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Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients

Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients. Alexander T Cohen On behalf of the MAGELLAN Steering Committee and Investigators. Potential conflicts.

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Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients

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  1. Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients Alexander T Cohen On behalf of the MAGELLAN Steering Committee and Investigators

  2. Potential conflicts • Dr AT Cohen is a medical consultant for and has received honoraria, consultancy and clinical trial funding from many pharmaceutical companies, including: • Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, GSK, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Sanofi-Aventis, Schering Plough and Takeda • Dr Cohen is an advisor to the UK Government Health Select Committee, the All-party Working Group on Thrombosis, Department of Health, and the NHS on the prevention of venous thromboembolism • Dr Cohen is also an advisor to Lifeblood: The Thrombosis Charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism Presentation includes discussion of the following off-label use of a drug or medical device: No Rivaroxaban is not currently approved for use in the United States

  3. Attributable risk for deep vein thrombosis/pulmonary embolism Medicalpatients Heit et al, 2002 3

  4. Contemporary studies of hospitalized patients MEDENOX, all venous thromboembolism (VTE) Day 1 to Day 14; PREVENT, asymptomatic proximal deep vein thrombosis (DVT), symptomatic VTE and sudden death Day 1 to Day 21; ARTEMIS, all VTE Day 1 to Day 15; EXCLAIM, proximal DVT, symptomatic PE or fatal PE Day 10 to Day 38TE, treatment-emergent 1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010 4

  5. Background and study questions Background • The optimal duration of thromboprophylaxis (short or extended) and the acutely ill patient population most likely to benefit from extended thromboprophylaxis is not well characterized Study question • Is 10 days of anticoagulation with rivaroxaban non-inferior to enoxaparin? • Is 35 days of anticoagulation with rivaroxaban superior to enoxaparin followed by placebo? Cohen et al, 2011 5

  6. MAGELLAN: clinical trial design Day 90(83–97) Day 10(6–14) Day 35(31–39) 8,101 patients randomized Oral rivaroxaban 10 mg od 35±4 days Patients ≥40 years hospitalized for acute medical illness with decreased level of mobility s.c. placebo 10±4 days Follow-up periodto Day 90 R Oral placebo 35±4 days s.c. enoxaparin40 mg od 10±4 days Ultrasonography on day 10±4 Ultrasonography on day 35±4 Primary efficacy outcome Day 10 (non-inferiority) Primary efficacy outcome Day 35* (superiority) *Events from Day 1 to Day 35 Cohen et al, 2011 6

  7. MAGELLAN: study outcomes Primary efficacy outcome • Composite of: • Asymptomatic proximal DVT detected by mandatory ultrasonography • Symptomatic DVT (proximal or distal) • Symptomatic non-fatal pulmonary embolism (PE) • VTE-related death • At Day 10 (test for non-inferiority) • At Day 35 (test for superiority) Main safety outcome • Composite of major bleeding and non-major clinically relevant bleeding observed not later than 2 days after the last intake of double-blind study medication (treatment emergent) Cohen et al, 2011 7

  8. Sample size and assumptions • Sample size: 2,876 valid patients per group was estimated to obtain a joint power of at least 90% Non-inferiority: Day 10 • Assumptions: 2.2% event rate in control group; 1.4% event rate in the rivaroxaban group; relative risk reduction (RRR) ≥35% • Non-inferiority margin: 1.5 Superiority: Day 35 • Assumptions: 4.0% event rate in the control group; 2.4% event rate in the rivaroxaban group; RRR ≥40% Cohen et al, 2011

  9. Patient flow: Day 10 and Day 35 endpoints Enoxaparin/placebo Rivaroxaban Randomized (n=8,101) 4,050 4,051 Safety 3,997 (99%) 4,001 (99%) Modified intent to treat (mITT) Day 10 3,232 (80%) 3,271 (81%) Day 35 2,967 (73%) 3,057 (75%) Per-protocol (PP) Day 10 2,993 (74%) 2,938 (73%) Day 35 2,516 (62%) 2,586 (64%)

  10. Patient characteristics* *Safety population; †some data missing

  11. Underlying medical conditions* *Safety population

  12. 0.968 1.334 0.713 Superior Non-inferior Inferior Primary efficacy outcome: Day 10* p=0.0025 for non-inferiority (one-sided) 0 1.50 1.00 Relative risk ratio *PP population, events up to Day 10+5 days; ‡includes cases where PE cannot be ruled out

  13. Superior Non-inferior Inferior Primary efficacy outcome: Day 35* 0.962 0.618 0.771 Absolute risk reduction:1.3% Relative risk reduction: 22.9% p=0.0211 for superiority (two-sided) 0 1.00 Relative risk ratio *mITT population, events up to Day 35+6 days; ‡4 confirmed fatal PEs but includes cases where PE cannot be ruled out

  14. Safety outcomes *Major plus non-major clinically relevant bleedingSafety population; treatment-emergent bleeding

  15. Components of major bleeding *Patients could have more than 1 event

  16. Other outcomes: Day 35 *The composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic non-fatal PE, VTE-related death, treatment-emergent major plus non-major clinically relevant bleeding in the mITT population‡Day 90+7 data

  17. Contemporary studies of hospitalized patients MEDENOX, all VTE Day 1 to Day 14; EXCLAIM, proximal DVT, symptomatic PE or fatal PE Day 10 to Day 38; MAGELLAN, asymptomatic proximal DVT, symptomatic VTE and VTE-related death Day 1 to Day 35TE, treatment-emergent 1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010 17

  18. Summary • MAGELLAN met its primary efficacy endpoints • Day 10: rivaroxaban was non-inferior to enoxaparin in reducing the risk of VTE • Day 35: extended thromboprophylaxis was superior to enoxaparin followed by placebo in reducing the risk of VTE • Overall bleeding rates were low, but significantly higher in the rivaroxaban arm across the entire study period • Rates of other adverse events, including liver and cardiovascular events, were similar in both arms 18

  19. Conclusion MAGELLAN confirms that there is a continued risk of VTE beyond the initial period of hospitalization or immobilization in acutely ill patients Based on the pre-specified net clinical benefit analysis, a consistently positive benefit-risk balance was not seen across the heterogeneous, acutely ill patient population studied, and further analysis is required to identify which groups of patients in MAGELLAN may derive benefit from thromboprophylaxis with rivaroxaban 19

  20. Acknowledgements Steering Committee: Alexander Cohen MBBS (Chairman); Harry Büller MD PhD; Alexander Mebazaa MD PhD; Sebastian Schellong MD; Geno Merli MD; Victor Tapson MD; Russell Hull MBBS; Dayi Hu MD PhD; Lloyd Haskell MD; Theodore Spiro MD Data Safety and Monitoring Board: Alain Leizorovicz MD (Chairman); Gordon Lowe MD; Charles Francis MD; Robin Roberts MT; Shotai Kobayashi MD PhD Bayer:Global Clinical Leader, Theodore Spiro MD; Medical Experts:  Eva Mühlhofer MD & Melanie Hemmrich MD; Statistician: Dr. Horst Beckmann; Study Managers: Andrea Duszczyszyn, Lynda Fielding, Teresa Twomey; Study Data Manager: Karin Müller; Johnson & Johnson: Physician: Lloyd Haskell MD Countries and individual sites: Argentina (7 sites); Australia (11 sites); Austria (14 sites); Belgium (10 sites); Brazil (8 sites); Bulgaria (8 sites); Canada (13 sites); Chile (2 sites); China (43 sites); Colombia (8 sites); Croatia (6 sites); Czech Republic (7 sites); Denmark (5 sites); Estonia (4 sites); Finland (2 sites); France (22 sites); Germany (27 sites); Greece (10 sites); Hong Kong (2 sites); Hungary (8 sites); India (14 sites); Indonesia (3 sites); Israel (10 sites); Italy (21 sites); Japan (32 sites); Korea (7 sites); Latvia (6 sites); Lithuania (10 sites); Luxembourg (2 sites); Malaysia (3 sites); Mexico (12 sites); The Netherlands (4 sites); New Zealand (3 sites); Norway (4 sites); Pakistan (3 sites); Peru (7 sites); Poland (14 sites); Portugal (10 sites); Russia (8 sites); Singapore (6 sites); Slovakia (5 sites); Slovenia (6 sites); South Africa (14 sites); Spain (11 sites); Sweden (9 sites); Switzerland (6 sites); Taiwan (5 sites); Thailand (3 sites); Turkey (6 sites); Ukraine (16 sites); UK (7 sites); US (72 sites)

  21. Acknowledgements INVESTIGATORS:DR. F BOTTARO, DR. H HENDLER, DR. B GRAND, DR. A MYKIETIUK, DR. M HOJMAN, DR. O CABERLOTTO, DR. R SALERNO, PROF. E PILGER, DR. N BAUER, PROF. P SIOSTRZONEK, PROF. R KIRCHMA, DR. W FORTUNAT, DR. C WENISCH, PROF. DR. A WELTERM, DR. L ERLACHEROA, DR. H-R SCHONR, DR. B BAUER, DR. E GRAFL, PROF. F KEIL, PROF. P BALCKE, PROF. F WEIDINGE, PROF. H SALEM, DR. M LEYDEN, PROF B CHONG, PROF B CHONG, DR. P CARROLL, DR. D COLQUHOUN, DR D JACKSONA, PROF. E GANA, PROF. S HALL, DR D SERISIERA, PROF R BAKER, PROF. D BLOCKMANS, DR. K HENDRICKX, DR. H STRIEKWOLD, DR. G VAN ROEY, DR. M-E VANDEN ABEELE, DR. C JACQUY, DR. A DELOBBE, PROF. A SOUPART, DR. L VAN ZANDWEGHE, DR. A VAN HOOF, PROF. V MINCHEVA, PROF. S MILANOV, DR. L LYUBENOV, DR. S NENKOVA, DR. D DIMOV, DR. M TASEVA, PROF. Y IVANOV, PROF. D POPOV, DR. B GARICOCHEA, DR. C CAVALHEIRO, DR D CHAMONE, DR. J BIZZACCHI, DR. E FISS, DR. A LOPES, DR. B VAN BELLEN, DR. R RDO MOREIRA, DR. A SHUAIB, DR. F DUBE, DR. D KUTSOGIANNIS, DR. S VERREAULT, DR. B BUCK, DR. A ROUSSIN, DR. G MODDEL, DR. G STOTTS, DR. H DESAI, DR. J-M BOULANGER, DR. F SILVER, DR. N DANEAULT, DR. C BERGERON, DR. M BANYAI, PROF. I BAUMGARTNER, PROF. A SCHIFFER, DR. A IMHOF, DR. C JEAN, DR. P NUSSBAUME, DR. G BUGEDO, DR. H TORRES, PROF. D HU, PROF C WANG, PROF. Y WANG, DR. Y YANG, PROF. Y CHEN, DR C SHEN, PROF. J LIU, PROF. S WU, PROF. W  LI, PROF Z ZHAO, DR. Q XIU, PROF. S-Y ZHANG, DR. T HU, PROF. X  YAN, DR. L GAI, DR. Y ZHAO, PROF. Q HUA, PROF. H LI, PROF. J LI, PROF. DP ZHANG, DR. B XU, PROF. Q WAN, PROF. R CHEN, PROF. S XIAN, DR. Y LIU, PROF. Q GAO, DR. C LIU, DR. G QI, PROF. P CHEN, PROF. S SUN, PROF. K YANG, DR. C WU, PROF. H WANG, PROF. L YANG, PROF. X QIN, DR. S GUO, PROF. Y SUN, DR. Y WANG, DR. Y-S LI, PROF. Y ZHOU, DR. K-N CHEN, DR. J WU, DR. J ZHANG, DR. D FAJARDO, DR. R BOTERO, DR. R RADA, DR. L GOMEZ, DR. L URIBE, DR. J CEDANO, DR. J VELASQUEZ, DR. C JARAMILLO, PROF. A LINHART, DR. O MAYER, DR. K GORICAN, DR. V PROCHAZKA, DR. J FIKSA, DR. I MACEL, DR. J SEDLACEK, PROF. W PETERMA, PROF. B MUHLBAUER, DR. J BARTH, DR. H LAWALL, PROF. C POHL, PROF. T KLOTZ, PROF. J-D. RINGE, PROF. J SCHMIDT LUCK, DR. T HEINTGES, DR. I SCHOFFAUER, DR. A DORMANN, DR. W THEELEN, DR. F-M. DROUVEN, PROF. C NIEDERAU, PROF. B SANNER, DR. H-R MILSTREY, DR. M BORST, PROF. J VOM DAHL, DR. H HINDAHL, DR. E STØLBEN, PROF. S SCHELL, DR. J BEYER-WESTENDORF, DR. R VELTKAMP, PROF. S MOBIUS-WINK, PROF. C ESPINO, PROF. M LESCHKE, PROF. I SCHARRER, DR. H NIELSEN, DR. S AVNSTRØM, DR. C TUXEN, DR. T NIELSEN, DR. O ØSTERGAARD, DR. T UUETOA, DR. T MARANDI, DR. M LEMBER, DR. O KOLBASSOVA, DR. M MONREAL, DR. A CASTRO, DR. C TOLOSA, DR. F CONGET, DR. J­A NIETO RODRIGU, DR. R TIRADO MIRANDA, DR. A MARIA GUIL, DR. J BISBE, DR. F CERETO CASTRO, DR. J TRUJILLO SANTOS, DR. J VILLALTA, DR. R LASSILA, DR. J KARMAKOSKI, PROF. P MISMETTI, PROF. D MOTTIER, PROF. J SCHMIDT, PROF. I QUERE, PROF. C LE JEUNNE, PROF. D VITAL-DURAND, PROF. I MAHE, DR. R RIHANI, PROF. J-F BERGM, PROF. P DEBOURDEAU, DR. M LAMBERT, PROF. D STEPHAN, PROF. B LORCERIE, PROF. P LACROIX, DR. A PROUST, PROF. D FARGE-BAN, PROF. C-H MARQUETTE, DR. D BRISOT, DR. C FOURNIER, DR. A DUCHEMIN, DR. S AQUILANTI, PROF. M GALINIER, DR. M SCULLY, DR. A COHEN, DR. P KESTEVEN, DR. M ELLIOTT, DR J LUCKIT, DR. P RAFFERTY, DR. R DURAIRAJ, PROF. H BASSARIS, PROF. A SKOUTELIS, DR. F VLASTOS, DR. M TOUBIS, DR. G PANOUTSOPOUL, DR. S APSOKARDOS, DR. D BABALIS, DR. A KARAFOULID, DR. A KATSIVAS, DR. S PATSILINAKOS, PROF. LKS WONG, DR. RSM WONG, PROF. M BERGOVEC, PROF. M SAMARZIJA, DR. S ZUPANCIC-SALEK DR. S HAJNSEK, DR. A KNEZEVIC, DR. R STEINER, DR. J NIKL, DR. I KONDAKOR, DR. G NYIRATI, DR. G JAKAB, DR. Z SZAKACS, DR. F NAGY, DR. N SZEGEDI, DR. Z FRANKFURTER, DR. K TAMBUNAN, PROF. HARMANI KALIM, DR. M MACHFØD, DR. D ZELTSER, PROF. S OREN DR. M LISHNER, PROF. R ZIMLICHMAN, DR. Z STHØGER, DR. H OSAMAH, DR. M ELIAS, PROF T HAYEK, DR. G TELMAN, DR. N ELIAS, DR. S BHAIRAPPA, DR. A CHEVIRI, DR. M GADKARI, DR. K PRADEEP KUMAR, DR. A NAIK, DR. A OOMMAN, DR. K KUCHIMANCHI, DR. A MAHAJAN, DR. D TALWAR, DR. P GRANT, DR. J WHIG, DR. G AVVARU, DR. RM PL RAMANATHAN, DR. C RAGHU, PROF. G AGNELLI, DR. W AGENO, DR. M GIORGI PIERFRANCESC, DR. C LODIGIANI, DR. M SILINGARDI, DR. R POGGIO, PROF. S SIRAGUSA, DR. E MORRA, DR. A DE BLASIO, DR. G CASTAMAN, DR. R BUZZONI, DR. A FONTANELLA, DR. A FALANGA, DR. R LANDOLFI, PROF. M PINI, DR. E DE GAUDENZI, PROF. P PARISE, DR. M BONDI, DR. M BERRETTINI, PROF. F VIOLI, DR. R QUINTAVALLA, DR. S NISHI, DR. K UTSUGISAWA, DR. T UCHIYAMA, DR. Y MOMIYAMA, DR. K FUKUI, DR. E TANAKA, DR. M NAGAOKA, DR. T OZAWA, DR. S SAKAGAMI, DR. T TSUJI, DR. N YAMADA, DR. O HATAJI, DR. A WADA, DR. T ICHINOSE, DR. J FUNADA, DR. Y NAKAMURA, DR. S ANDO, DR. K FUJIMOTO, DR. S MEKARU, DR. K OSHIRO, DR. Y SHIOHIRA, DR. O OKAZAKI, DR. A SHIMIZU, DR. M KATO, DR. H IBATA, DR. S IMAI, DR. H IKEFUJI, DR. T SAITO, DR. K ITO, DR. T MIO, DR. H KANI, DR. H NAKAGAWA, DR. D-W KANG, DR. C-S CHUNG, DR. B-W YOON, DR. Y-S LEE, DR. D YEUNOH, DR. S­M BANG, DR. Y-K KIM, DR. B ALEKNIENE, DR. Z BUTKIENE, DR. R PETRAUSKIENE, PROF. A BAGDONAS, DR. G GUMBREVICIUS, DR. A VITKAUSKAS, DR. V BASIJOKIENE, DR. S STONKUS, DR. V GRISKEVICIENE, DR. R NORVILIENE, DR. P MULLER, DR. S RAUH, DR. U KUPCS, DR. V ROZITIS, DR. I STUKENA, DR. D KRIEVINS, DR. N PONTAGA,DR. I AIZSILNIECE, DR. R PEREA SANCHEZ, DR. J GONZALEZ GARZA, DR. M GOMEZ LARA, DR. J CARDOZA AMADOR, DR. A TANAKA CHAVEZ, DR. V VELASCO RODRIGU, DR. F NARES OCHOA, DR. M VAZQUEZ LOPEZ, DR. C ROMERO LOPE, DR. J GALLEGOS MARTINEZ, DR. D HERNANDEZ GAETA, DR. M HERVER CABRERA, DR. S PIAW CHIN, DR K HAN SIM, DR. B WAN AHMAD WAN AZMAN, DR. R FIJNHEERD, DR. H CATE, DR. A DEES. DR. AM KREUK, DR. R TORP, DR. I STOKSTAD, DR. F SCHJESVOLD, DR. W GHANIMA, DR. S JACKSON, DR. D SIMPSON, DR. P OCKELFORD, DR. R COTRINA, DR. M SALAS PEREZ, DR. V ULLOA PEREZ, DR. Z MONCADA VILELA, DR. F ARRIETA DIAS, DR. O SALAZAR CANDIO, DR. R CASTILLO LEON, DR. Z AZIZ, DR. G UN NABI TAYYAB, DR. N RIZVI, PROF. A SZCZEKLIK, PROF. L WALASEK, DR. M  BOJARSKA­LOS, PROF. T PASIERSKI, DR M GUTOWSKA-JABLONS, DR. W KRYSIAK, DR. T ZECHOWICZ, PROF. K JAHNZ-ROZYK, DR. E MIREK-BRYNIARSKA, PROF. M GORSKA, DR. M BIEDRZYCKA, DR. A GOCH, DR M OGOREK, DR. A SYDOR, DR. K WRZESINSKI, DR. F FERREIRA, PROF. L PROVIDENCIA, DR. A MARTINS, DR. F GOMES, PROF. F SANTOS, PROF. P BETTENCOURT, PROF. J DUCLA SOARES, DR. A MELLO E SILVA, DR. T RODRIGUES, DR. A FERREIRA, DR. S KHATKOVA, DR A SOTNIKOV, PROF. T FEDOROVA, PROF. G AROUTYNOV, PROF. M GLEZER, PROF. VN MOISEEV, DR. N SHILKINA, DR. O ERSHOVA, DR. P SVENSSON, DR. I TORSTENSSON, DR. A SJAELANDER, DR. J OSTERGREN, DR. I TIMBERG, DR A-C LASKA, DR. PG WIKLUND, DR. E BERTHOLDS, DR. M CWIKIEL, DR. T HOW ONG, DR. R TAN, DR. A NG, DR. G CHUA, DR H WOOI GAN, PROF. O TENG TANG, DR. M JEREB, DR. B ZVAN, DR. M FLEZAR, DR. G TRATAR, DR. ML SOK, DR. V GORJUP, DR. L GASPAR, DR. J STEVLIK, DR. V SPISAK, DR. F KOVAR, DR. M SZENTIVANYI, PROF. C PERMPIKUL, DR. A WATTANATHUM, DR. C POTHIRAT, PROF.  S KUCUKOGLU, PROF. B ILERIGELEN, PROF. E GOKER, PROF. H SIRIN, PROF. U YILMAZ, PROF. S NALBANTGIL, DR. Y-H LIN, DR. B-F GUO, DR. C-L HAN, DR. K-G SHYU, DR. K YIN-CHING CHUANG, DR. V SKREBKOV, PROF. V SORKIN, PROF. Y SVYSHCHENKO, PROF. O KORZH, PROF. S GENYK, PROF. L VORONKOV, DR. V TSELUYKO, DR. O KARPENKO, PROF. I VAKALIUK, DR. M PEREPELIUK, PROF. O LEGKONOGOV, DR. V KOVAL, DR. A POLYAKOV, DR. Y GONCHAROVA, DR. T RYABICHENKO, PROF.  M VATUTIN, DR. A HEYDER, DR. R MURRAY, DR. P RASTOGI, DR. M PLAUTZ, DR. R YUSEN, DR. R LAVENDER, DR. G MERLI, DR. A JAFFER, DR. P MEHRA, DR. G JOHNSON, DR. P MANOS, DR. S KAATZ, DR. V NADAR, DR. T WUN, DR. J MASSON, DR. R LERNER, DR. A SEIBERT, DR. R MCLAFFERTY, DR. J WELKER, DR. P WRIGHT JR., DR. K RAJAMANI, DR. D SCHULLER, DR. A SHARMA, DR. J SIMMONS, DR. F WHITTIER, DR. J WARD, DR. N DABOUL, DR. S CHASTAIN, DR. J DEXTER, DR. J UPDEGROVE, DR. W REITER, DR. S STOLTZ, DR. S CONRAD, DR. M HAZELRIGG, DR. T LING, DR. D CHEN, DR. K MAYNOR, DR. W FRENCH, DR. D DIETRICH, DR. C LAWTON, DR. J BRENSILVER, DR. B HELLER, DR. C ALBRECHT III, DR. C COWLEY, DR. S MAHAL, DR. S ANDERSON, DR. W TØ, DR. P POKHAREL, DR. M FONTES, DR. H MINKOWITZ, DR. M CONCHA, DR. R STEIN, DR. M PEBERDY, DR. T BIRCH, DR. R LIGHT, DR. G SOFF, DR. M COX, DR. A NATHANSON, DR. R FEI, DR. J REYES, DR. M KAZIMIR, DR. D WILLIAMS, DR. T ZIEDALSKI, DR. G HILL JR, DR. J SUEN, DR. C GREENBERG, DR. P MEHTA, DR. K WAXMAN, DR. W PATTON, DR. A COMEROTA, DR. C THURM, DR. E GONZALES, DR. P JETTY, DR. M BENNINGHOFF, DR. M BIDAIR, DR. O QUINTANA, DR. D ADLER, PROF. L DREOSTI, DR. JOHAN ENGELBRECHT, DR. C KØGELENBERG, DR B RAPOPORT, DR. A ROODT, DR. C SMITH, DR. F STEENKAMP, DR. R SOMMERS, DR. H JANSE VAN RENSBURG, DR. B BLOY, DR. H NORTJE, DR. W RABIE, DR. E VAN NIEUWENHUIZEN, DR. L VAN ZYL

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