An introduction to Lipschitz geometry of complex singularities

The aim of this paper to introduce the reader to a recent point of view on the Lipschitz classifications of complex singularities. It presents the complete classification of Lipschitz geometry of complex plane curves singularities and in particular, it introduces the so-called bubble trick and bubble trick with jumps which are key tools to study Lipschitz geometry of germs. It describes also the thick-thin decomposition of a normal complex surface singularity and built two geometric decompositions of a normal surface germ into standard pieces which are invariant by respectively inner and outer bilipschitz homeomorphisms. This leads in particular to the complete classification of Lipschitz geometry for the inner metric.Comment: 50 pages, 36 figure

Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.

OBJECTIVE: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed. RESULTS: In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Production of light (anti)nuclei in pp collisions at root s=13 TeV

none1026siUnderstanding the production mechanism of light (anti)nuclei is one of the key challenges of nuclear physics and has important consequences for astrophysics, since it provides an input for indirect dark-matter searches in space. In this paper, the latest results about the production of light (anti)nuclei in pp collisions at root s = 13TeV are presented, focusing on the comparison with the predictions of coalescence and thermal models. For the first time, the coalescence parameters B-2 for deuterons and B-3 for helions are compared with parameter-free theoretical predictions that are directly constrained by the femtoscopic measurement of the source radius in the same event class. A fair description of the data with a Gaussian wave function is observed for both deuteron and helion, supporting the coalescence mechanism for the production of light (anti)nuclei in pp collisions. This method paves the way for future investigations of the internal structure of more complex nuclear clusters, including the hypertriton.noneAcharya, S.; Adamova, D.; Adler, A.; Adolfsson, J.; Rinella, G. Aglieri; Agnello, M.; Agrawal, N.; Ahammed, Z.; Ahmad, S.; Ahn, S. U.; Ahuja, I; Akbar, Z.; Akindinov, A.; Al-Turany, M.; Alam, S. N.; Aleksandrov, D.; Alessandro, B.; Alfanda, H. M.; Molina, R. Alfaro; Ali, B.; Ali, Y.; Alici, A.; Alizadehvandchali, N.; Alkin, A.; Alme, J.; Alt, T.; Altenkamper, L.; Altsybeev, I; Anaam, M. N.; Andrei, C.; Andreou, D.; Andronic, A.; Angeletti, M.; Anguelov, V; Antinori, F.; Antonioli, P.; Anuj, C.; Apadula, N.; Aphecetche, L.; Appelshaeuser, H.; Arcelli, S.; Arnaldi, R.; Arsene, I. C.; Arslandok, M.; Augustinus, A.; Averbeck, R.; Aziz, S.; Azmi, M. D.; Badala, A.; Baek, Y. W.; Bai, X.; Bailhache, R.; Bailung, Y.; Bala, R.; Balbino, A.; Baldisseri, A.; Balis, B.; Banerjee, D.; Barbera, R.; Barioglio, L.; Barlou, M.; Barnafoldi, G. G.; Barnby, L. S.; Barret, V; Bartels, C.; Barth, K.; Bartsch, E.; Baruffaldi, F.; Bastid, N.; Basu, S.; Batigne, G.; Batyunya, B.; Bauri, D.; Alba, J. L. Bazo; Bearden, I. G.; Beattie, C.; Belikov, I; Hechavarria, A. D. C. Bell; Bellini, F.; Bellwied, R.; Belokurova, S.; Belyaev, V; Bencedi, G.; Beole, S.; Bercuci, A.; Berdnikov, Y.; Berdnikova, A.; Bergmann, L.; Besoiu, M. G.; Betev, L.; Bhaduri, P. P.; Bhasin, A.; Bhat, I. R.; Bhat, M. A.; Bhattacharjee, B.; Bhattacharya, P.; Bianchi, L.; Bianchi, N.; Bielcik, J.; Bielcikova, J.; Biernat, J.; Bilandzic, A.; Biro, G.; Biswas, S.; Blair, J. T.; Blau, D.; Blidaru, M. B.; Blume, C.; Boca, G.; Bock, F.; Bogdanov, A.; Boi, S.; Bok, J.; Boldizsar, L.; Bolozdynya, A.; Bombara, M.; Bond, P. M.; Bonomi, G.; Borel, H.; Borissov, A.; Bossi, H.; Botta, E.; Bratrud, L.; Braun-Munzinger, P.; Bregant, M.; Broz, M.; Bruno, G. E.; Buckland, M. D.; Budnikov, D.; Buesching, H.; Bufalino, S.; Bugnon, O.; Buhler, P.; Buthelezi, Z.; Butt, J. B.; Bylinkin, A.; Bysiak, S. A.; Cai, M.; Caines, H.; Caliva, A.; Calvo Villar, E.; Camacho, J. M. M.; Camacho, R. S.; Camerini, P.; Canedo, F. D. M.; Carnesecchi, F.; Caron, R.; Castellanos, J. Castillo; Casula, E. A. R.; Catalano, F.; Sanchez, C. Ceballos; Chakraborty, P.; Chandra, S.; Chapeland, S.; Chartier, M.; Chattopadhyay, S.; Chauvin, A.; Chavez, T. G.; Cheng, T.; Cheshkov, C.; Cheynis, B.; Barroso, V. Chibante; Chinellato, D. D.; Cho, S.; Chochula, P.; Christakoglou, P.; Christensen, C. H.; Christiansen, P.; Chujo, T.; Cicalo, C.; Cifarelli, L.; Cindolo, F.; Ciupek, M. R.; Clai, G.; Cleymans, J.; Colamaria, F.; Colburn, J. S.; Colella, D.; Collu, A.; Colocci, M.; Concas, M.; Balbastre, G. Conesa; del Valle, Z. Conesa; Contin, G.; Contreras, J. G.; Coquet, M. L.; Cormier, T. M.; Cortese, P.; Cosentino, M. R.; Costa, F.; Costanza, S.; Crochet, P.; Cruz-Torres, R.; Cuautle, E.; Cui, P.; Cunqueiro, L.; Dainese, A.; Danisch, M. C.; Danu, A.; Das, I; Das, P.; Das, S.; Dash, S.; De, S.; De Caro, A.; de Cataldo, G.; De Cilladi, L.; de Cuveland, J.; De Falco, A.; De Gruttola, D.; De Marco, N.; De Martin, C.; De Pasquale, S.; Deb, S.; Degenhardt, H. F.; Deja, K. R.; Dello Stritto, L.; Deng, W.; Dhankher, P.; Di Bari, D.; Di Mauro, A.; Diaz, R. A.; Dietel, T.; Ding, Y.; Divia, R.; Dixit, D. U.; Djuvsland, O.; Dmitrieva, U.; Do, J.; Dobrin, A.; Doenigus, B.; Dordic, O.; Dubey, A. K.; Dubla, A.; Dudi, S.; Dukhishyam, M.; Dupieux, P.; Dzalaiova, N.; Eder, T. M.; Ehlers, R. J.; Eikeland, V. N.; Eisenhut, F.; Elia, D.; Erazmus, B.; Ercolessi, F.; Erhardt, F.; Erokhin, A.; Ersdal, M. R.; Espagnon, B.; Eulisse, G.; Evans, D.; Evdokimov, S.; Fabbietti, L.; Faggin, M.; Faivre, J.; Fan, F.; Fantoni, A.; Fasel, M.; Fecchio, P.; Feliciello, A.; Feofilov, G.; Fernandez Tellez, A.; Ferrero, A.; Ferretti, A.; Feuillard, V. J. G.; Figiel, J.; Filchagin, S.; Finogeev, D.; Fionda, F. M.; Fiorenza, G.; Flor, F.; Flores, A. N.; Foertsch, S.; Foka, P.; Fokin, S.; Fragiacomo, E.; Frajna, E.; Fuchs, U.; Funicello, N.; Furget, C.; Furs, A.; GaardhOje, J. J.; Gagliardi, M.; Gago, A. M.; Gal, A.; Galvan, C. D.; Ganoti, P.; Garabatos, C.; Garcia, J. R. A.; Garcia-Solis, E.; Garg, K.; Gargiulo, C.; Garibli, A.; Garner, K.; Gasik, P.; Gauger, E. F.; Gautam, A.; Ducati, M. B. Gay; Germain, M.; Ghosh, P.; Ghosh, S. K.; Giacalone, M.; Gianotti, P.; Giubellino, P.; Giubilato, P.; Glaenzer, A. M. C.; Glassel, P.; Goh, D. J. Q.; Gonzalez, V; Gonzalez-Trueba, L. H.; Gorbunov, S.; Gorgon, M.; Gorlich, L.; Gotovac, S.; Grabski, V; Graczykowski, L. K.; Greiner, L.; Grelli, A.; Grigoras, C.; Grigoriev, V; Grigoryan, S.; Grosa, F.; Grosse-Oetringhaus, J. F.; Grosso, R.; Guardiano, G. G.; Guernane, R.; Guilbaud, M.; Gulbrandsen, K.; Gunji, T.; Guo, W.; Gupta, A.; Gupta, R.; Guzman, S. P.; Gyulai, L.; Habib, M. K.; Hadjidakis, C.; Halimoglu, G.; Hamagaki, H.; Hamid, M.; Hannigan, R.; Haque, M. R.; Harlenderova, A.; Harris, J. W.; Harton, A.; Hasenbichler, J. A.; Hassan, H.; Hatzifotiadou, D.; Hauer, P.; Havener, L. B.; Heckel, S. T.; Hellbaer, E.; Helstrup, H.; Herman, T.; Hernandez, E. G.; Herrera Corral, G.; Herrmann, F.; Hetland, K. F.; Hillemanns, H.; Hills, C.; Hippolyte, B.; Hofman, B.; Hohlweger, B.; Honermann, J.; Hong, G. H.; Horak, D.; Hornung, S.; Horzyk, A.; Hosokawa, R.; Hou, Y.; Hristov, P.; Hughes, C.; Huhn, P.; Huhta, L. M.; Humanic, T. J.; Hushnud, H.; Husova, L. A.; Hutson, A.; Hutter, D.; Iddon, J. P.; Ilkaev, R.; Ilyas, H.; Inaba, M.; Innocenti, G. M.; Ippolitov, M.; Isakov, A.; Islam, M. S.; Ivanov, M.; Ivanov, V; Izucheev, V; Jablonski, M.; Jacak, B.; Jacazio, N.; Jacobs, P. M.; Jadlovska, S.; Jadlovsky, J.; Jaelani, S.; Jahnke, C.; Jakubowska, M. J.; Jalotra, A.; Janik, M. A.; Janson, T.; Jercic, M.; Jevons, O.; Jimenez, A. A. P.; Jonas, F.; Jones, P. G.; Jowett, J. M.; Jung, J.; Jung, M.; Junique, A.; Jusko, A.; Kaewjai, J.; Kalinak, P.; Kalteyer, A. S.; Kalweit, A.; Kaplin, V; Uysal, A. Karasu; Karatovic, D.; Karavichev, O.; Karavicheva, T.; Karczmarczyk, P.; Karpechev, E.; Kazantsev, A.; Kebschull, U.; Keidel, R.; Keijdener, D. L. D.; Keil, M.; Ketzer, B.; Khabanova, Z.; Khan, A. M.; Khan, S.; Khanzadeev, A.; Kharlov, Y.; Khatun, A.; Khuntia, A.; Kileng, B.; Kim, B.; Kim, C.; Kim, D. J.; Kim, E. J.; Kim, J.; Kim, J. S.; Kim, M.; Kim, S.; Kim, T.; Kirsch, S.; Kisel, I; Kiselev, S.; Kisiel, A.; Kitowski, J. P.; Klay, J. L.; Klein, J.; Klein, S.; Klein-Boesing, C.; Kleiner, M.; Klemenz, T.; Kluge, A.; Knospe, A. G.; Kobdaj, C.; Koehler, M. K.; Kollegger, T.; Kondratyev, A.; Kondratyeva, N.; Kondratyuk, E.; Konig, J.; Konigstorfer, S. A.; Konopka, P. J.; Kornakov, G.; Koryciak, S. D.; Kotliarov, A.; Kovalenko, O.; Kovalenko, V; Kowalski, M.; Kralik, I; Kravcakova, A.; Kreis, L.; Krivda, M.; Krizek, F.; Gajdosova, K. Krizkova; Kroesen, M.; Krueger, M.; Kryshen, E.; Krzewicki, M.; Kucera, V; Kuhn, C.; Kuijer, P. G.; Kumaoka, T.; Kumar, D.; Kumar, L.; Kumar, N.; Kundu, S.; Kurashvili, P.; Kurepin, A.; Kurepin, A. B.; Kuryakin, A.; Kushpil, S.; Kvapil, J.; Kweon, M. J.; Kwon, J. Y.; Kwon, Y.; La Pointe, S. L.; La Rocca, P.; Lai, Y. S.; Lakrathok, A.; Lamanna, M.; Langoy, R.; Lapidus, K.; Larionov, P.; Laudi, E.; Lautner, L.; Lavicka, R.; Lazareva, T.; Lea, R.; Lehrbach, J.; Lemmon, R. C.; Leon Monzon, I; Lesser, E. D.; Lettrich, M.; Levai, P.; Li, X.; Li, X. L.; Lien, J.; Lietava, R.; Lim, B.; Lim, S. H.; Lindenstruth, V; Lindner, A.; Lippmann, C.; Liu, A.; Liu, D. H.; Liu, J.; Lofnes, I. M.; Loginov, V; Loizides, C.; Loncar, P.; Lopez, J. A.; Lopez, X.; Torres, E. Lopez; Luhder, J. R.; Lunardon, M.; Luparello, G.; Ma, Y. G.; Maevskaya, A.; Mager, M.; Mahmoud, T.; Maire, A.; Malaev, M.; Malik, N. M.; Malik, Q. W.; Malik, S. K.; Malinina, L.; Mal'Kevich, D.; Mallick, N.; Malzacher, P.; Mandaglio, G.; Manko, V; Manso, F.; Manzari, V; Mao, Y.; Mares, J.; Margagliotti, G., V; Margotti, A.; Marin, A.; Markert, C.; Marquard, M.; Martin, N. A.; Martinengo, P.; Martinez, J. L.; Martinez, M., I; Garcia, G. Martinez; Masciocchi, S.; Masera, M.; Masoni, A.; Massacrier, L.; Mastroserio, A.; Mathis, A. M.; Matonoha, O.; Matuoka, P. F. T.; Matyja, A.; Mayer, C.; Mazuecos, A. L.; Mazzaschi, F.; Mazzilli, M.; Mazzoni, M. A., I; Mdhluli, J. E.; Mechler, A. F.; Meddi, F.; Melikyan, Y.; Menchaca-Rocha, A.; Meninno, E.; Menon, A. S.; Meres, M.; Mhlanga, S.; Miake, Y.; Micheletti, L.; Migliorin, L. C.; Mihaylov, D. L.; Mikhaylov, K.; Mishra, A. N.; Modak, A.; Mohanty, A. P.; Mohanty, B.; Khan, M. Mohisin; Molander, M. A.; Moravcova, Z.; Mordasini, C.; De Godoy, D. A. Moreira; Morozov, I; Morsch, A.; Mrnjavac, T.; Muccifora, V; Mudnic, E.; Mughal, B. J.; Muehlheim, D.; Muhuri, S.; Mulligan, J. D.; Mulliri, A.; Munhoz, M. G.; Munzer, R. H.; Murakami, H.; Murray, S.; Musa, L.; Musinsky, J.; Myrcha, J. W.; Naik, B.; Nair, R.; Nandi, B. K.; Nania, R.; Nappi, E.; Nassirpour, A. F.; Nath, A.; Nattrass, C.; Neagu, A.; Nellen, L.; Nesbo, S., V; Neskovic, G.; Nesterov, D.; Nielsen, B. S.; Nikolaev, S.; Nikulin, S.; Nikulin, V; Noferini, F.; Noh, S.; Nomokonov, P.; Norman, J.; Novitzky, N.; Nowakowski, P.; Nyanin, A.; Nystrand, J.; Ogino, M.; Ohlson, A.; Okorokov, V. A.; Oleniacz, J.; Da Silva, A. C. Oliveira; Oliver, M. H.; Onnerstad, A.; Oppedisano, C.; Velasquez, A. Ortiz; Osako, T.; Oskarsson, A.; Otwinowski, J.; Oya, M.; Oyama, K.; Pachmayer, Y.; Padhan, S.; Pagano, D.; Palasciano, A.; Pan, J.; Panebianco, S.; Pareek, P.; Park, J.; Parkkila, J. E.; Pathak, S. P.; Patra, R. N.; Paul, B.; Pei, H.; Peitzmann, T.; Peng, X.; Pereira, L. G.; Da Costa, H. Pereira; Peresunko, D.; Perez, G. M.; Perrin, S.; Pestov, Y.; Petracek, V; Petrovici, M.; Pezzi, R. P.; Piano, S.; Pikna, M.; Pillot, P.; Pinazza, O.; Pinsky, L.; Pinto, C.; Pisano, S.; Ploskon, M.; Planinic, M.; Pliquett, F.; Poghosyan, M. G.; Polichtchouk, B.; Politano, S.; Poljak, N.; Pop, A.; Porteboeuf-Houssais, S.; Porter, J.; Pozdniakov, V; Prasad, S. K.; Preghenella, R.; Prino, F.; Pruneau, C. A.; Pshenichnov, I; Puccio, M.; Qiu, S.; Quaglia, L.; Quishpe, R. E.; Ragoni, S.; Rakotozafindrabe, A.; Ramello, L.; Rami, F.; Ramirez, S. A. R.; Ramos, A. G. T.; Rancien, T. A.; Raniwala, R.; Raniwala, S.; Rasanen, S. S.; Rath, R.; Ravasenga, I; Read, K. F.; Redelbach, A. R.; Redlich, K.; Rehman, A.; Reichelt, P.; Reidt, F.; Reme-ness, H. A.; Renfordt, R.; Rescakova, Z.; Reygers, K.; Riabov, A.; Riabov, V; Richert, T.; Richter, M.; Riegler, W.; Riggi, F.; Ristea, C.; Rodriguez Cahuantzi, M.; Roed, K.; Rogalev, R.; Rogochaya, E.; Rogoschinski, T. S.; Rohr, D.; Rohrich, D.; Rojas, P. F.; Rokita, P. S.; Ronchetti, F.; Rosano, A.; Rosas, E. D.; Rossi, A.; Rotondi, A.; Roy, A.; Roy, P.; Roy, S.; Rubini, N.; Rueda, O., V; Ruggiano, D.; Rui, R.; Rumyantsev, B.; Russek, P. G.; Russo, R.; Rustamov, A.; Ryabinkin, E.; Ryabov, Y.; Rybicki, A.; Rytkonen, H.; Rzesa, W.; Saarimaki, O. A. M.; Sadek, R.; Sadovsky, S.; Saetre, J.; Safarik, K.; Saha, S. K.; Saha, S.; Sahoo, B.; Sahoo, P.; Sahoo, R.; Sahoo, S.; Sahu, D.; Sahu, P. K.; Saini, J.; Sakai, S.; Salvan, M. P.; Sambyal, S.; Samsonov, V; Sarkar, D.; Sarkar, N.; Sarma, P.; Sarti, V. M.; Sas, M. H. P.; Schambach, J.; Scheid, H. S.; Schiaua, C.; Schicker, R.; Schmah, A.; Schmidt, C.; Schmidt, H. R.; Schmidt, M. O.; Schmidt, M.; Schmidt, N., V; Schmier, A. R.; Schotter, R.; Schukraft, J.; Schwarz, K.; Schweda, K.; Scioli, G.; Scomparin, E.; Seger, J. E.; Sekiguchi, Y.; Sekihata, D.; Selyuzhenkov, I; Senyukov, S.; Seo, J. J.; Serebryakov, D.; Serksnyte, L.; Sevcenco, A.; Shaba, T. J.; Shabanov, A.; Shabetai, A.; Shahoyan, R.; Shaikh, W.; Shangaraev, A.; Sharma, A.; Sharma, H.; Sharma, M.; Sharma, N.; Sharma, S.; Sharma, U.; Sheibani, O.; Shigaki, K.; Shimomura, M.; Shirinkin, S.; Shou, Q.; Sibiriak, Y.; Siddhanta, S.; Siemiarczuk, T.; Silva, T. F.; Silvermyr, D.; Simantathammakul, T.; Simonetti, G.; Singh, B.; Singh, R.; Singh, V. K.; Singhal, V; Sinha, T.; Sitar, B.; Sitta, M.; Skaali, T. B.; Skorodumovs, G.; Slupecki, M.; Smirnov, N.; Snellings, R. J. M.; Soncco, C.; Song, J.; Songmoolnak, A.; Soramel, F.; Sorensen, S.; Sputowska, I; Stachel, J.; Stan, I; Steffanic, P. J.; Stiefelmaier, S. F.; Stocco, D.; Storehaug, I; Storetvedt, M. M.; Stratmann, P.; Stylianidis, C. P.; Suaide, A. A. P.; Sugitate, T.; Suire, C.; Sukhanov, M.; Suljic, M.; Sultanov, R.; Sumberia, V; Sumowidagdo, S.; Swain, S.; Szabo, A.; Szarka, I; Tabassam, U.; Taghavi, S. F.; Taillepied, G.; Takahashi, J.; Tambave, G. J.; Tang, S.; Tang, Z.; Takaki, J. D. Tapia; Tarhini, M.; Tarzila, M. G.; Tauro, A.; Tejeda Munoz, G.; Telesca, A.; Terlizzi, L.; Terrevoli, C.; Tersimonov, G.; Thakur, S.; Thomas, D.; Tieulent, R.; Tikhonov, A.; Timmins, A. R.; Tkacik, M.; Toia, A.; Topilskaya, N.; Toppi, M.; Torales-Acosta, F.; Tork, T.; Torres, S. R.; Trifiro, A.; Tripathy, S.; Tripathy, T.; Trogolo, S.; Trubnikov, V; Trzaska, W. H.; Trzcinski, T. P.; Trzeciak, B. A.; Tumkin, A.; Turrisi, R.; Tveter, T. S.; Ullaland, K.; Uras, A.; Urioni, M.; Usai, G. L.; Vala, M.; Valle, N.; Vallero, S.; van der Kolk, N.; van Doremalen, L. V. R.; van Leeuwen, M.; Vande Vyvre, P.; Varga, D.; Varga, Z.; Varga-Kofarago, M.; Vasileiou, M.; Vasiliev, A.; Doce, O. Vazquez; Vechernin, V.; Vercellin, E.; Vergara Limon, S.; Vermunt, L.; Vertesi, R.; Verweij, M.; Vickovic, L.; Vilakazi, Z.; Baillie, O. Villalobos; Vino, G.; Vinogradov, A.; Virgili, T.; Vislavicius, V.; Vodopyanov, A.; Volkel, B.; Volkl, M. A.; Voloshin, K.; Voloshin, S. 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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.)