Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Intake of dehydrated nopal (Opuntia ficus indica) improves bone mineral density and calciuria in adult Mexican women

Background: The intake of dehydrated nopal (DN) at a high stage of maturity along with high calcium content could improve bone mineral density (BMD) and calciuria and thus prevent osteoporosis. Objective: To evaluate the effect of calcium intake from a vegetable source (DN) on BMD and calciuria covering a 2-year period in menopausal and non-menopausal women with low bone mass (LBM). Methods: The study was quasi-experimental, blinded, and randomized, and included 131 Mexican women aged 35&#x2013;55. Urinary calcium/creatinine index (CCI) was determined; BMD was analyzed on lumbar spine and total hip regions. Four groups were studied: Control group (CG), women with normocalciuria and a minimum dose of DN; experimental group 1 (EG1), women with hypercalciuria and a minimum dose of DN; experimental group 2 (EG2), women with hypercalciuria, and a maximum dose of DN; and normal group (NG) for reference in BMD. Results: After the first semester of treatment, calciuria levels in women from both experimental groups returned to normal, remaining constant for the rest of the treatment. The percentage difference in BMD increased in the total hip region in the CG (pre 4.5% and post 2.1%) and EG2 (pre 1.8% and post 2.5%) groups significantly in comparison to NG and EG1, which exhibited a significant decrease in their BMD. BMD increased only for the lumbar region in the EG2 group (premenopausal). Conclusion: The use of a vegetable calcium source such as nopal improves BMD in women with LBM in the total hip and lumbar spine regions principally in the premenopausal women, maintaining constant and normal calciuria levels

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study (Intensive Care Medicine, (2021), 47, 2, (160-169), 10.1007/s00134-020-06234-9)

1832The original version of this article unfortunately contained a mistake. The members of the ESICM Trials Group Collaborators were not shown in the article but only in the ESM. The full list of collaborators is shown below. The original article has been corrected.openopenLabeau S.O.; Afonso E.; Benbenishty J.; Blackwood B.; Boulanger C.; Brett S.J.; Calvino-Gunther S.; Chaboyer W.; Coyer F.; Deschepper M.; Francois G.; Honore P.M.; Jankovic R.; Khanna A.K.; Llaurado-Serra M.; Lin F.; Rose L.; Rubulotta F.; Saager L.; Williams G.; Blot S.I.; Muzha D.; Ribas A.M.; Lipovesty F.; Loudet C.; Eller P.; Mostafa N.; Honore P.M.; Telleria V.M.; Smajic J.; Nogueira P.C.; Nafees K.M.K.; Hentchoya R.; Soledad J.; Cardenas Y.; Reyes A.G.; Sustic A.; Mpouzika M.; Vymazal T.; Jensen H.I.; Aguirre-Bermeo H.; Maddison L.; Valta M.; Bloos F.; Adipa F.E.; Koulouras V.; Enamorado J.; Agoston Z.; Birgisdottir H.; Gupta A.; Gurjar M.; Kilapong B.; Hashemian S.M.; Martin-Loeches I.; Cortegiani A.; Fletcher K.; Hayashi Y.; Waweru-Siika W.; Abidi K.; Lee S.-M.; Hadri B.; Dolgusevs M.; Abillama F.F.; Jovaisa T.; Thix C.; Elhadi M.; Nor B.M.; Ratnam S.; Mazlan M.Z.; Maiyalagan S.; Sanchez-Hurtado L.; Belii A.; Naranpurev M.; Gautam P.; De lange D.; Parke R.; Ilesanmi R.E.; Shosholcheva M.; Petosic A.; Lind R.; Ffarcsi M.H.; Bogarin J.; Hernandez A.M.; Mikaszewska-Sokolewicz M.; Sousa B.; Tomescu D.; Sandesc D.; Twagirumugabe T.; Gusarov V.; Ebaid M.; Slobodianiuk G.; Martonova A.; Knafelj R.; Mer M.; Maseda E.; Panka B.; Schefold J.C.; Joelsson-Alm E.; Trongtrakul K.; Merritt-Charles L.; Besbes L.O.; Dikmen Y.; Zgrzheblovska L.; Fielding M.; von der Osten I.; Muzha D.; Greca A.; Cani A.; Xhindi N.; Hyska G.; Ribas A.M.; Pinto S.; Alves P.; Esposito R.; Valgolio E.; Minope J.T.S.; Abdala A.; Ayala M.; Bravo S.; Bantar A.; Delgado P.; Badariotti G.; Lipovestky F.; Diaz A.; Saul P.; Setten M.; Aucapina A.; Acosta Y.; Gonzalez V.; Camputaro L.; Baccaro F.; Villa R.; Diaz A.; Mastantuono M.; Dean E.; Rostello O.F.; Brizuela P.; Bartoli J.R.; Guereschi M.; Quiroga C.; Putruele S.; Villegas P.; Curilen V.; Fernandez R.; Nocheretti M.G.; Escalante R.G.; Loudet C.I.; Fernandez S.; Gonzalez A.L.; Alvarez G.A.; Iglesias F.; Chaparro S.; Zakalik G.; Pagella G.; Baini M.; Campos P.A.; Sabbag I.; Schmukler A.; Fonseca I.P.; Alvarez G.M.; Ramirez M.; Tapia F.; Bascary C.A.; del Valle Gimenez G.; Bertoletti F.P.; Milioto E.; Bonsignore P.J.M.; Fernandez M.A.; Smith J.; Chimunda T.; Thompson L.; Maguire T.; Watts S.; Mitchell M.; Powell M.; Lye I.; Parsons L.; Baker N.; Reynolds C.; Thompson A.; Masters K.; Sosnowski K.; Morrison L.; Leslie G.D.; Lakshmanan R.; Tabah A.; Brown W.; McDowell-Skaines S.; McLucas A.; Smith C.; Tallot M.; Jones S.; Barakat-Johnson M.; Leong T.; Butcher R.; Martin K.; Douschan P.; von Lewinski D.; Eller P.; Schmutz R.; Kolussi U.; Salman F.; Ateya Z.; Mostafa N.; De Decker K.; Van Regenmortel N.; Jans A.; Wijnands P.; Coremans S.; De Bels D.; Depuydt T.; Paillet C.; Jacquet L.-M.; Swinnen W.; Hannes F.; Mergeay M.; Van de Velde S.; Allaert S.; Hoste P.; Borin C.; Balon S.; Fraipont V.; Biston P.; De Schryver N.; Dugernier T.; Van Cotthem I.; Telleria V.M.; Smajic J.; de Almeida A.O.; Jorge S.A.; Becker D.; Schmidt R.C.; Oliveira E.; Ramalho A.; Mazocoli E.; Fioretti A.; Barros E.; Serpa L.; Bianchini S.; Campanili T.; Pantaleao T.; Garcia P.C.; Ronchini A.L.V.; Santos R.; Nafees K.M.K.; Manap N.B.A.; Hentchoya R.; Bagshaw S.; Carney D.; Bagshaw S.; Davidow J.; Bagshaw S.; Rokosh E.; Bagshaw S.; Laizner A.M.; Smith S.; McQuirter M.; Kampayana B.S.; Favre R.; Sills M.; Laizner A.M.; Dallaire J.; Laizner A.M.; Becker C.; Microys S.; Bowes B.; Lajeunesse J.; Ghosh R.; Baptiste-Savoie J.; Raizman R.; Bagshaw S.; Suen G.; Taghavi N.; Smith O.; Fielding C.; Canales J.; Molina P.; Chaparro J.; Sepulveda M.I.; Zamorano M.J.F.; Rocha P.; Villanueva X.; Araya P.; Dayan M.; Avalos F.; Li X.; Liu Y.; Li X.; Chen X.; Jiang Z.; Yang J.; Chen J.; Yang L.; Wang K.; Gao J.; Fang X.; Zhao R.; Xia X.; Liu H.; Li J.; Wang H.; Meng G.; Di Y.; Wang D.; Zhao R.H.; Hu L.P.; Fang X.; Peipei X.; Jiao Q.F.; Wang H.Y.; Xia C.J.; Liu Y.; Ye M.; Wan Y.; Wang W.; Ding Y.; Ren A.; Gao Y.; Li Q.; Du G.; Yang J.; Shen Y.; Ding Y.; Li N.; Yuan C.; Li J.; Tan L.; Lin Q.; Guo H.; Yan H.; Xu X.; Zhang W.; Liang J.; Zhang L.; Tian E.; Zhao Q.; InSu L.; Dong J.; Gu Y.; Liu Y.; Zhao L.; Wang W.; Qiao H.; Tuo L.; Lv M.; Zhu J.Y.; Zhu J.F.; Wei Y.; Liu M.; He Y.; Cheng J.; Liu J.; Jia N.; Wei D.; Li Q.; Wu X.; Duan H.; Lin D.; Liang Q.; Luo X.; Xiong Y.; Huang R.F.; Fu J.; Zan T.; Ye M.; Shi Z.; Long Y.; Lei Y.; Liu X.; Yumei C.; Wang L.L.; Zhang Y.; Xu Y.; Cheng; Zhijuan W.; Sun C.; Song J.H.; Wang Y.; Liu X.M.; Liu Y.; Yuan Y.; Huang Q.; Yang F.; Wu Y.; Luo X.; Bai X.; Zheng H.; Song M.; Sun Y.; Li Z.S.; Luo F.; Liu M.; Li L.C.; Li X.; Zhang G.; Xiao L.; Yu T.; Gao G.; Wei W.; Wang F.; Han T.; Li T.; Zeng Q.; Zeng J.M.; Long Y.; Pan F.; Wang J.; He G.; Chen H.; Zhang F.; Chao Y.; Chunhua G.; Yao X.; Bai D.; Liu L.; Xu X.; Wang Y.; Liang X.; Zhang N.; Li X.; Zhang A.; Chen X.; Hu X.C.; Zhang H.; Wang R.X.; Tak P.S.; Ho S.W.; Jiang Q.X.; Ding X.; Hong L.; Miao L.; Feng Z.; Huang L.P.; Wu J.; Wang Y.; Guo J.; Zhang B.; Ma C.; Han Y.; Liu C.; Ding M.; Luan L.; Zheng J.; Lv S.; Jiang S.; Cao W.; Xue X.; Li J.; Liu G.; Wang J.; Wei X.; Zhang W.; Jiang Y.; Yao Z.; Gao L.; Li J.; Zhao W.; Jiang M.; Hao J.; Zhang J.; Song C.; Chen F.; Wang S.; Hu L.; Cao D.; Liu Y.; Wan J.; Wang X.; Shao H.; Zhang Z.; Cui X.; Liu J.; Zhao L.; Li X.; Fan L.; Zhang L.; Yu M.; Li B.; Li C.; Liu L.; Liu X.L.; Chen W.; Li Y.; Zhigang Z.; Yuchen W.; Mu C.; Zhu G.; Yang F.; Bo Q.; Li L.; Chen M.; Jiang J.H.; Yin H.; Pang X.; Gong Y.Y.; Yang S.; Yan X.; Zheng X.; Lei D.H.; Lei L.; Guo Y.; Liu L.; Yu J.; Sun W.; Bi A.P.; Li W.; Wu Y.; Li J.; Ni D.; Li X.; Liu Y.; Wu Z.; Song B.; Chen J.; Fei Q.; Xiaoyan Y.; Ran Q.; Xixi L.; Jiao X.; Ji H.; Zhiping S.; Hong M.; Jianhong M.; Hao Y.; Yin L.; Wang Y.; Hui C.; Ju W.; Xia X.; Huo Y.; Wang Y.; Chen L.; Yan Y.; Zhao Q.; Chen H.; Bao G.; Cao Y.; Hong L.; Zhang H.; Zhang Y.; Xu L.; Guixiang J.; Li Y.; Zhao H.M.; Huang X.; Dai Z.; Jian Y.; Zhang H.; Tian Z.; Cao Z.Q.; Li M.; Liu Y.; Ouyang F.; Ma F.; Jin W.; Ge L.; Wu S.F.; Li J.; Yuan W.; Chen T.; Shi G.; Chen Z.; Liu K.; Lin X.; Yuemen L.; Lijuan S.; Tian X.F.; Wang S.; Feng Z.X.; Liu X.Z.; Dong Y.; Zhang J.; Bocui N.; Jiang Z.X.; Yang J.; Wang G.X.; Zhao Y.; Wu X.; Yang Q.; Hu R.L.; Li X.Q.; Yu Z.J.; Yao Y.; Deng X.; Xiao Y.; Xie Y.; Yang Y.; Yang H.; Zhou Y.; Li Z.; Xiao M.; Yang Y.X.; Tian Y.; Gama L.M.S.; Hernandez J.S.; Cardenas Y.; Caicedo N.; Marin J.; Ochoa M.-E.; Gomez M.; Rojas-Suarez J.; Gonzalez J.; Reyes A.J.G.; Chapeta E.; Orozco E.; Filipovic-Grcic I.; Vukovic A.; Pecenkovic S.; Suput A.; Sustic A.; Zivanovic-Posilovic G.; Bozena A.; Udiljak N.; Milic M.; Radivojevic R.C.; Mihaljevic S.; Matas M.; Tonkovic D.; Culjak H.; Herceg I.; Pavlisa G.; Dobric M.; Beker T.; Adam V.N.; Goranovic T.; Markoulias C.; Mathaios M.; Mylordou M.; Achilleos E.; Kleanthous P.; Kotanidi V.; Foka M.; Charalabous I.; Alexandrou A.; Georgiou M.; Patsalos A.; Zepoy S.; Constantinou C.; Piza P.; Vymazal T.; Wiborg E.; Bruhn L.; Kaasby K.; Pedersen K.R.; Mikkelsen S.; Collet M.; Langvad A.; Andresen H.; Fischer S.; Kjaergard I.E.; Jepsen B.; Husted B.; Bestle M.; Kodal A.M.; Hansen T.C.B.; Pedersen A.S.B.; Thomsen T.D.; Hoegenhaven A.; From M.; Frandsen T.M.; Henning G.; Hansen A.; Jensen H.I.; Bliksted I.A.; Tamayo L.M.; Mogrovejo P.; Aguirre-Bermeo H.; Palaez C.; Tutillo D.R.M.; Hurtado C.V.; Garcia M.F.; Alvarez D.; Guerrero F.; Vasquez A.; Kutimets M.; Tamme K.; Maddison L.; Anvelt E.; Dlamini-Sserumaga L.; Lofqvist C.; Lusenius V.; Kauppi O.; Sakki J.-K.; Tervo-Heikkinen T.; Kesti U.; Merilainen M.; Karjula E.; Peltomaa M.; Palmu A.; Ahtiala M.; Valta M.A.; Mentec H.; Plantefeve G.; Besch G.; Pili-Floury S.; Ledochowski S.; Deserts M.D.; Giacardi C.; Daubin C.; Massard A.; Le Guen Y.; Blanc A.; Mandaroux S.; Gunther S.C.; Avogadro P.; Radavidson A.; Turc J.; Jochmans S.; Quintard H.; Boyer L.; Bruel C.; Philippart F.; Montravers P.; Atchade E.; Flessel N.; Chinardet B.; Soulisse L.; Pillard C.; Ngo D.; Bongiorno B.; Heitzler N.; Souppart V.; Gautheret N.; Timsit J.-F.; Essardy F.; Fartoukh M.; Mehay D.; Etourneau F.; Farkas J.-C.; Beuret P.; Preda G.; De Montmollin E.; Castelain V.; Jaschinski U.; Rothenfusser M.; Kindgen-Milles D.; Dimski T.; Fiedler C.; Heinicke T.; Meybohm P.; Schulze T.; Bota M.; Pelz S.; Odenthal T.; Christ M.; Bloos F.; Bosl K.; Chovas A.; Stehr S.; Simon P.; Grotheer S.; Schuppel S.; Schaller S.; Albrecht L.; Stubner A.; Graeser S.; Kolbe N.; Lausch M.; Diers A.; Guenther U.; Riessen R.; Roller M.; Osei I.P.; Kusi-Appiah A.-C.; Yakubu Y.H.; Guadi-Gosh B.; Dragoumanis C.; Christofis C.; Kazakos N.; Bastani S.; Martinos C.; Bekos V.; Papanikolaou M.; Papavasilopoulou T.; Efthymiou A.; Chantziara V.; Kyriakoudi A.; Kakaras N.; Diakaki C.; Flevari A.; Nikolaou C.; Katerina K.; Avramopoulou L.; Tsikritsaki K.; Gkiokas G.; Pantiora E.; Katsenos C.; Patsiou E.-C.; Alexandropoulou P.; Koutsodimitropoulos I.; Farmakis E.; Nestora K.; Chatzis M.; Kondili E.; Soundoulounaki S.; Mousafiri O.; Lepida D.; Liarmakopoulou A.; Koulouras V.; Papathanakos G.; Oikonomou M.; Ioannides P.; Papadopoulos D.; Staikos I.; Stafylaraki M.; Raitsiou B.; Mandis K.; Ravani I.; Kourelea S.; Efthimiou A.; Thoma G.; Bakas A.; Psarulis K.; Anisoglou S.; Papageorgiou E.; Michailidou E.; Tholioti T.; Lavrentieva A.; Sourla E.; Spyropoulou A.; Pantelas N.; Stalika K.M.M.; Georgakas I.; Karathanou A.; Tsikriki S.; Dimoula A.; Kanakaki S.; Vakalos A.; Pagioulas K.; Enamorado J.E.; Nardai G.; Hawchar F.; Blondal A.; Rygvadottir B.; Jonasdottir R.J.; Birgisdottir H.; Shah B.; Kaushik S.; Tripathy S.; Singh M.; Agarwal S.; Gupta M.; Ahmad M.; Mangal K.; Bhargava V.; Kushare V.; Jha S.; Bhakhtiani L.; Gupta A.; Kamal M.; Gurjar M.; Baronia A.; Kilapong B.; Susanti A.; Lestari M.I.; Zulkifli Z.; Baskoro W.; Zand F.; Zarei F.; Mahmoodpoor A.; Heidari F.; Jafaraghaee F.; O'Shea A.; O'Shea F.; O'Donnell C.; Craig G.; Fitzpatrick G.; Dunne L.; Hastings J.; Marsh B.; Cody C.; Campbell E.; Doyle D.; Pacturanan M.; Sheehan C.; Carey A.; Carter C.; Mulvey R.; Finn D.O.C.R.; Motherway C.; Walsh A.; Kehoe J.; Delossantos S.; Lalor J.; O'Nuallain S.; Behan H.; McPherson S.; Corcoran A.; Gordon P.; Rooney G.; Levy D.; Azencot M.; Gurevich V.; Lavy A.; Bendelari V.; Marconi R.; Barone A.; Gatti C.; Giampaoletti A.; Borgognoni C.; Ghioldi D.M.; Raimondo A.; Castiglione G.; Bruno A.V.; Rubulotta G.; Mo A.; Corso A.; Girianni S.; Bruni A.; Garofalo E.; Maggiore S.M.; Di Risio A.; Calamai I.; Spina R.; Spadaro S.; Volta C.A.; Cotoia A.; Mirabella L.; Maulicino L.; Abregal G.; Donvito M.; D'Ambrosio P.; Binda F.; Adamina I.; Galazzi A.; Negro A.; Vaschetto R.; Capuzzi F.; Boschetto M.; Stivanello L.; Bonaccorso L.; Megna C.; Cortegiani A.; Iozzo P.; Rizzo A.; Scire G.; Taibi M.R.; Tranello F.P.; Manzo A.; Traina L.; Pastore B.; Quaini A.; Giusti G.D.; Montaldi G.; Piergentili F.; Mancini F.; Casaioli S.; Uccelli F.; Guarracino F.; Onelli A.; Di Gravio V.; Cossu M.; Matrona O.; Rocco M.; Alampi D.; Dellafiore F.; Ranalli F.; Bossolasco M.; Brizio E.; Migliorino P.; Cortellazi P.; Rosati M.; D'Ambrosio F.; Quagliotto C.; Roman-Pognuz E.; Peratoner A.; De Rosa S.; Martin M.A.; De Sanctis F.; Ciorba P.; Fletcher K.; Toppin P.; Harding-Goldson H.; Taito S.; Shime N.; Yamamoto R.; Kanda F.; Hirao A.; Egi M.; Noguchi A.; Hashimoto S.; Aya U.; Sakuramoto H.; Ohuchi A.; Kataoka J.; Maruyama K.; Nakayama I.; Nishime Y.; Fujimoto K.; Takahashi K.; Tsujimoto M.; Shimizu M.; Waweru-Siika W.; Tole E.; Correia M.C.; Kim J.H.; Park S.; Kim K.C.; Baek J.; Bae J.-M.; Park S.Y.; Park T.S.; Lee H.B.; Park S.Y.; Park J.; Yeon-Joo L.; Young-Jae C.; Lee S.-M.; Jeon K.; Kim S.C.; Lee J.; Chee H.K.; Huh J.W.; Sim Y.S.; Kim J.; Chang Y.; Ahn J.-J.; Kang B.J.; Lee W.-Y.; Lee S.J.; Hadri B.; Baftiu N.; Krastins I.; Dolgusevs M.; Abillama F.F.; Stiban S.; Feghaly M.E.; Gharios E.; Merheb M.; Benlamin M.; Khaled A.; Belkhair W.A.; Tabib M.; Ashour F.; Elhadi A.; Tababa O.W.E.; Khaled T.; Alkhumsi S.I.R.; Alshrif A.I.; Aboufray A.A.; Alabuzidi A.; Triki A.R.; Elgammudi M.; Zahra H.B.; Soula E.; Al-Alawi M.M.S.; Ahmed H.; Ghula M.A.A.; Vosylius S.; Mouton L.; Rastegar T.; Sertznig C.; Martin G.; Thix C.; Theisen C.; Ferretti C.; Gils F.; Gallion M.; Zainudin A.; Bahrin L.K.K.; Deva S.R.; Rahim A.H.A.; Wahab S.; Mazlan M.Z.; Hassan W.N.W.; Ismail W.N.W.; Ali M.N.; Khoo T.M.; Samat N.M.; Tong J.M.G.; Adib N.A.N.; Nor M.B.M.; Ratnam S.; Ismail N.; Ratnam S.; Sulaiman S.R.; Foong K.W.; Alias A.; Hua N.P.; Maiyalagan S.; Maiyalagan S.; Zermeno J.M.; Blanco D.; Duran K.; Nava C.L.L.; Nandyelly S.J.R.; Sanchez-Hurtado L.A.; Tejeda-Huezo B.; Del Moral Armengol M.; Nava L.P.A.; Herrera J.G.; de Anda G.F.V.; Gallegos-Perez H.; Hernandez-Sanchez N.; Hernandez-Ponce L.; Gorordo-Delsol L.; Hernandez-Romero M.; Gomez S.; Molinar F.; Namendys-Silva S.A.; Romero-Gonzalez J.P.; Gonzalez D.; Landaverde A.; Sosa M.A.; Navarro B.; de Molina Serrano J.I.R.; Iburrigarro S.R.; Ibarra A.; Aguirre J.; Martinez-Gonzalez M.; Padilla N.R.C.; Pineda A.A.V.; Villafuerte M.V.E.; Herrera M.O.G.; Belii A.; Naranpurev M.; Baasanjav B.; Hachimi A.; Elkhayari M.; Abidi K.; Dendane T.; Subedi N.B.; Pathak S.D.; Gautam P.; Manandhar M.; Van Gulik L.; Van Den Brink M.; Van Vliet P.; Gerretsen B.; Van Den Berg L.; De Haan M.; Tuinstra B.; Kuijpers P.; Reijntjens J.; Vermeijden J.W.; Rinket M.; Vanroest M.; Reidinga A.; Loef B.; Dieperink W.; Onrust M.; Dormans T.; Bormans L.; Koopmans M.; Gerritsen R.T.; Van Den Elst A.; Evers M.; Oiting O.; Wilting R.; Ramaker B.; van der Kuil M.; Fijen J.-W.; Haas L.; De Lange D.; Haringman J.; Newby L.; Parke R.; Gilder E.; Hacking D.; Dagooc R.; Song R.; Waibel H.; Dawn F.; Rapley J.; Chadwick L.; Chapman C.; Crone P.; Albrett J.; Marko P.; Goodson J.; Browne T.; Whitticase R.; Davidson C.; Judd H.; Owens D.; Onyeka T.; Ugwu I.; Ilesanmi R.; Adejumo P.O.; Owojuyigbe A.; Adenekan A.; Uba S.; Chime C.; Jibrin D.; Sankey B.J.; Adekola O.; Olanipekun S.; Olanipekun S.; Adekola O.; Shosolcheva M.; Gievski V.; Kartalov A.; Naumovski F.; Kuzmanovska B.; Trposak A.; Bogoevska-Miteva Z.; Rosalia R.; Olsen B.F.; Sjobo B.; Jensen K.D.; Sykehus D.; Johansen B.F.; Straede E.; Johansen E.; Finnstrom I.J.; Toellefsen A.; Ostenjo H.; Bjorgen H.; Bratsberg B.; Kristoffersen E.; Skorstad E.M.; Hansen S.; Vullum S.; Lunde G.A.; Arntsen W.; Lund M.; Akselsen G.R.; Monstad K.R.; Stenset A.; Haugom H.; Monsen B.; Hogvall L.; Trudvang S.; Galaaen B.; Malmin S.K.; Andersen M.H.; Hargott R.F.; Andersen Y.; Steffenak E.; Nyhus M.; Meland B.; Hashmi M.; Rivas N.; Maidana E.; de Jesus Ortiz A.; Cabral D.M.B.; Simi M.; Aponte C.; Rivas J.C.; Gill S.; Garcia A.; Alvarenga G.; Cespedes L.; Perez H.; Moreira M.L.; Canete F.; Gonzalez R.; Monges N.; Garcia A.; Coman M.; Pederzani M.; Franco N.; Aganon F.; Martinez R.; Noblezada-Uy D.; Ellazar C.G.; Cerezo F.D.; Hernandez A.M.; Palo J.E.; Aperocho C.A.J.; Isanan M.; Tubacka M.; Jasiewicz P.; Czuczwar M.; Borys M.; Gutysz-Wojnicka A.; Glinka L.; Gawda R.; Mikaszewska-Sokolewicz M.; Bilawicz J.; Cabrita P.; Vieira J.; Figueiredo M.F.; Pinheiro C.M.; Antunes N.; Pedro L.; Ferreira F.; Parente I.; Varela M.; Fernandes F.; Martins C.; Viveiros A.; Cavaco R.; Rita C.S.; Dias S.; Feranandes A.M.; Silva P.; Nunes C.; Cabral J.; Sousa B.; Pires F.; Ferreira H.; Santos J.; Pinto V.M.V.; Bispo B.M.; Ferreira A.; Molinos E.; Lafuente E.; Gregorio R.; Costa H.; Lima A.; Ferreira S.; Seromenho V.; Luis E.; Valerio I.; Cesar H.; Tavares A.; Alsheikhly A.S.; Mahmood S.; Guran C.T.; Moise A.; Filipescu D.C.; Luchian M.; Tomescu D.; Popescu M.; Scutariu M.A.; Petrisor C.; Hagau N.; Grigoras I.; Patrichi T.; Gusarev V.; Pivkina A.; Kulakov V.; Ignatenko O.; Kovaleva J.; Zhivotneva T.; Zhedaeva M.; Matiushkov N.; Ershova O.; Egorova N.; Khoronenko V.; Baskakov D.; Sergeev D.; Piradov M.; Grishina L.; Magomedov M.; Zuev E.; Gorokhovatsky U.; Leonova A.; Fadeeva L.; Belskiy V.; Galishevskiy D.; Zubareva N.; Tribulev M.; Zueva O.; Kiselev A.; Kamenshchikov N.; Tokareva E.; Petrushin M.; Starchenko I.; Twagirumugabe T.; Nshimyumuremyi I.; Muhizi J.; Buregeya E.; Nzarora J.; Assiri A.; Ebaid M.S.; Almekhlafi G.; Mandourah Y.; Velickovic J.; Velickovic D.; Jovanovic B.; Hadzibegovic A.; Stefanovic B.; Misic V.; Bumbasirevic V.; Rajkovic M.; Stojanovic M.; Gavrilovic S.; Stanojevic M.; Martonova A.; Yaghi A.; Turcan A.; Firment P.; Slobodianiuk G.; Rabarova D.; Lancaricova D.; Vlaovic J.; Groznik M.; Lukic M.; Perme J.; Sostaric M.; Umek N.; Mirkovic T.; Dolenc S.; Knafelj R.; Fister M.; Zorko N.; Markota A.; Yeni N.P.; Jali P.; Schmollgruber S.; Syed M.R.; Parag N.; Wise R.; Galiana M.; Navarro J.A.; De Pablo A.M.; Albert P.; Martinez P.; Mendiara Y.; Garcia B.; Llinas A.A.; Riveiro M.; Gallart E.; Riera A.; Sanz M.; Salo S.; Lajara M.A.G.; Nieto M.V.; Garcia R.; Pena J.M.G.; Gorgolas M.C.; Isasi M.A.; Sierra R.; Gordo F.; Conejo I.; Salva-Costa V.; Garzon-Tovar C.; Lospitao S.; Gonzalez R.; Gutierrez P.; Girona M.; Adamuz J.; Olivares P.G.; de Ceballos J.P.G.; Tirado C.; De Wit I.; Polo A.B.C.; del Mar Diaz Salcedo M.; Ripolles-Melchor J.; Martinez-Hurtado E.; Alvarez J.D.; Arcas M.L.B.; Gonzalez J.I.T.; de la Ventana A.B.S.; Calleja P.L.-A.; Alvarez R.G.; Zamora P.S.; Guerrero A.O.; Cosano R.; Perez-Vacas J.; Campos-Perez M.; Barreiro E.M.; Sanchez L.C.; Diaz M.G.; Jimenez R.; Del Rio Cabajo L.; Muriel D.S.; Alonso H.F.; Fernandez A.W.; Pinan I.S.; Albaiceta G.M.; Fernandez M.C.I.; Abos F.J.S.; Monedero P.; Chueca R.M.; Aguirre L.G.; Manosa S.C.; Luque C.P.; Calpe N.; Losilla M.R.; Fores M.T.; Farre O.; Fernandez O.; del Rosario Villar Redondo M.; Arteta Arteta D.S.; Sanchez M.A.H.; Espinosa C.P.; Reyes L.M.; Domenech L.C.; Guillen C.V.; Alvarez J.T.; del Cotillo M.; Barrueco-Francioni J.E.; Conde B.B.; Blanco M.P.S.; Blasco M.L.; Clement A.I.; Hurtado C.; Sanz L.C.; Perez-Torres D.; Prol-Silva E.; Pereira J.; Gonzalez I.A.; Cano A.E.; Nunez C.R.; Fernadez I.L.; Fernandez A.A.M.; Del Bosque Diez R.; Hilario B.; Zalba-Etayo B.; Pascual-Bielsa A.; Panka B.; Banwarie P.; Nahar D.; van Axel A.; Boedjawan N.N.; Jansson E.B.; Malvemyr A.-S.; Johansson L.; Sandberg U.; Tingsvik C.; Mattsson G.; Lof G.; Spangfors M.; Ringdal M.; Geijer S.; Orvelius L.; Hylen M.; Lagerhall C.; Joelsson-Alm E.; Akerman E.; Hellkvist V.H.; Mickelsson U.; Akerman E.; Wahlbom E.; Larsson I.-M.; Wallin E.; Boroli F.; Ory S.; Jong M.L.; Dullenkopf A.; Lang M.; Fleury Y.; Maus M.; Ben-Hamouda N.; Fishman A.; Hsu M.Y.; Chang S.C.; Trongtratul K.; Sawawiboon C.; Morakul S.; Khwannimit B.; Merritt-Charles L.; Singh K.; Ventour D.; Figaro-Barclay D.; Sankar-Maharaj S.; Mebazaa M.S.; Kamoun S.; Elatrous S.; Besbes L.; Abroug F.; Naija W.; Elhechmi Y.Z.; Sellami W.; Hajjej Z.; Merhabene T.; Talik I.; Kuscu O.O.; Dilek O.; Zerman A.; Dal H.C.; Turan S.; Aydemir S.; Yilmaz H.; Calili D.K.; Izdes S.; Cengiz M.; Gumus A.; Tasdemir B.; Kagnici A.; Ay M.; Ay S.A.; Caliskan G.; Akbas T.; Balbay A.O.; Efe S.; Inal V.; Elay G.; Karabacak P.; Ozserezli B.; Senturk E.; Demirkiran O.; Bozbay S.; Dikmen Y.; Erdogan E.; Akker M.; Peker N.; Ozgultekin A.; Serin S.O.; Turan C.; Karaoren G.; Goksu S.; Karakurt S.; Arikan H.; Gul F.; Cinel I.; Kara I.; Undar H.N.; Bayraktar Y.S.; Celik J.B.; Tokur M.E.; Aydin D.T.; Yildiz I.; Ozcan B.; Erdivanli B.; Erdivanli B.; Ozcan B.; Eroglu A.; Akdag D.; Unlu N.; Fielding M.; Dungca A.; Ali A.; Thankamma B.; Reyes P.E.; John S.; Rajendran A.; Ahmad F.K.E.; Smiley K.A.; Hojden S.; Miller M.T.; Das Sasidharan Nair V.; Antonio M.G.S.; Qawasmeh K.A.; Shawish S.A.; Twiggs H.; Rosado I.; Babych V.; Morren F.; Young C.; Vaughan-Jones N.; Harris S.; Burns K.; Georgiev C.; Shayamano R.; Kerslake I.; Creber P.; Vochin A.; O'Brien C.; Caddell P.; Hagan S.; Hughes M.; Torlinski T.; Sherwin J.; Kannan S.; Markham A.; Lebon R.; Cupitt J.; Cranshaw J.; White N.; Marriott V.; Milner W.; Groba C.B.; Azoia J.; Polgarova P.; George S.; Kapoor R.; Lynch C.; Fox N.; Cranmer K.; Fox N.; Llewellym T.; Matthews K.; Maltby L.; Ibao J.; Boulton K.; Jarman R.; Baxter K.; Raj A.S.; Moghal A.; White J.; Barrowcliffe S.; Pulletz M.; Ganeshalingam V.; Baruah R.; Baker H.; Woods J.; Ei P.P.; Ogbeide V.; Hayden P.; Matthews K.; Hughes J.; Balasubramanian M.; Salberg A.; Saha R.; Holmquist D.; Young C.; Derbyshire C.; Smith N.; Stones E.; Ademokun J.; Popescu M.; Legorburo M.S.; North S.; Brett C.; Jaundoo H.; Craig J.; Whiteley S.; Howcroft C.; Wilby L.; Delve P.; Shaw D.; Williams K.; Welters I.D.; McMullen J.; Brett S.; Flores L.; Trueman-Dawkins T.; Templeton M.; Adams J.; Smith C.; Prowle J.; Byers H.; McDonnell A.; Rose B.O.; Reece-Anthony R.; Mendes L.; Vizcaychipi M.; Bull R.; Lacaden G.; Santiago E.; Delgado C.C.; Farnell-Ward S.; Thorpe E.; Somerville J.; Williams A.; Cummings D.; Derrick H.; Brumwell S.; Randell C.; McCann N.; Aves E.; Berry G.; Szakmany T.; Gunter U.; Pulak P.; Sarkar N.; Wright K.; Gomes V.; Jones J.; Palfrey R.; Camsooksai J.; Lewis A.; Eneas A.; Tridente A.; Barr L.; Jovaisa T.; Thomas B.; Parkin E.; Horner D.; Frey C.; Bench S.; Baumber R.; Broadhurst P.; Jackson M.; Williams L.; Clark M.; Paddle J.; Bean S.; Buckley S.; Palfreeman C.; Liu S.; Allison N.; Attwood B.; Parsons P.; Houghton V.; Turner S.J.; Higgins D.; Bielskute E.; Horrigan N.; Jacob R.; Habgood K.; Zaki A.; Collins A.; Lord J.; Ramiro C.; Kubisz-Pudelko A.; Kotze M.; Williams H.; Iovenko I.; Tsarev A.; Zgrzheblovska L.; Briva A.; Mendez G.; Napolitano L.; Teig M.; Lee J.; Rodriguez G.E.; Ben-Jacob T.; Potestio C.; Eng T.; Mahanes D.; Khanna A.; Duggal A.;

Edoxaban versus warfarin in patients with atrial fibrillation

Contains fulltext : 125374.pdf (publisher's version ) (Open Access)BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.)