as Topic, Clinical Competence, Guideline Adherence, Clinical competence, Cardiology and Cardiovascular Medicine, business, Specialization
Abstract

AIMS: To assess awareness of heart failure (HF) management recommendations in Europe among cardiologists (C), internists and geriatricians (I/G), and primary care physicians (PCPs). METHODS AND RESULTS: The Study group on HF Awareness and Perception in Europe (SHAPE) surveyed randomly selected C (2041), I/G (1881), and PCP (2965) in France, Germany, Italy, the Netherlands, Poland, Romania, Spain, Sweden, and the UK. Each physician completed a 32-item questionnaire about the diagnosis and treatment of HF (left ventricular ejection fraction 90% of their patients (64 vs. 82% C, P < 0.0001), whereas only 47% PCP would routinely prescribe an ACE-inhibitor. Worsening HF was considered a risk of ACE-inhibitor therapy by 35% PCP. I/G and PCP consistently do not prescribe target ACE-inhibitor doses (P < 0.0001 vs. C). Only 39% I/G would use a beta-blocker in >50% of their patients (vs. 73% C, P < 0.0001). Also, only 5% PCP would always, and 35% often, prescribe a beta-blocker and reach target doses in only 7-29%. Moreover, 34% PCP and 26% I/G vs. 11% C (P < 0.0001) do not start a beta-blocker in patients with mild HF, who are already on an ACE-inhibitor and are on diuretic. In mild, stable HF, 39% PCP and 18% I/G would only prescribe diuretics, vs. 7% C (P < 0.0001). In patients with worsening HF in sinus rhythm and on an optimal ACE-inhibitor, beta-blockade and diuretics, significantly more C would add spironolactone, but I/G would more often add digoxin. CONCLUSION: Although each physician group lacks complete adherence to guideline-recommended management strategies, these are used significantly less well by I, G, and PCPs, indicating the need for education of these essential healthcare providers.

Published
2008

17. Risk of stroke in chronic heart failure patients without atrial fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials

Author

Azmil H, Abdul-Rahim, Ana-Cristina, Perez, Rachael L, Fulton, Pardeep S, Jhund, Roberto, Latini, Gianni, Tognoni, John, Wikstrand, John, Kjekshus, Gregory Y H, Lip, Aldo P, Maggioni, Luigi, Tavazzi, Kennedy R, Lees, John J V, McMurray, and Donata, Lucci

Subjects
Male, New York Heart Association Class, Tetrazoles, heart failure, Kaplan-Meier Estimate, Natriuretic Peptide, Brain, risk factors, Sinus rhythm, atrial fibrillation, Rosuvastatin Calcium, Stroke, Randomized Controlled Trials as Topic, Aged, 80 and over, Sulfonamides, sinus rhythm, Hazard ratio, Atrial fibrillation, Middle Aged, stroke, Cardiology, Female, Cardiology and Cardiovascular Medicine, medicine.drug, Adult, medicine.medical_specialty, macromolecular substances, Physiology (medical), Diabetes mellitus, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, Rosuvastatin, cardiovascular diseases, Aged, Proportional Hazards Models, business.industry, Biphenyl Compounds, Cardiovascular Agents, Stroke Volume, medicine.disease, Peptide Fragments, Fluorobenzenes, Diabetes Mellitus, Type 1, Pyrimidines, Heart failure, ventricular ejection fraction, Benzimidazoles, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Biomarkers, Follow-Up Studies
Abstract

Background— Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). Methods and Results— We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ 2 value): age (hazard ratio, 1.34; 95% confidence interval, 1.18–1.63 per 10 years), New York Heart Association class (1.60, 1.21–2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22–2.88), body mass index (0.74, 0.60–0.91 per 5 kg/m 2 up to 30), and previous stroke (1.81, 1.19–2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11–1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. Conclusions— A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

Published
2015

18. Elevation in High-Sensitivity Troponin T in Heart Failure and Preserved Ejection Fraction and Influence of Treatment With the Angiotensin Receptor Neprilysin Inhibitor LCZ696

Author

Pardeep S, Jhund, Brian L, Claggett, Adriaan A, Voors, Michael R, Zile, Milton, Packer, Burkert M, Pieske, Elisabeth, Kraigher-Krainer, Amil M, Shah, Margaret F, Prescott, Victor, Shi, Marty, Lefkowitz, John J V, McMurray, Scott D, Solomon, David, Colan, and Cardiovascular Centre (CVC)

Subjects
Male, medicine.medical_specialty, Angiotensin receptor, animal structures, BIOMARKERS, Tetrazoles, heart failure, RELAXATION, macromolecular substances, neprilysin, Angiotensin Receptor Antagonists, SYSTOLIC FUNCTION, Internal medicine, Natriuretic Peptide, Brain, Medicine, Humans, Neprilysin, Aged, Aged, 80 and over, RISK, Ejection fraction, troponin T, biology, Troponin T, business.industry, NATRIURETIC PEPTIDE, Aminobutyrates, Biphenyl Compounds, DEATH, Valine, ASSOCIATION, medicine.disease, Troponin, Peptide Fragments, PREVALENCE, HYPERTROPHY, Drug Combinations, Valsartan, Heart failure, biology.protein, Cardiology, Female, TRIAL, Cardiology and Cardiovascular Medicine, business, Heart failure with preserved ejection fraction, Angiotensin II Type 1 Receptor Blockers, medicine.drug
Abstract

Background— Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. Methods and Results— We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 μg/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P =0.05) and at 36 weeks (14% reduction; P =0.03) compared with valsartan. Conclusions— Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N-terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00887588.

Published
2014

19. Endothelium-Derived Hyperpolarizing Factor

Author

Chris Hillier, John MacDonald, Fiona Johnston, John J. V. McMurray, and Paul Coats

Subjects
medicine.medical_specialty, Endothelium-derived hyperpolarizing factor, Endothelium, Vasodilator Agents, Vasodilation, Prostacyclin, In Vitro Techniques, Nitric Oxide, Phospholipases A, Ouabain, Nitric oxide, Biological Factors, chemistry.chemical_compound, Physiology (medical), Internal medicine, medicine, Cytochrome P-450 Enzyme Inhibitors, Humans, Cyclooxygenase Inhibitors, Enzyme Inhibitors, Cyclic GMP, Aged, Arachidonic Acid, Dose-Response Relationship, Drug, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Arteries, Membrane hyperpolarization, Hyperpolarization (biology), Epoprostenol, Acetylcholine, medicine.anatomical_structure, Endocrinology, Adipose Tissue, chemistry, Barium, Potassium, cardiovascular system, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background —Both a vascular endothelial cytochrome P450 (CYP450) product of arachidonic acid metabolism and the potassium ion (K + ) have been identified as endothelium-derived hyperpolarizing factors (EDHFs) in animal vascular tissues. We studied the relative importance of EDHF, nitric oxide (NO), and prostacyclin (PGI 2 ) as vasodilators in human subcutaneous arteries. We also examined the mechanisms underlying the vasodilator action of EDHF to elucidate its identity. Methods and Results —Subcutaneous resistance arteries were obtained from 41 healthy volunteers. The contribution of EDHF to the vasodilation induced by acetylcholine was assessed by inhibiting production of NO, PGI 2 , and membrane hyperpolarization. The mechanisms underlying the relaxation evoked by K + and EDHF were elucidated. EDHF was found to account for ≈80% of acetylcholine-mediated vasorelaxation. Its action was insensitive to the combination of barium and ouabain, whereas barium and ouabain reversed K + -mediated vasorelaxation. EDHF-mediated vasorelaxation, however, was sensitive to the phospholipase A 2 inhibitor oleyloxyethyl phosphorylcholine and the CYP450 inhibitor ketoconazole. Conclusions —EDHF is the major contributor to endothelium-dependent vasorelaxation in human subcutaneous resistance arteries. A product of phospholipase A 2 /CYP450–dependent metabolism of arachidonic acid and not K + is the likely identity of EDHF in human subcutaneous resistance arteries.

Published
2001

20. Clinical Trials Report: Cardiovascular & Renal: Ongoing and planned clinical trials in chronic heart failure and left ventricular dysfunction

Author

John J. V. Mcmurray, Alan J. Cowley, and John G.F. Cleland

Subjects
Inotrope, medicine.medical_specialty, Sympathetic nervous system, Digoxin, Disease, Internal medicine, medicine, Pharmacology (medical), cardiovascular diseases, Intensive care medicine, Pharmacology, biology, business.industry, High mortality, Angiotensin-converting enzyme, General Medicine, medicine.disease, Clinical trial, medicine.anatomical_structure, Heart failure, cardiovascular system, Cardiology, biology.protein, business, circulatory and respiratory physiology, medicine.drug
Abstract

Chronic heart failure (CHF) remains an extremely disabling disease with high mortality. Current therapy for CHF encompasses unloading drugs (e.g., the loop diuretics), inotropic agents (e.g., digoxin) and inhibitors of the sympathetic nervous system (e.g., β-blockers) and renin-angiotensin-aldosterone system (e.g., angiotensin converting enzyme inhibitors). This report reviews current therapies for CHF, the rationale behind the development of new agents for this indication, and the ongoing and planned clinical trials for the treatment of CHF and left ventricular dysfunction.

Published
1995

21. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial

Author

Scott D, Solomon, Michael, Zile, Burkert, Pieske, Adriaan, Voors, Amil, Shah, Elisabeth, Kraigher-Krainer, Victor, Shi, Toni, Bransford, Madoka, Takeuchi, Jianjian, Gong, Martin, Lefkowitz, Milton, Packer, John J V, McMurray, David, Colan, Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
Male, medicine.medical_specialty, PATHOPHYSIOLOGY, Tetrazoles, GUIDELINES, Sacubitril, law.invention, Angiotensin Receptor Antagonists, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Natriuretic Peptide, Brain, Clinical endpoint, Medicine, Humans, Aged, Heart Failure, CARDIOMYOPATHY, Ejection fraction, HYPERTENSION, ABNORMALITIES, business.industry, Aminobutyrates, Biphenyl Compounds, Stroke Volume, Valine, DIASTOLIC DYSFUNCTION, General Medicine, Middle Aged, NATRIURETIC-PEPTIDES, medicine.disease, EUROPEAN-SOCIETY, Peptide Fragments, PREVALENCE, Drug Combinations, Valsartan, Heart failure, Cardiology, Female, Neprilysin, ECHOCARDIOGRAPHY, Heart failure with preserved ejection fraction, business, Sacubitril, Valsartan, medicine.drug
Abstract

Summary Background Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. Methods PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II–III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. Findings 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670–914], 12 weeks, 605 pg/mL [512–714]; valsartan: baseline, 862 pg/mL [733–1012], 12 weeks, 835 [710–981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64–0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. Interpretation In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. Funding Novartis.

Published
2012

22. Recent Advances: Cardiology II: Treatment of heart failure and atrial fibrillation and arrhythmias

Author

Andrew Rankin and John J. V. Mcmurray

Subjects
medicine.medical_specialty, Digoxin, biology, business.industry, medicine.medical_treatment, General Engineering, Atrial fibrillation, Catheter ablation, Angiotensin-converting enzyme, General Medicine, medicine.disease, Placebo, Amiodarone, Heart failure, Internal medicine, polycyclic compounds, biology.protein, Cardiology, General Earth and Planetary Sciences, Medicine, cardiovascular diseases, Myocardial infarction, business, General Environmental Science, medicine.drug
Abstract

In the first part of our review of the advances in cardiology over the past year we considered treatment of myocardial infarction and angina.1 In this part we summarise the most important advances in the treatment of heart failure, atrial fibrillation, and arrhythmias. A glossary of study abbreviations is given in the appendix. In the past year, more has been learnt about what does not help patients with chronic heart failure than what is of benefit. Important American guidelines on treatment have also been issued.2 Two trials have investigated whether digoxin is of benefit in patients with chronic heart failure who are in sinus rhythm.3 4 In both trials the condition was stabilised by digoxin treatment before patients were randomly allocated in a double blind fashion to withdrawal (placebo substitution) or continuation of digoxin. In one study (PROVED) patients were not treated with an angiotensin converting enzyme inhibitor whereas in the other (RADIANCE) they were. During follow up of three months the patients in both groups who had had digoxin withdrawn showed clinical deterioration (table I). View this table: Table I Outcomes after three months in trials of digoxin withdrawal in patients with chronic heart failure3–4 The results of these trials are important advances in our understanding of the role of digoxin in chronic heart failure. For patients who remain symptomatic while taking a diuretic but cannot tolerate an angiotensin converting enzyme inhibitor, digoxin is an option. Similarly, patients who remain symptomatic despite taking an angiotensin converting enzyme inhibitor should also be treated with digoxin. The one caveat to these conclusions is whether deterioration after digoxin withdrawal (as seen in the studies) is the same as clinical improvement when the drug is added to existing drug treatment. Other studies suggest that the addition of digoxin to diuretics is of …

Published
1994

23. Recent Advances: Cardiology - I: Treatment of myocardial infarction, unstable angina, and angina pectoris

Author

John J. V. Mcmurray and A Rankin

Subjects
medicine.medical_specialty, Heart disease, business.industry, Unstable angina, medicine.medical_treatment, General Engineering, General Medicine, Thrombolysis, medicine.disease, Angina, Internal medicine, medicine, Balloon dilation, Cardiology, General Earth and Planetary Sciences, Myocardial infarction, Fast track, business, General Environmental Science, Cohort study
Abstract

In the past 12 months there have been many advances in our understanding of how to treat heart disease. In the first part of this two part review we summarise the most important of these advances in the treatment of myocardial infarction, unstable angina, and angina pectoris. A glossary of study abbreviations is given in the appendix. Two recent large trials, EMIP and the MITI project, have compared thrombolysis started before admission to hospital with that started in hospital, which adds to the findings of GREAT (table I).*RF 1-3* The results of EMIP and the MITI project were much less encouraging than those of GREAT, showing only a marginal benefit during short term follow up for prehospital treatment over hospital treatment (table I). This difference between GREAT and the two recent trials probably reflects the much shorter delay in starting thrombolysis in hospital in EMIP and the MITI project. This, in part, reflected the effect of the trials on “usual practice.” In EMIP the median time from arrival in hospital to injection was only 15 minutes compared with over 80 minutes in recent British and American surveys.4 In support of this, patients in the MITI project who were treated within 70 minutes of the onset of symptoms had a mortality in hospital of only 1.2% compared with 8.7% in those who were not treated within 70 minutes (P=0.04). The clear message of these studies is the earlier treatment is given the better: when matters more than where. View this table: TABLE I Trials of prehospital thrombolysis Initiating thrombolysis just 30-60 minutes earlier, the sort of time saving that can be achieved by regular audit and the introduction of fast track systems, will typically save about 15 extra lives for each 1000 patients treated (see discussion of GUSTO study below).4 An even greater benefit …

Published
1994

24. Pharmacist intervention in primary care to improve outcomes in patients with left ventricular systolic dysfunction

Author

Richard, Lowrie, Frances S, Mair, Nicola, Greenlaw, Paul, Forsyth, Pardeep S, Jhund, Alex, McConnachie, Brian, Rae, John J V, McMurray, and Nicola, Watson

Subjects
Adult, Male, medicine.medical_specialty, Population, Adrenergic beta-Antagonists, Pharmacist, Angiotensin-Converting Enzyme Inhibitors, Primary care, Community Pharmacy Services, primary care, Ventricular Dysfunction, Left, ACE inhibitor, β-blocker, Internal medicine, Intervention (counseling), medicine, Humans, Prospective Studies, education, Aged, education.field_of_study, business.industry, Drug Substitution, Hazard ratio, Odds ratio, Middle Aged, medicine.disease, Hospitalization, Treatment Outcome, Heart failure, Physical therapy, Female, Cardiology and Cardiovascular Medicine, business, Family Practice, left ventricular systolic dysfunction, medicine.drug
Abstract

Background Meta-analysis of small trials suggests that pharmacist-led collaborative review and revision of medical treatment may improve outcomes in heart failure.\ud \ud Methods and results We studied patients with left ventricular systolic dysfunction in a cluster-randomized controlled, event driven, trial in primary care. We allocated 87 practices (1090 patients) to pharmacist intervention and 87 practices (1074 patients) to usual care. The intervention was delivered by non-specialist pharmacists working with family doctors to optimize medical treatment. The primary outcome was a composite of death or hospital admission for worsening heart failure. This trial is registered, number ISRCTN70118765. The median follow-up was 4.7 years. At baseline, 86% of patients in both groups were treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In patients not receiving one or other of these medications, or receiving less than the recommended dose, treatment was started, or the dose increased, in 33.1% of patients in the intervention group and in 18.5% of the usual care group [odds ratio (OR) 2.26, 95% CI 1.64–3.10; P< 0.001]. At baseline, 62% of each group were treated with a β-blocker and the proportions starting or having an increase in the dose were 17.9% in the intervention group and 11.1% in the usual care group (OR 1.76, 95% CI 1.31–2.35; P< 0.001). The primary outcome occurred in 35.8% of patients in the intervention group and 35.4% in the usual care group (hazard ratio 0.97, 95% CI 0.83–1.14; P = 0.72). There was no difference in any secondary outcome.\ud \ud Conclusion A low-intensity, pharmacist-led collaborative intervention in primary care resulted in modest improvements in prescribing of disease-modifying medications but did not improve clinical outcomes in a population that was relatively well treated at baseline.

Published
2011

25. Acute effects of captopril on the renal actions of furosemide in patients with chronic heart failure

Author

A. B. Bridges, John J. V. Mcmurray, Allan D. Struthers, James S. McLay, and Callum G. Fraser

Subjects
Male, medicine.medical_specialty, Captopril, Time Factors, medicine.medical_treatment, Urology, Administration, Oral, Natriuresis, Diuresis, Renal function, Blood Pressure, Placebo, Urine flow rate, Double-Blind Method, Furosemide, Internal medicine, medicine, Humans, Drug Interactions, cardiovascular diseases, Aged, Heart Failure, business.industry, Middle Aged, medicine.disease, Urodynamics, Endocrinology, Heart failure, Chronic Disease, Diuretic, Cardiology and Cardiovascular Medicine, business, hormones, hormone substitutes, and hormone antagonists, Tablets, circulatory and respiratory physiology, medicine.drug
Abstract

This study examined the effects of conventional doses of oral captopril on the renal responses to oral furosemide in ambulant patients with stable chronic heart failure. Twenty-five men (mean age 63 years) were randomized to one of two groups. Group 1 received placebo on days 1 and 2 before furosemide. Group 2 received placebo on day 1 before furosemide and captopril thereafter (i.e., captopril before furosemide on day 2). Urine was collected after either placebo or captopril and after furosemide (taken after placebo or captopril pretreatment). Captopril by itself did not affect renal function. Captopril did, however, significantly affect the renal response to furosemide. The increase in urine flow rate after furosemide in group 2 was decreased from 225% with placebo to 128% with captopril (p < 0.02). The increase in sodium excretion after furosemide was decreased from 623% with placebo to 242% with captopril (p < 0.001). Pretreatment with captopril abolished the increase in creatine clearance after furosemide. The increase in urinary albumin excretion (used as a marker of glomerular function) after furosemide was also significantly blunted by captopril. Conventional doses of captopril acutely inhibit the natriuretic and diuretic responses to furosemide at the glomerular level in ambulant patients with stable chronic heart failure.

Published
1993

26. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis

Author

John J V, McMurray, John, Kjekshus, Lars, Gullestad, Peter, Dunselman, Ake, Hjalmarson, Hans, Wedel, Magnus, Lindberg, Finn, Waagstein, Peer, Grande, Jaromir, Hradec, Gabriel, Kamenský, Jerzy, Korewicki, Timo, Kuusi, François, Mach, Naresh, Ranjith, John, Wikstrand, and Karl, Swedberg

Subjects
Male, Kaplan-Meier Estimate, Gastroenterology, Risk Factors, Heart Failure, Systolic/blood/drug therapy/mortality, Multicenter Studies as Topic, Myocardial infarction, Rosuvastatin Calcium, Randomized Controlled Trials as Topic, ddc:616, Aged, 80 and over, Cholesterol, HDL/blood, Sulfonamides, biology, Hazard ratio, C-Reactive Protein/*metabolism, Hospitalization, Triglycerides/blood, C-Reactive Protein, Cholesterol, LDL/blood, Female, Cardiology and Cardiovascular Medicine, Pyrimidines/*therapeutic use, medicine.drug, medicine.medical_specialty, Placebo, Sulfonamides/*therapeutic use, Fluorobenzenes/*therapeutic use, Physiology (medical), Internal medicine, medicine, Humans, Rosuvastatin, Triglycerides, Hospitalization/statistics & numerical data, Aged, Retrospective Studies, business.industry, C-reactive protein, Cholesterol, HDL, nutritional and metabolic diseases, Cholesterol, LDL, medicine.disease, Confidence interval, Fluorobenzenes, Endocrinology, Pyrimidines, Heart failure, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Heart Failure, Systolic
Abstract

Background— We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. Methods and Results— We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) P =0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P >0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P =0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P =0.14; P for interaction=0.026). Conclusion— In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP ≥2.0 mg/L. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Published
2009

27. Increased mortality after dronedarone therapy for severe heart failure

Author

Lars, Køber, Christian, Torp-Pedersen, John J V, McMurray, Ole, Gøtzsche, Samuel, Lévy, Harry, Crijns, Jan, Amlie, Jan, Carlsen, and P, Smedgård

Subjects
Drug, Adult, Male, medicine.medical_specialty, Heart disease, media_common.quotation_subject, medicine.medical_treatment, Amiodarone, Kaplan-Meier Estimate, Antiarrhythmic agent, Vernakalant, chemistry.chemical_compound, Ventricular Dysfunction, Left, Double-Blind Method, Internal medicine, Cause of Death, medicine, Humans, Treatment Failure, Intensive care medicine, Dronedarone, Kaplan-Meiers Estimate, media_common, Cause of death, Aged, Aged, 80 and over, Heart Failure, business.industry, General Medicine, Middle Aged, medicine.disease, chemistry, Cardiovascular Diseases, Heart failure, Cardiology, Female, business, Anti-Arrhythmia Agents, medicine.drug
Abstract

Udgivelsesdato: 2008-Jun-19 BACKGROUND: Dronedarone is a novel antiarrhythmic drug with electrophysiological properties that are similar to those of amiodarone, but it does not contain iodine and thus does not cause iodine-related adverse reactions. Therefore, it may be of value in the treatment of patients with heart failure. METHODS: In a multicenter study with a double-blind design, we planned to randomly assign 1000 patients who were hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction to receive 400 mg of dronedarone twice a day or placebo. The primary end point was the composite of death from any cause or hospitalization for heart failure. RESULTS: After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated for safety reasons, at the recommendation of the data and safety monitoring board, in accordance with the board's predefined rules for termination of the study. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (hazard ratio in the dronedarone group, 2.13; 95% confidence interval [CI], 1.07 to 4.25; P=0.03). The excess mortality was predominantly related to worsening of heart failure--10 deaths in the dronedarone group and 2 in the placebo group. The primary end point did not differ significantly between the two groups; there were 53 events in the dronedarone group (17.1%) and 40 events in the placebo group (12.6%) (hazard ratio, 1.38; 95% CI, 0.92 to 2.09; P=0.12). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo group. CONCLUSIONS: In patients with severe heart failure and left ventricular systolic dysfunction, treatment with dronedarone was associated with increased early mortality related to the worsening of heart failure. (ClinicalTrials.gov number, NCT00543699.)

Published
2008

28. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial

Author

Jean-Claude, Tardif, John J V, McMurray, Eric, Klug, Robert, Small, Jennifer, Schumi, Jasmine, Choi, Jim, Cooper, Robert, Scott, Eldrin F, Lewis, Philippe L, L'Allier, Marc A, Pfeffer, and J, Zebrack

Subjects
Adult, Male, medicine.medical_specialty, Acute coronary syndrome, Endpoint Determination, Placebo-controlled study, Placebo, Antioxidants, law.invention, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Clinical endpoint, Humans, Myocardial infarction, Acute Coronary Syndrome, Aged, Intention-to-treat analysis, business.industry, Unstable angina, General Medicine, Middle Aged, medicine.disease, Surgery, Probucol, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Female, business
Abstract

Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments.After an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898.All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p0.0001 for all).Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.

Published
2008

29. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

Author

Marc A, Pfeffer, John J V, McMurray, Eric J, Velazquez, Jean-Lucien, Rouleau, Lars, Køber, Aldo P, Maggioni, Scott D, Solomon, Karl, Swedberg, Frans, Van de Werf, Harvey, White, Jeffrey D, Leimberger, Marc, Henis, Susan, Edwards, Steven, Zelenkofske, Mary Ann, Sellers, Robert M, Califf, and A, Trapani

Subjects
Male, medicine.medical_specialty, Captopril, Population, Myocardial Infarction, Tetrazoles, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Ventricular Dysfunction, Left, Double-Blind Method, Internal medicine, medicine, Humans, cardiovascular diseases, Myocardial infarction, education, Aged, Heart Failure, education.field_of_study, business.industry, Valine, General Medicine, Middle Aged, medicine.disease, Angiotensin II, Valsartan, Cardiovascular Diseases, Heart failure, ACE inhibitor, Cardiology, Myocardial infarction complications, Drug Therapy, Combination, Female, business, circulatory and respiratory physiology, medicine.drug
Abstract

background Angiotensin-converting–enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients. methods Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. results During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartanand-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P

Published
2003

30. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme

Author

Marc A, Pfeffer, Karl, Swedberg, Christopher B, Granger, Peter, Held, John J V, McMurray, Eric L, Michelson, Bertil, Olofsson, Jan, Ostergren, Salim, Yusuf, and Stuart, Pocock

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Cardiac Output, Low, Tetrazoles, Angiotensin-Converting Enzyme Inhibitors, Placebo, Placebos, Angiotensin Receptor Antagonists, Double-Blind Method, Internal medicine, Cause of Death, medicine, Humans, Antihypertensive Agents, Cause of death, Heart Failure, Ejection fraction, Intention-to-treat analysis, business.industry, Hazard ratio, Biphenyl Compounds, General Medicine, medicine.disease, Angiotensin II, Surgery, Candesartan, Treatment Outcome, Cardiovascular Diseases, Heart failure, Benzimidazoles, Female, business, medicine.drug, Follow-Up Studies
Abstract

Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin-receptor blocker could reduce mortality and morbidity.In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensin-converting-enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83-1.00], p=0.055; covariate adjusted 0.90 [0.82-0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79-0.97], p=0.012; covariate adjusted 0.87 [0.78-0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia.Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects.

Published
2003

31. Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure

Author

John J. V. McMurray, John R. Teerlink, Gadi Cotter, Robert C. Bourge, John G. F. Cleland, Guillaume Jondeau, Henry Krum, Marco Metra, Christopher M. O’Connor, John D. Parker, Guillermo Torre-Amione, Dirk J. van Veldhuisen, Jim Lewsey, Aline Frey, Maurizio Rainisio, Isaac Kobrin, and for the VERITAS Investigators

Subjects
Endothelin Receptor Antagonists, Male, Heart disease, Pyridines, Vasodilator Agents, Tetrazoles, Rolofylline, chemistry.chemical_compound, Double-Blind Method, Tezosentan, Humans, Medicine, Pulmonary Wedge Pressure, Cardiac Output, Infusions, Intravenous, Pulmonary wedge pressure, Aged, Heart Failure, Ejection fraction, business.industry, Endothelin receptor antagonist, General Medicine, Pulmonary edema, medicine.disease, Dyspnea, Treatment Outcome, chemistry, Anesthesia, Heart failure, Acute Disease, Female, Vascular Resistance, business, medicine.drug
Abstract

ContextPlasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure.ObjectiveTo determine if tezosentan improves outcomes in patients with acute heart failure.Design, Setting, and ParticipantsThe Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro–B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction.InterventionInfusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718).Main Outcome MeasuresThe coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined.ResultsOf the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of −12 (95% confidence interval [CI], −105 to 81) mm · h (P = .80) in the first trial and −25 (95% CI, −119 to 69) mm · h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95).ConclusionThe endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.Trial Registrationclinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).

Published
2007

32. Effects of sympathetic inhibition on exertional dyspnoea, ventilatory and metabolic responses to exercise in normotensive humans

Author

Stuart D.R. Galloway, Giuseppe De Vito, Sam McCLURE, Myra A. Nimmo, and John J. V. McMURRAY

Subjects
Mean arterial pressure, medicine.medical_specialty, Moxonidine, business.industry, VO2 max, Physical exercise, General Medicine, medicine.disease, Endocrinology, Blood pressure, Heart failure, Internal medicine, Heart rate, medicine, Cardiology, Exertion, business, medicine.drug
Abstract

Augmentation of circulating noradrenaline concentration stimulates ventilation during the initial stages of exercise and this is accompanied by an increased sensation of dyspnoea and exertion. This previous study [Clark, Galloway, MacFarlane, Henderson, Aitchison and McMurray (1997) Eur. Heart J. 18, 1829‐1833] suggested a link between dyspnoea, which commonly limits exercise tolerance in heart failure patients, and high circulating noradrenaline concentration in these patients. The present study investigated this relationship further using sympathetic inhibition. Ten healthy normotensive males performed 10 min of submaximal cycling exercise at approx. 70% of maximal oxygen uptake per min (Vd O 2max ) on three occasions one week apart. The first of these sessions was a familiarization session and the other two were experimental study days. On each of the study days, subjects attended the laboratory in the morning after an overnight fast and, following a resting blood sample, were administered placebo or moxonidine (0.4 mg) in a double blind cross-over design. After a 90-min absorption period, subjects undertook the exercise task. Blood was drawn, expired gas was analysed breath by breath, blood pressure, heart rate and ratings of perceived dyspnoea and exertion were obtained. Moxonidine treatment significantly reduced plasma noradrenaline concentration (P ! 0.01), mean arterial pressure (P ! 0.01), and blood glycerol concentration (P ! 0.05), but no dierences were observed in heart rate, the ventilatory response to exercise or subjective ratings of dyspnoea and exertion. This study indicates that reducing sympathetic activity does not aect ventilation, perceived dyspnoea or perceived exertion in normotensive males. Therefore it can be concluded that reducing sympathetic activity may not be an appropriate strategy to help reduce perceived dyspnoea.

Published
2000

33. Venous endothelin receptor function in patients with chronic heart failure

Author

David J. Webb, William G. Haynes, John J. V. Mcmurray, and Michael P. Love

Subjects
Agonist, medicine.medical_specialty, Heart disease, business.industry, medicine.drug_class, General Medicine, respiratory system, Peptide hormone, medicine.disease, Preload, Endocrinology, medicine.anatomical_structure, Heart failure, Internal medicine, cardiovascular system, medicine, business, Vein, Receptor, Endothelin receptor, circulatory and respiratory physiology
Abstract

Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-I in this disease. Two main subtypes of endothelin receptor, ET A and ET B , exist in human blood vessels. We studied the venoconstrictor effects of endothelin-I (a non-selective ET A and ET B agonist) and sarafotoxin S6c (a selective ET B agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least I week apart, locally active doses of endothelin- or sarafotoxin S6c were infused into a suitable dorsal hand vein for I h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-I was significantly blunted in heart failure patients compared with controls (26 ± 7% and 51 ± 6% peak reduction in vein calibre respectively; P = 0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17 ± 5% and 17 ± 4% peak reduction in vein calibre respectively). Both ET A and ET B receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-I in chronic heart failure may therefore require administration of an antagonist with ET A - and ET B -receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET A receptor sensitivity, but further studies are required to clarify the functional significance of this observation.

Published
2000

34. Noradrenaline attenuates the natriuretic effect of atrial natriuretic factor in man

Author

R.A. Brown, PH Seidelin, John J. V. Mcmurray, and Allan D. Struthers

Subjects
Adult, Male, Sympathetic nervous system, medicine.medical_specialty, Sympathetic Nervous System, Renal function, Hemodynamics, Context (language use), Kidney, Excretion, Norepinephrine (medication), Norepinephrine, Internal medicine, Humans, Medicine, Drug Interactions, Pharmacology (medical), Pharmacology, Dose-Response Relationship, Drug, business.industry, Sodium, Drug interaction, medicine.anatomical_structure, Endocrinology, business, Systemic haemodynamics, Atrial Natriuretic Factor, Glomerular Filtration Rate, Research Article, medicine.drug
Abstract

1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.

Published
1989

35. Mechanisms of the antinatriuretic action of physiological doses of angiotensin II in man

Author

Allan D. Struthers, John J. V. Mcmurray, and PH Seidelin

Subjects
Adult, Male, medicine.medical_specialty, Aldosterone, Reabsorption, Sodium, Angiotensin II, Renal function, chemistry.chemical_element, Natriuresis, Urination, General Medicine, Nephron, Excretion, Free water clearance, Kidney Tubules, Proximal, chemistry.chemical_compound, medicine.anatomical_structure, Endocrinology, chemistry, Internal medicine, medicine, Humans
Abstract

1. Angiotensin 11 (ANG II; 1 ng min−1 kg−1) or 5% (w/v) d-glucose (placebo) was infused in six normal male volunteers, pretreated with 500 mg of lithium carbonate, who were undergoing maximal water diuresis. 2. This dose of ANG II caused a circulating increment within the physiological range (27 ± 4 to 48 ± 9 pmol/l). 3. Compared with placebo, ANG II caused a significant fall in urinary sodium excretion (113 ± 13 to 82 ± 10 μmol/min). This antinatriuretic effect occurred without a fall in creatinine clearance (107 ± 3 versus 113 ± 3 ml/min). 4. ANG II caused a significant fall in fractional lithium clearance (28 ± 2 to 23 ± 2%). This may indicate a proximal tubular effect of ANG II. 5. ANG II also reduced fractional distal delivery [(sodium clearance plus free water clearance) divided by creatinine clearance], another measure of proximal tubular outflow. A parallel change in these two separate markers of proximal function supports an action of ANG II at this nephron segment. 6. Furthermore, the antinatriuretic effect of ANG II was unlikely to be due to stimulation of aldosterone secretion because (a) the fall in sodium excretion was temporally dissociated from the rise in aldosterone secretion, (b) potassium excretion also tended to fall during ANG II infusion and (c) aldosterone has a distal nephron effect, while, in this study, proximal nephron fractional reabsorption of sodium increased and distal nephron fractional reabsorption of sodium was unchanged. 7. These observations suggest that physiological increments in ANG II can have an antinatriuretic effect in man, which, at least initially, results from increased proximal tubular sodium reabsorption and is independent of the effect of aldosterone.

Published
1989

36. The Effect of ANF on Urinary Protein Excretion in Man

Author

Allan D. Struthers, PH Seidelin, Jea Howey, and John J. V. Mcmurray

Subjects
Urinary protein, Excretion, medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, Medicine, General Medicine, business
Published
1988

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