Alexander T Cohen On behalf of the MAGELLAN Steering Committee and Investigators Potential conflicts Dr AT Cohen is a medical consultant for and has received honoraria consultancy and clinical trial funding from many pharmaceutical companies including ID: 160349
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Slide1
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 InvestigatorsSlide2
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 StatesSlide3
3
Attributable risk for deep vein thrombosis/
pulmonary embolism
Risk factor
Attributable risk (%)
(95% CI)
Hospitalization with surgery
23.8
(20.3
–
27.3)Hospitalization without surgery21.5(17.3–25.6)Malignant neoplasm18.0(13.4–22.6)Congestive heart failure9.5(3.3–15.8)Neurological disease with extremity paresis6.9(3.5–10.2)
Heit et al, 2002
MedicalpatientsSlide4
4
Contemporary studies of hospitalized patients
Short-term thromboprophylaxis
Primary efficacy endpoint* (%)
TE major bleeding (%)
MEDENOX (1999)
1
Placebo
14.9
1.1
Enoxaparin 40 mg od5.51.7PREVENT (2004)2Placebo5.00.0Dalteparin2.80.4ARTEMIS (2006)3Placebo10.50.2Fondaparinux5.6
0.2
Extended thromboprophylaxis
EXCLAIM (2010)
4
Placebo
4.00.3Extended enoxaparin2.50.8
1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010
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 38
TE, treatment-emergentSlide5
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
, 2011Slide6
6
Patients
≥
40 years hospitalized for acute medical illness with decreased level of mobility
Oral rivaroxaban 10 mg od 35±4 days
s.c. enoxaparin
40 mg od 10±4 days
Day 35
(31–39)
Oral placebo
35±4 daysFollow-up periodto Day 90s.c. placebo 10±4 daysUltrasonography on day 10±4Ultrasonography on day 35±4 Primary efficacy outcome Day 10 (non-inferiority)Primary efficacy outcome Day 35* (superiority)Day 10(6–14)8,101 patients randomizedMAGELLAN: clinical trial designRDay 90(83–97)Cohen et al, 2011*Events from Day 1 to Day 35Slide7
7
MAGELLAN: study outcomes
Primary efficacy outcome
Composite of: Asymptomatic proximal DVT detected by mandatory ultrasonographySymptomatic 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, 2011Slide8
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: 1.5Superiority: Day 35Assumptions: 4.0% event rate in the control group; 2.4% event rate in the rivaroxaban group; RRR
≥
40%
Cohen
et al
, 2011Slide9
Patient flow: Day 10 and Day 35 endpoints
Modified intent to treat (mITT)
Day 10
Safety
Randomized
(n=8,101)
Per-protocol (PP)
Day 10
4,050
3,997 (99%)
3,232 (80%)2,938 (73%)Enoxaparin/placebo4,0514,001 (99%)3,271 (81%)2,993 (74%)2,967 (73%)3,057 (75%)2,516 (62%)2,586 (64%)RivaroxabanDay 35Day 35Slide10
Patient characteristics*
Rivaroxaban
(N=3,997)
Enoxaparin/placebo
(N=4,001)
Age, median (years)
71.0
71.0
Male (%)
55.6
52.6Weight, mean (kg)77.577.3Body mass index, mean (kg/m2)28.228.2Median duration of hospitalization (days)11.011.0Creatinine clearance (%)†<30 ml/min
2
2
30 to <50 ml/min
20
20
50 to ≤80 ml/min3738>80 ml/min 3938
Race (%)†
White
69
69
Asian
20
20
Other
7
7
*Safety
population;
†
some data missingSlide11
Underlying medical conditions*
Acute medical conditions
Rivaroxaban
(N=3,997)
(%)
Enoxaparin/placebo
(N=4,001)
(%)
Acute infectious diseases
46
45Heart failure3233Acute respiratory insufficiency2729Acute ischemic stroke1717Active cancer77Acute inflammatory/rheumatic diseases44Other medical conditions
1
1
≥
2
underlying medical conditions
3031*Safety populationSlide12
Primary efficacy outcome: Day 10*
Rivaroxaban (n=2,939)
Enoxaparin
(n=2,993)
n
(%)
n
(%)
Primary efficacy outcome
78
(2.7)82(2.7)Asymptomatic proximal DVT71(2.4)71(2.4)Symptomatic lower extremity DVT7(0.2)6(0.2)Symptomatic non-fatal PE6(0.2)
2
(<0.1)
VTE-related death
‡
3
(0.1)6(0.2)*PP population, events up to Day 10+5 days; ‡includes cases where PE cannot be ruled outRelative risk ratiop=0.0025 for non-inferiority (one-sided) 1.00 0
0.7131.3340.968
1.50
Inferior
Superior
Non-inferiorSlide13
Primary efficacy outcome: Day 35*
Rivaroxaban (n=2,967)
Enoxaparin/
placebo
(n=3,057)
n
(%)
n
(%)
Primary efficacy outcome
131(4.4)175(5.7)Asymptomatic proximal DVT103(3.5)133(4.4)Symptomatic lower extremity DVT13(0.4)15(0.5)Symptomatic non-fatal PE10
(0.3)
14
(0.5)
VTE-related death
‡
19(0.6)30(1.0)*mITT population, events up to Day 35+6 days; ‡4 confirmed fatal PEs but includes cases where PE cannot be ruled out0.6180.9620.771p=0.0211 for superiority (two-sided)
Absolute risk reduction:
1.3%
Relative risk reduction: 22.9%
1.00
0
Relative risk ratio
Inferior
Superior
Non-inferiorSlide14
Safety outcomes
Rivaroxaban (n=3,997)
Enoxaparin/
placebo
(n=4,001)
RR
p
value
n
(%)
n(%)Day 1 to 10 (principal safety outcome)Clinically relevant bleeding*111(2.8)49(1.2)2.3<0.0001Major bleeding
24
(0.6)
11
(0.3)
2.2
0.0318Day 1 to 35 (principal safety outcome)Clinically relevant bleeding* 164(4.1)67(1.7)2.5
<0.0001
Major bleeding
43
(1.1)
15
(0.4)
2.9
0.0004
Day 10 to 35
Clinically relevant bleeding*
56
(1.4)
19
(0.5)
3.0
<0.0001
Major bleeding
19
(0.5)
4
(0.1)
4.8
0.0045
*
Major plus non-major clinically relevant bleeding
Safety population;
treatment-emergent bleedingSlide15
Components of major bleeding
Rivaroxaban (n=3,997)
Enoxaparin/
placebo
(n=4,001)
Day 1 to 10
n
(%)
n
(%)
Major bleeding*24(0.6)11(0.3)Fall in Hb ≥2g/dL17(0.4)7(0.2)Transfusions ≥2 units of blood15(0.4)
4
(0.1)
Fatal
5
(0.1)
1(<0.1)Day 1 to 35
Major bleeding*
43
(1.1)
15
(0.4)
Fall in Hb ≥2g/dL
31
(0.8)
10
(0.2)
Transfusions ≥2 units of blood
24
(0.6)
8
(0.2)
Fatal
7
(0.2)
1
(0.1)
*
Patients could have more than 1 eventSlide16
Other outcomes: Day 35
Outcomes
Rivaroxaban
(N=3,997) (%)
Enoxaparin/placebo
(N=4,001)
(%)
Net clinical benefit*
9.4
7.8
Any cardiovascular event1.81.6All-cause mortality5.14.8Liver functionALT >3× ULN + bilirubin >2× ULN‡0.20.2*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 dataSlide17
17
Contemporary studies of
hospitalized patients
Short-term thromboprophylaxis
Primary efficacy endpoint* (%)
TE major bleeding
(%)
MEDENOX (1999)
1
Placebo
14.91.1Enoxaparin 40 mg od5.51.7Extended thromboprophylaxisEXCLAIM (2010)4Placebo4.00.3Extended enoxaparin2.50.8MAGELLAN
Enoxaparin/placebo
5.7
0.4
Extended rivaroxaban
4.4
1.11. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010MEDENOX, 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-emergentSlide18
18
Summary
MAGELLAN met its primary efficacy endpoints
Day 10: rivaroxaban was non-inferior to enoxaparin in reducing the risk of VTEDay 35: extended thromboprophylaxis was superior to enoxaparin followed by placebo in reducing the risk of VTEOverall 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 Slide19
19
Conclusion
MAGELLAN confirms that there is a continued risk of VTE beyond the initial period of hospitalization or immobilization in
acutely ill patientsBased 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 rivaroxabanSlide20
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 PhDBayer: 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)Slide21
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