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, and has received honoraria, consultancy and clinical trial funding from many pharmaceutical companies, including: Astellas, AstraZeneca, Bayer, Boheringer-Ingelheim, BMS,

Daiichi Sankyo, GSK, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Sanofi-Aventis, Schering Plough, and Takeda

He is an advisor to the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE

He 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

33

Attributable risk for DVT/PE

Risk factorAttributable

risk (%)(95% CI)

Hospitalization with surgery 23.8 (20.3–27.3)

Hospitalization without surgery

21.5 (17.3–25.6)

Malignant neoplasm 18.0 (13.4–22.6)

CHF 9.5 (3.3–15.8)

Neurological disease with extremity paresis

6.9 (3.5–10.2)

Heit et al, 2002

Medicalpatients

44

Contemporary studies of hospitalized patients

Short-term thromboprophylaxis Primary efficacy endpoint* (%)

Major bleeding (%)

MEDENOX (1999)1 Placebo 14.9 1.1

Enoxaparin 40 mg od 5.5 1.7

PREVENT (2004)2 Placebo 5.0 0.2

Dalteparin 2.8 0.5

ARTEMIS (2006)3 Placebo 10.5 0.2

Fondaparinux 5.6 0.2

Extended thromboprophylaxis

EXCLAIM (2010)4 Placebo (after open-label enoxaparin run-in)

4.0 0.3

Extended enoxaparin 2.5 0.8

1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010

MEDENOX, all VTE between day 1 and 14; PREVENT, asymptomatic proximal DVT, symptomatic VTE, and sudden death up to day 21; ARTEMIS, all VTE up to day 15; EXCLAIM, all VTE up to day 28

55

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

66

Patients ≥40 years hospitalized for acute medical illness with decreased level of mobility

Oral rivaroxaban 10 mg od 35±4 days

s.c. enoxaparin40 mg od 10±4 days

Day 35(31–39)

Oral placebo 35±4 days

Follow-up period

to Day 90

s.c. placebo 10±4 days

Ultrasonography on day 10±4

Ultrasonography on day 35±4

Primary efficacy outcome (non-inferiority)

Primary efficacy outcome (superiority)

Day 10(6–14)

8,101 patients randomized

MAGELLAN: clinical trial design

R

Day 90(83–97)

Cohen et al, 2011

77

MAGELLAN: study outcomes

Primary efficacy outcome

Composite of: Asymptomatic proximal DVT detected by mandatory ultrasonography Symptomatic DVT (proximal or distal) Symptomatic non-fatal 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

88

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; 35% RRR

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; 40% RRR

Cohen et al, 2011

9

Patient flow: Day 10 and 35 endpoints

Modified intent to treat Day 10

Safety

Randomized (n=8,101)

Per-protocol Day 10

4,050

3,997 (99%)

3,232 (80%)

2,938 (73%)

Enoxaparin/placebo

4,051

4,001 (99%)

3,271 (81%)

2,993 (74%)

2,967 (73%) 3,057 (75%)

2,516 (62%) 2,586 (64%)

Rivaroxaban

Day 35

Day 35

1010

Patient characteristics*

Rivaroxaban(N=3,997)

Enoxaparin/placebo(N=4,001)

Age, median (years) 71.0 71.0Male (%) 55.6 52.6Weight, mean (kg) 77.5 77.3Body mass index, mean (kg/m2) 28.2 28.2

Median duration of hospitalization (d) 11.0 11.0Creatinine clearance (%)†

<30 ml/min 2 230-<50 20 2050-<80 ml/min 37 38

≥80 ml/min 39 38Race (%)†

White 69 69 Asian 20 20 Other 7 7

* Safety population; †some data missing

1111

Underlying medical conditions*

Acute medical conditions

Rivaroxaban(N=3,997)

Enoxaparin/placebo(N=4,001)

% %

Heart failure 32 33

Active cancer 7 7

Acute ischemic stroke 17 17

Acute infectious diseases 46 45

Acute inflammatory/rheumatic diseases

4 4

Acute respiratory insufficiency 27 29

Other medical conditions 1 1

≥2 underlying medical conditions 31 31

* Safety population

1212

Primary efficacy outcome: Day 10*

* PP population, events up to Day 10 + 5 days; ‡includes cases where PE cannot be ruled out

Rivaroxaban (n=2,939)

Enoxaparin(n=2,993)

n % n %

Primary efficacy outcome 78 2.7 82 2.7

Asymptomatic proximal DVT 71 2.4 71 2.4

Symptomatic lower extremity DVT 7 0.2 6 0.2

Symptomatic non-fatal PE 6 0.2 2 <0.1

VTE-related death‡ 3 0.1 6 0.2

0.713 1.3340.968

Relative risk ratio

Superior Non-inferior

Inferior

p=0.0025 for non-inferiority (one-sided)

1.00 0 1.50

1313

Primary efficacy outcome: Day 35*

*mITT population, events up to Day 35 + 6 days; †4 confirmed fatal PEs

Rivaroxaban (n=2,967)

Enoxaparin/placebo(n=3,057)

n % n %

Primary efficacy outcome 131 4.4 175 5.7

Asymptomatic proximal DVT 103 3.5 133 4.4

Symptomatic lower extremity DVT 13 0.4 15 0.5

Symptomatic non-fatal PE 10 0.3 14 0.5

VTE-related death† 19 0.6 30 1.0

1.00 0

0.618 0.9620.771

Relative risk ratio

p=0.0211 for superiority (two-sided)

ARR 1.3%, RRR 22.9%

Superior Non-inferior

Inferior

14

Principal safety outcome

Rivaroxaban (n=3,997)

Enoxaparin/placebo

(n=4,001)RR p value

Day 10

Clinically relevant bleeding (major + non-major clinically relevant bleeding)

111 (2.8%) 49 (1.2%) 2.3 <0.0001

Major bleeding 24 (0.6%) 11 (0.3%) 2.2 0.0318

Fatal 5 (0.1%) 1 (<0.1%) 5.0 0.1415

Day 35

Clinically relevant bleeding (major + non-major 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

Fatal 7 (0.2%) 1 (<0.1%) 7.0 0.0687

Safety population; Treatment-emergent bleeding

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Other outcomes: Day 35

Rivaroxaban(N=3,997)

Enoxaparin/placebo(N=4,001)

Outcome % %

Net clinical benefit* 9.4 7.8

Any cardiovascular event 1.8 1.6

All-cause mortality 5.1 4.8

Liver functionALT >3 x ULN + bilirubin >2 x ULN**

0.2 0.2

*The composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic non-fatal PE, VTE-related death, treatment-emergent major bleeding, and non-major clinically relevant bleedingModified-intention-to-treat population; **day 90+7 data

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Western Europe North/South America

Riva %Enox/PBO

%RR

(95% CI)Riva %

Enox/PBO %

RR (95% CI)

Primary efficacy

3.5 7.1 0.5 (0.32–0.78)

4.5 5.1 0.9 (0.56–1.55)

Major bleeding

0.8 0.5 1.7 (0.61–4.57)

1.3 0.1 10.2 (1.31–79.53)

Net clinical benefit*

4.8 7.7 0.6 (0.42–0.93)

6.3 5.2 1.2 (0.75–1.92)

Eastern Europe Asia/Africa

Primary efficacy

4.8 5.3 0.9 (0.61–1.31)

4.7 5.3 0.9 (0.55–1.40)

Major bleeding

0.9 0.3 2.7 (0.87–8.54)

1.4 0.5 3.0 (0.97–9.24)

Net clinical benefit*

5.7 5.7 1.0 (0.70–1.43)

6.3 5.9 1.1 (0.70–1.63)

Pre-specified regions: Day 35 net clinical benefit

*Composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic non-fatal PE, VTE-related death and treatment-emergent major bleeding

1717

Contemporary studies of hospitalized patients

Short-term thromboprophylaxis Primary efficacy endpoint* (%)

Major bleeding (%)

MEDENOX (1999)1 Placebo 14.9 1.1

Enoxaparin 40 mg od

5.5 1.7

Extended thromboprophylaxis

EXCLAIM (2010)4 Placebo (after open-label enoxaparin run-in)

4.0 0.3

Extended enoxaparin 2.5 0.8

MAGELLAN Enoxaparin/placebo 5.7 0.4

Extended rivaroxaban 4.4 1.1

1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010

MEDENOX, all VTE between day 1 and 14; PREVENT, asymptomatic proximal DVT, symptomatic VTE, and sudden death up to day 21; ARTEMIS, all VTE up to day 15; EXCLAIM, all VTE up to day 28; MAGELLAN, asymptomatic proximal DVT, symptomatic VTE and VTE-related death up to day 35

1818

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

1919

Conclusion

MAGELLAN confirms that there is a continued risk of VTE beyond the period of hospitalization or immobilization in acutely ill patients

The risk of bleeding must be weighed against the benefit of preventing DVT and PE events in deciding which patients to treat

Further analysis is required to identify which group of patients studied in the MAGELLAN trial may benefit from extended thromboprophylaxis with rivaroxaban

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AcknowledgementsSteering 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: Physicians: 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)

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AcknowledgementsINVESTIGATORS: MR. DR. FEDERICO BOTTAROMR. DR. HECTOR HENDLERMRS. DR. BEATRIZ GRANDMRS. DR. ANALIA MYKIETIUKMR. DR. MARTIN HOJMANMR. DR. OSCAR CABERLOTTOMR. DR. RAUL SALERNO, HR. PROF. DR. ERNST PILGERPRIM. DR. NORBERT BAUERPROF. DR. PETER SIOSTRZONEKUNIV. PROF. DR. RUDOLF KIRCHMAHR. PRIM. DR. WERNER FORTUNATPRIM. DR. CHRISTOPH WENISCHPRIM. PROF. DR. ANSGAR WELTERMPRIM. DOZ. DR. LUDWIG ERLACHEROA DR. HANS-ROBERT SCHONHERRPRIM. DR. BERND BAUERPRIM. DR. ERWIN GRAFLUNIV. PROF. DR. FELIX KEILPRIM. PROF. DR. PETER BALCKEPRIM. PROF. DR. FRANZ WEIDINGE, PROF. HATEM SALEMDR MICHAEL LEYDENPROFESSOR BENG CHONGPROFESSOR BENG CHONGDR PATRICK CARROLLDR DAVID COLQUHOUNDR DAVID JACKSONA/PROF. ENG GANA/PROF. STEPHEN HALLDR DAVID SERISIERA/PROF ROSS BAKER, PROF. DR. DANIEL BLOCKMANSDR. KØNRAAD HENDRICKXDR. HARRY STRIEKWOLDDR. GUY VAN ROEYDR. MARIE-ELENA VANDEN ABEELEDR. CAROLINE JACQUYDR. ALAIN DELOBBEPROF. ALAIN SOUPARTDR. LUC VAN ZANDWEGHEDR. ACHIEL VAN HOOF, PROF. VALENTINA MINCHEVAPROF. STEFAN MILANOVDR. LYUBOMIR LYUBENOVDR. STOYANKA NENKOVADR. DIMO DIMOVDR. MARGARITA TASEVAPROF. YAVOR IVANOVPROF. DIMITAR POPOV, MR DR. BERNARDO GARICOCHEAMR DR CYRILLO CAVALHEIROMR DR DALTON CHAMONEMR DR JOYCE BIZZACCHIMR DR ELIE FISSMR DR ANTONIO LOPESMR. DR. BONNO BELLENMR DR. RICA RDO MOREIRA, DR. ASHFAQ SHUAIBDR. FRANCOIS DUBEDR. DEMETRIOS KUTSOGIANNISDR. STEVE VERREAULTDR. BRIAN BUCKDR. ANDRE ROUSSINDR. GARRY MODDELDR. GRANT STOTTSDR. HIREN DESAIDR. JEAN-MARTIN BOULANGERDR. FRANK SILVERDR. NICOLE DANEAULTDR. CELINE BERGERON, HR. DR. MED. MARTIN BANYAIFR. PROF. DR. IRIS BAUMGARTNERPROF. DR. MED. ALFRED SCHIFFERHR. DR. MED. ALEXANDER IMHOFFR. PD DR. MED. CHRISTINA JEANHR. DR. MED. PATRICK NUSSBAUME, MR. DR. GUILLERMO BUGEDOMR. DR. HUMBERTO TORRES, PROF. DAYI HUPROF CHEN WANGPROF YONGJUN WANGDR YUEJIN YANGPROF. YIHAN CHENDR CE SHENPROF. JIANGRONG LIUPROF SHIYAO WUPROF. WEI LIPROF ZHONGXIN ZHAODR QINGYU XIUPROF. SUI-YANG ZHANGDR TAOHONG HUPROF XIAOWEI YANDR LUYUE GAIDR YUSHENG ZHAOPROF QI HUAPROF. HONGWEI LIPROF. JIMEI LIPROF. DE PING ZHANGDR BIAO XUPROF. QI WANPROF. RONGCHANG CHENPROF SHAOXIANG XIANDR YAN LIUPROF QINGCHUN GAODR CHUNTAO LIUDR GUOXIAN QIPROF. PING CHENPROF. SHENGHUA SUNPROF KAN YANGDR CHANGGUI WUPROF HAICHANG WANGPROF. LAN YANGPROF XINYUE QINDR. SHULIANG GUOPROF YINGXIAN SUNDR YANNI WANGDR YAN-SHENG LIPROF YUJIE ZHOUDR KANG-NING CHENDR JIANG WUDR. JIAN ZHANG, MR. DR. DIEGO FAJARDOMR. DR. RODRIGO BOTEROMR. DR. ROBIN RADAMR. DR. LUIS GOMEZMR. DR. LUIS URIBEMR. DR. JORGE CEDANOMR. DR. JUAN VELASQUEZMR. DR. CARLOS JARAMILLO, PROF. ALES LINHARTDR. OTTO MAYERDR KAREL GORICANDR VLASTIMIL PROCHAZKADR. JAN FIKSADR. IGOR MACELDR JAN SEDLACEK, HR. PROF. DR. WOLFGANG PETERMAHR. PROF. DR. BERND MUHLBAUERHR. PD DR. JURGEN BARTHHR. DR. HOLGER LAWALLHR. PROF. DR. CHRISTOPH POHLHR. PROF. DR. THEODOR KLOTZHR. PROF. DR. J.-D. RINGEHR. PROF. DR. JAN SCHMIDT-LUCKHR. PD DR. TOBIAS HEINTGESFR. DR. IRINA SCHOFFAUERHR. PD DR. ARNO DORMANNHR. DR. WINFRED THEELENHR. DR. FRANK-M. DROUVENHR. PROF. DR. CLAUS NIEDERAUHR. PROF. DR. BERND SANNERHR. DR. HANS-RUDOLF MILSTREYHR. PD DR. MATHIAS BORSTHR. PROF. DR. JURGEN VOM DAHLFR. DR. HEIDRUN HINDAHLHR. PD DR. ERICH STØLBENHR. PROF. DR. SEBASTIAN SCHELLHR. DR. JAN BEYER-WESTENDORFHR. PD DR. ROLAND VELTKAMPHR. PROF. DR. SVEN MOBIUS-WINKFR. PROF. DR. CHRISTINE ESPINOHR. PROF. DR. MATTHIAS LESCHKEFR. PROF. DR. INGE SCHARRER, DR HENRIK NIELSENDR. SØREN AVNSTRØMDR CHRISTIAN TUXENDR. TONNY NIELSENDR OVE ØSTERGAARD, DR TIINA UUETOADR TOOMAS MARANDIDR MARGUS LEMBERDR OLGA KOLBASSOVA, DR. MANUEL MONREALDR. ANTONI CASTRODR. CARLES TOLOSADR. FRANCISCO CONGETDR. JOSE-ANTONIO NIETO RODRIGUDR. RAIMUNDO TIRADO MIRANDADRA. MARIA GUILDR. JOSEP BISBEDR. FERNANDO CERETO CASTRODR. JAVIER TRUJILLO SANTOSDR. JAUME VILLALTA, DR RIITTA LASSILADR. JUHANI KARMAKOSKI, PROFESSEUR PATRICK MISMETTIPR DOMINIQUE MOTTIERPR JEANNOT SCHMIDTPROFESSEUR ISABELLE QUEREPROFESSEUR CLAIRE LE JEUNNEPROFESSEUR DENIS VITAL-DURANDPR ISABELLE MAHEDOCTEUR RIADH RIHANIPROFESSEUR JEAN-FRANCOIS BERGMPR PHILIPPE DEBOURDEAUDR MARC LAMBERTPROFESSEUR DOMINIQUE STEPHANPR BERNARD LORCERIEPR PHILIPPE LACROIXDR ALAIN PROUSTPROFESSEUR DOMINIQUE FARGE-BANPR CHARLES-HUGO MARQUETTEDR DOMINIQUE BRISOTDR CLEMENT FOURNIERDR AUDREY DUCHEMINDR SANDRO AQUILANTIPR MICHEL GALINIER, DR MARIE SCULLYDR ANDER COHENDR PATRICK KESTEVENDR MARK ELLIOTTDR JOHN LUCKITDR P RAFFERTYDR RAMESH DURAIRAJ, MR. PROF. DR. HARRY BASSARISPROF. DR. ATHANASIOS SKOUTELISMR.DR. FREDERICOS VLASTOSMR. DR. MICHAIL TOUBISDR. MR. GEORGIOS PANOUTSOPOULDR. MR. STYLIANOS APSOKARDOSDR. DIMITRIOS BABALISDR., MRS. ANASTASIA KARAFOULIDDR. APOSTOLOS KATSIVASDR. SOTIRIOS PATSILINAKOS, PROF LAWRENCE K. S. WONGDR RAYMOND S.M. WONG, PROF. MIJO BERGOVECPROF. MIROSLAV SAMARZIJADR SILVA ZUPANCIC-SALEKDOC. SANJA HAJNSEKDR. ALEKSANDAR KNEZEVICDR. ROBERT STEINER, DR. JANOS NIKLDR ISTVAN KONDAKORDR GABOR NYIRATIDR. GABOR JAKABDR ZOLTAN SZAKACSDR FERENC NAGYDR NORBERT SZEGEDIDR ZSUZSANNA FRANKFURTER, DR KARMEL TAMBUNANMD, MPH HARMANI KALIMDR MOH MACHFØD, DR. DAVID ZELTSERPROF. SHMUEL ORENDR. MICHAEL LISHNERPROF. REUVEN ZIMLICHMANDR. ZEV STHØGERDR. HUSSEIN OSAMAHDR. MAZEN ELIASPROF TONY HAYEKDR. GREGORY TELMANDR. NIZAR ELIAS, DR. SHIVAKUMAR BHAIRAPPADR. ASHOKAN CHEVIRIDR. MILIND GADKARIDR. KARKAL PRADEEP KUMARDR. AJAY NAIKDR. ABRAHAM OOMMANDR. KAMESHWARAO KUCHIMANCHIDR. AJAY MAHAJANDR DEEPAK TALWARDR PURVEZ GRANTDR JAGDEEP WHIGDR . GURUPRAKASH AVVARUDR RM PL RAMANATHANDR CHERUKUPALLI RAGHU, PROF. GIANCARLO AGNELLIDR. WALTER AGENODR. MATTEO GIORGI PIERFRANCESCDR. CORRADO LODIGIANIDR. MAURO SILINGARDIDR. RENZO POGGIOPROF. SERGIO SIRAGUSADR. ENRICA MORRADR. ANGELO DE BLASIODR. GIANCARLO CASTAMANDR. ROBERTO BUZZONIDR. ANDREA FONTANELLADR. ANNA FALANGADR. RAFFAELE LANDOLFIPROF. MARIO PINIDR. 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GINTAUTAS GUMBREVICIUSDR ALGIRDAS VITKAUSKASDR VIDA BASIJOKIENEDR SIGITAS STONKUSDR VIOLETA GRISKEVICIENEDR RITA NORVILIENE, DR. PHILIPPE MULLERDR. STEFAN RAUH, DR ULDIS KUPCSDR VIESTURS ROZITISDR INGA STUKENADR. DAINIS KRIEVINSDR NATALIJA PONTAGADR ILZE AIZSILNIECE, MR. DR. ROBERTO PEREA SANCHEZMR. DR. JAIME GONZALEZ GARZAMR. DR. MARTIN GOMEZ LARAMR. DR. JORGE CARDOZA AMADORMR. DR. ALFREDO TANAKA CHAVEZMR. DR. VICTOR VELASCO RODRIGUMR. DR. FELIPE NARES OCHOAMR. DR. MIGUEL VAZQUEZ LOPEZMR. DR. CUAUHTEMOC ROMERO LOPEMR. DR. JOSE GALLEGOS MARTINEZMR. DR. DAVID HERNANDEZ GAETAMRS. DR. MARIA HERVER CABRERA, DR SZE PIAW CHINDR KUI HAN SIMDR BIN WAN AHMAD WAN AZMAN, DR. R. FIJNHEERDHR. DR. H. CATEDHR.DR. A. DEESDHR. A.M. KREUK, DR ROALD TORPDR INGVAR STOKSTADDR FREDRIK SCHJESVOLDDR WALEED GHANIMA, DR SHARON JACKSONDR DAVID SIMPSONDR PAUL OCKELFORD, MRS. DR. ROSA COTRINAMS. DR. MARCIA SALAS PEREZMR. DR. VICTOR ULLOA PEREZMRS. DR. ZANDRA MONCADA VILELAMR. DR. FERNANDO ARRIETA DIASMR. DR. ORESTES SALAZAR CANDIOMR. DR. REYNALDO CASTILLO LEON, DR. ZEBA AZIZDR. GHIAS UN NABI TAYYABDR./MR. NADEEM RIZVI, MR. PROF. ANDRZEJ SZCZEKLIKPROF. LECH WALASEKDR MONIKA BOJARSKA-LOSPROF. TOMASZ PASIERSKIDR MALGORZATA GUTOWSKA-JABLONSDR WALDEMAR KRYSIAKDR TADEUSZ ZECHOWICZMS.PROF. KARINA JAHNZ-ROZYKDR EWA MIREK-BRYNIARSKAPROF. MARIA GORSKADR MALGORZATA BIEDRZYCKADOC. ALEKSANDER GOCHDR MICHAL OGOREKDR ANTONI SYDORDR KAZIMIERZ WRZESINSKI, DR. FAUSTINO FERREIRAPROF. DR. LUIS PROVIDENCIADR. ALFREDO MARTINSDR. FERNANDO GOMESPROF. DR. FERNANDO SANTOSPROF. DR. PAULO BETTENCOURTPROF. DR. JOSE DUCLA SOARESDR. ALBERTO MELLO E SILVADR. TERESA RODRIGUESDR. AVELINO FERREIRA, DR SVETLANA KHATKOVADR ALEXANDER SOTNIKOVPROF. TATIANA FEDOROVAPROF. GRIGORY AROUTYNOVPROF. MARIA GLEZERPROF. VALENTIN MOISEEVDR. NATALIYA SHILKINADR. OLGA ERSHOVA, DR PETER SVENSSONDR INGEMAR TORSTENSSONDR ANDERS SJAELANDERDR JAN OSTERGRENDR INGAR TIMBERGDR ANN-CHARLOTTE LASKADR. PG WIKLUNDDR ERIC BERTHOLDSDR MAGDALENA CWIKIEL, DR THUN HOW ONGDR RU TANDR ALAN NGDR GERALD CHUADR HWA WOOI GANPROF ONG TENG TANG, MR. DR. MATJAZ JEREBDOC BOJANA ZVANDOC MATJAZ FLEZARDR GREGOR TRATARDR. MIHAEL SOKDR VOJKA GORJUP, DR. LUDOVIT GASPARDR. JAN STEVLIKDR. VLADIMIR SPISAKDR. FRANTISEK KOVARDR. MIROSLAV SZENTIVANYI, ASSOC. PROF. CHAIRAT PERMPIKULCOL.,MD. ANAN WATTANATHUMDR. CHAICHARN POTHIRAT, PROF. SERDAR KUCUKOGLUPROF. BARIS ILERIGELEN, PROF. ERDEM GOKERPROF. HADIYE SIRINPROF. UGUR YILMAZPROF. SANEM NALBANTGIL, DR YEN-HUNG LINDR BIH-FANG GUODR CHIH-LU HANDR KOU-GI SHYUDR KENNETH YIN-CHING CHUANG, DR VLADIMIR SKREBKOVPROF. VITALIY SORKINPROF. YEVGENIA SVYSHCHENKOPROF. OLEKSII KORZHPROF. STEPAN GENYKPROF. LEONID VORONKOVDR. VIRA TSELUYKODR. OLEXANDR KARPENKOPROF. IGOR VAKALIUKDR. MYKOLA PEREPELIUKPROF. OLEXANDER LEGKONOGOVDR. VALENTYNA KOVALDR. ANATOLIY POLYAKOVDR. YANA GONCHAROVADR. TETIANA RYABICHENKOPROF. MYKOLA VATUTIN, DR. ALBRECHT HEYDERDR. R. MURRAYDR. PADMASHRI RASTOGIDR. MARK PLAUTZDR. ROGER YUSENDR. ROBERT LAVENDERDR. GENO MERLIDR. AMIR JAFFERDR. PURVI MEHRADR. GERHARD JOHNSONDR. PAUL MANOSDR. SCOTT KAATZDR. VENKATESH NADARDR. TED WUNDR. JOHN MASSONDR. ROBERT LERNERDR. ALLAN SEIBERTDR. ROBERT MCLAFFERTYDR. JAMES WELKERDR. PATRICK WRIGHT, JR.DR. KUMAR RAJAMANIDR. DAN SCHULLERDR. AMIT SHARMADR. JOHN SIMMONSDR. FREDERICK WHITTIERDR. JOHN WARDDR. NIZAR DABOULDR. STEPHEN CHASTAINDR. JAMES DEXTERDR. JOHN UPDEGROVEDR. WILLIAM REITERDR. STEVEN STOLTZDR. STEVEN CONRADDR. MONICA HAZELRIGGDR. THOMAS LINGDR. DAVID CHENDR. KENRIC MAYNORDR. WILLIAM FRENCHDR. DENNIS DIETRICHDR. CHARLES LAWTONDR. JEFFREY BRENSILVERDR. BARRY HELLERDR. CHARLES ALBRECHT, IIIDR. CARLOS COWLEYDR. SHARAN MAHALDR. SUZANNE ANDERSONDR. WIN TØDR. PARESH POKHARELDR. MANUEL FONTESDR. HAROLD MINKOWITZDR. MAURICIO CONCHADR. ROBERT STEINDR. MARYANN PEBERDYDR. THOMAS BIRCHDR. RICHARD LIGHTDR. GERALD SOFFDR. MICHAEL COXDR. AVERY NATHANSONDR. RICHARD FEIDR. JUAN REYESDR. MICHAL KAZIMIRDR. DAVID WILLIAMSDR. TOMASZ ZIEDALSKIDR. GORDON HILL, JR.DR. JOHN SUENDR. CHARLES GREENBERGDR. PARAG MEHTADR. KENNETH WAXMANDR. WILLIAM PATTONDR. ANTHONY COMEROTADR. CRAIG THURMDR. ENGLISH GONZALESDR. PREETHAM JETTYDR. MICHAEL BENNINGHOFFDR. MOHAMED BIDAIRDR. OFSMAN QUINTANA, DR DAVID ADLERPROF LYDIA DREOSTIDR. JOHAN ENGELBRECHTDR. CØNIE KØGELENBERGDR BERNARDO RAPOPORTDR. ANDRE ROODTDR. C SMITHDR FRANCOIS STEENKAMPDR. RITA SOMMERSDR HANNES JANSE VAN RENSBURGDR BLAINE BLOYDR HENDRIK NORTJEDR. WILLIAM RABIEDR ELANE VAN NIEUWENHUIZENDR LOUIS VAN ZYL