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
 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
2
Attributable risk for DVT/PE
Attributable
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)
Risk factor
CHF
9.5
(3.3–15.8)
Neurological disease with
extremity paresis
6.9
(3.5–10.2)
Heit et al, 2002
Medical
patients
3
Contemporary studies of hospitalized
patients
Short-term thromboprophylaxis
MEDENOX (1999)1
PREVENT (2004)2
ARTEMIS (2006)3
Primary efficacy
endpoint* (%)
Major bleeding
(%)
Placebo
14.9
1.1
Enoxaparin 40 mg od
5.5
1.7
Placebo
5.0
0.2
Dalteparin
2.8
0.5
Placebo
10.5
0.2
Fondaparinux
5.6
0.2
Placebo (after open-label
enoxaparin run-in)
4.0
0.3
Extended enoxaparin
2.5
0.8
Extended thromboprophylaxis
EXCLAIM (2010)4
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
1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010
4
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
MAGELLAN: clinical trial design
Day 10
(6–14)
8,101 patients
randomized
Day 35
(31–39)
Day 90
(83–97)
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
R
Follow-up
period
to Day 90
Oral placebo
35±4 days
s.c. enoxaparin
40 mg od 10±4 days
Ultrasonography
on day 10±4
Primary efficacy outcome
(non-inferiority)
Cohen et al, 2011
Ultrasonography
on day 35±4
Primary efficacy outcome
(superiority)
6
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
7
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
8
Patient flow: Day 10 and 35 endpoints
Enoxaparin/placebo
Rivaroxaban
4,050
Randomized
(n=8,101)
4,051
3,997 (99%)
Safety
4,001 (99%)
3,232 (80%)
Modified intent to treat
Day 10
3,271 (81%)
2,967 (73%)
Day 35
3,057 (75%)
2,938 (73%)
Per-protocol
Day 10
Day 35
2,993 (74%)
2,516 (62%)
2,586 (64%)
9
Patient characteristics*
Age, median (years)
Male (%)
Weight, mean (kg)
Body mass index, mean (kg/m2)
Median duration of hospitalization (d)
Creatinine clearance (%)†
<30 ml/min
30-<50
50-<80 ml/min
≥80 ml/min
Race (%)†
White
Asian
Other
Rivaroxaban
(N=3,997)
Enoxaparin/placebo
(N=4,001)
71.0
55.6
77.5
28.2
11.0
71.0
52.6
77.3
28.2
11.0
2
20
37
39
2
20
38
38
69
20
7
69
20
7
* Safety population; †some data missing
10
Underlying medical conditions*
Rivaroxaban
(N=3,997)
Enoxaparin/placebo
(N=4,001)
Acute medical conditions
%
%
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
1
1
31
31
Other medical conditions
≥2 underlying medical conditions
* Safety population
11
Primary efficacy outcome: Day 10*
Rivaroxaban
(n=2,939)
n %
78 2.7
71 2.4
7 0.2
Primary efficacy outcome
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Symptomatic non-fatal PE
VTE-related death‡
0.713
0
6 0.2
3 0.1
0.968
2 <0.1
6 0.2
1.334
1.00 1.50
Relative risk ratio
Superior
Enoxaparin
(n=2,993)
n %
82 2.7
71 2.4
6 0.2
Noninferior
p=0.0025 for non-inferiority
(one-sided)
Inferior
* PP population, events up to Day 10 + 5 days; ‡includes cases where PE cannot be ruled out
12
Primary efficacy outcome: Day 35*
Primary efficacy outcome
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Symptomatic non-fatal PE
VTE-related death†
0.618
0
0.771
Rivaroxaban
(n=2,967)
n %
131 4.4
103 3.5
13 0.4
10 0.3
19 0.6
0.962
ARR 1.3%, RRR 22.9%
1.00
Relative risk ratio
Superior
Enoxaparin/placebo
(n=3,057)
n %
175 5.7
133 4.4
15 0.5
14 0.5
30 1.0
Noninferior
*mITT population, events up to Day 35 + 6 days; †4 confirmed fatal PEs
p=0.0211 for superiority
(two-sided)
Inferior
13
Principal safety outcome
Enoxaparin/
placebo
(n=4,001)
RR
p value
111 (2.8%)
49 (1.2%)
2.3
<0.0001
24 (0.6%)
11 (0.3%)
2.2
0.0318
5 (0.1%)
1 (<0.1%)
5.0
0.1415
164 (4.1%)
67 (1.7%)
2.5
<0.0001
43 (1.1%)
15 (0.4%)
2.9
0.0004
7 (0.2%)
1 (<0.1%)
7.0
0.0687
Rivaroxaban
(n=3,997)
Day 10
Clinically relevant bleeding (major +
non-major clinically relevant bleeding)
Major bleeding
Fatal
Day 35
Clinically relevant bleeding (major +
non-major clinically relevant bleeding)
Major bleeding
Fatal
Safety population; Treatment-emergent bleeding
14
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 function
ALT >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 bleeding
Modified-intention-to-treat population; **day 90+7 data
15
Pre-specified regions: Day 35 net clinical
benefit
Western Europe
Primary
efficacy
3.5
Enox/PBO
%
7.1
Major
bleeding
Net clinical
benefit*
0.8
0.5
4.8
7.7
Riva %
RR
(95% CI)
0.5
(0.32–0.78)
1.7
(0.61–4.57)
0.6
(0.42–0.93)
North/South America
Riva %
4.5
1.3
0.1
6.3
5.2
Eastern Europe
Primary
efficacy
Major
bleeding
4.8
5.3
0.9
0.3
Net clinical
benefit*
5.7
5.7
Enox/PBO
%
5.1
RR
(95% CI)
0.9
(0.56–1.55)
10.2
(1.31–79.53)
1.2
(0.75–1.92)
Asia/Africa
0.9
(0.61–1.31)
2.7
(0.87–8.54)
4.7
5.3
1.4
0.5
1.0
(0.70–1.43)
6.3
5.9
0.9
(0.55–1.40)
3.0
(0.97–9.24)
1.1
(0.70–1.63)
*Composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic non-fatal PE, VTE-related death
and treatment-emergent major bleeding
16
Contemporary studies of hospitalized
patients
Short-term thromboprophylaxis
Primary efficacy
endpoint* (%)
Major bleeding
(%)
14.9
1.1
5.5
1.7
Placebo (after openlabel enoxaparin run-in)
4.0
0.3
Extended enoxaparin
2.5
0.8
Enoxaparin/placebo
5.7
0.4
Extended rivaroxaban
4.4
1.1
MEDENOX (1999)1 Placebo
Enoxaparin
40 mg od
Extended thromboprophylaxis
EXCLAIM (2010)4
MAGELLAN
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
1. Samama et al, 1999; 2. Leizorovicz et al, 2004; 3. Cohen et al, 2006; 4. Hull et al, 2010
17
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
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
19
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: 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)
20
Acknowledgements
INVESTIGATORS: 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
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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
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