Transcript ASH 2009 Advisory Board v4

Thrombosis Management in Cardiology:
The relevance of direct Factor Xa inhibition
Prevention and Treatment of
Venous Thromboembolism
Alexander G G Turpie
Professor of Medicine
McMaster University
Hamilton ON
Canada
VTE is a Serious Disease that Affects Hundreds
of Thousands People each Year
22
1.Goldhaber SZ Am Coll Cardiol. 1992;19:246-247
2.Heit JA,et al ASH Annual Meeting Abstracts 2005;106:910
3.Cohen AT, et al. Thromb Haemost 2007;98:756−64
4.Cohen AT. Poster ISPOR 8th, 2005

3rd most common cardiovascular
disease world-wide after ischaemic
heart disease and stroke1

Causes ~300,000 deaths in the
United States and over 500,000
deaths in Europe per year2,3

In the EU, more than twice as many
people die from VTE than from
AIDS, breast cancer, prostate cancer
and transportation accidents
combined3

3.1 billion Euros per year total
estimated costs for VTE-associated
care4
Known Consequences of VTE

Increased future risk of recurrent VTE
Pulmonary embolus
 3-10% recurrent VTE at 1-year1

Chronic post-thrombotic syndrome (PTS)

Fatal Pulmonary Embolism (PE)

Chronic thromboembolic pulmonary
hypertension
Deep Venous Thromboembolism (DVT)
33

Markedly increased risk of disability and
reduced quality of life for the patient

Costs of investigating and treating add
considerable healthcare costs1,3
1. Kearon C. Circulation. 2003;107(23 Suppl 1):I22I30.
2. Cohen AT, et al. Thromb Haemost 2007;98:756–764.
3. Ginsberg JS, et al. Arch Intern Med. 2000;160:669672.
PTS is a Relatively Common but Serious
Complication
PTS occurs in nearly one-third of pts
within 5 years of initial DVT1
 DVT-induced valvular incompetence
leads to lower limb hypertension2
 PTS is characterized by3:







44
Pain
Odema
Hyperpigmentation
Eczema
Varicose collateral veins
Severe PTS can lead to intractable,
painful venous leg ulcers requiring
ongoing nursing and medical care4
1. Prandoni P, et al. Ann Intern Med. 1996;125:1–7.
2. Kahn SR, et al. Arch Intern Med. 2004;164:17–26.
3. Kahn SR. J Thromb Thrombolysis. 2006; 21(1) 41-48.
4. Kahn SR, et al. J Gen Intern Med. 2000;15:425–429.
© Diepgen TL, et al. Dermatology
Online Atlas (Reprinted with permission).
New Drugs in Phase III Development Directly
Targeting Coagulation Factors
Initiation
phase
Factor VIIa
Tissue factor
Phospholipids
Ca2+
Factor IX
Factor X
Propagation phase =
thrombin-generation
phase
Rivaroxaban
Apixaban,
Endoxaban
and others
Phospholipids
Factor Va – Factor Xa
Ca2+
Prothrombin
Adapted from: Kubitza & Haas. Expert Opin Investig Drugs 2006
Dabigatran
and others
Thrombin
Fibrinogen
66
Factor IXa
Factor VIIIa
Phospholipids
Ca2+
Factor Xa
Prothrombinasecomplex
Thrombin
phase
Factor IXa
Fibrin
RECORD Phase III Programme:
Study Design
Double blind
S
U
R
G
E
R
Y
R
Rivaroxaban 10 mg od
6–8 hours post-surgery in all RECORD studies
RECORD4: 12–24 hours post-surgery
Enoxaparin
RECORD1–3: Evening before surgery
Day 1
88
U
P
Last dose, day
before venography
Rivaroxaban therapy
Dose
Duration
Study
*Followed
Mandatory
bilateral
venography
F
O
L
L
O
W
Enoxaparin therapy
Dose
Duration
THR
10 mg od
5 weeks
40 mg od
5 weeks1
THR
10 mg od
5 weeks
40 mg od
2 weeks*2
TKR
10 mg od
2 weeks
40 mg od
2 weeks3
TKR
10 mg od
2 weeks
30 mg bid
2 weeks4
by oral placebo for 3 weeks
1. Eriksson et al. New Engl J Med 2008; 2. Kakkar et al. Lancet 2008; 3. Lassen et al. New Engl J Med 2008;
4. Turpie et al. Lancet 2009
Pooled analysis: Time points
Day 1
Day 12±2 active
treatment pool
Total treatment
duration pool
Day 12
(10–14)
Day 35
(31–39)
Hip1
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Hip2
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Knee3
Knee4
Placebo
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Day 12
(10–14)
99
Total study
duration
pool
Follow up by:
30–35 days
after last dose
Follow up by:
30–35 days
after last dose
1.Eriksson et al. New Engl J Med 2008; 2.Kakkar et al. Lancet 2008; 3.Lassen et al. New Engl J Med 2008;
4. Turpie et al. Lancet 2009
RECORD1–4* Pooled Analysis: Summary
Endpoints
in total treatment
duration pool#
2.5
Incidence (%)
2.0
RRR
Endpoints
in day 12±2 active
treatment pool
Enoxaparin regimens
Rivaroxaban regimens
58%‡
p<0.001
RRR 52%¶
1.5
p=0.001
1.3%
1.0
1.0%
0.5
0.6%
p=0.076 (NS)
0.4%
0
0.5%
0.2%
p=0.175 (NS)
0.2%
0.3%
Symptomatic VTE Major bleeding
Symptomatic VTE
Major bleeding
and all-cause mortality
and all-cause mortality
p-values analysed using a Cox regression model; safety population, n=12,383; *RECORD2 compared extended-duration (35±4 days) rivaroxaban
with short-duration (12±2 days) enoxaparin; #5 weeks in RECORD1 and RECORD2 (includes placebo-controlled period in RECORD2) and
2 weeks in RECORD3 and RECORD4; ‡Homogeneity test, p=0.313; ¶Homogeneity test, p=0.431
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Turpie et al. Oral presentation at the XXII Congress of the ISTH. Boston, MA, USA. July 11–16, 2009.
Turpie et al. Blood 2008;112(11):Abstract 36.
RECORD1–4*: PE and all-cause mortality#
Total study duration pool
1.5
Day 1 = day of
surgery
Cumulative event rate (%)
2.0
1.0
Enoxaparin regimens
47 events
HR = 0.61
(95% CI: 0.39–0.98)
p=0.039
0.5
Rivaroxaban regimens
29 events
0
0
10
20
30
40
50
60
Time-to-event relative to surgery (days)
70
*RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin
#Post-hoc analysis; safety population, n=12,383
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Turpie et al. Blood (ASH Annual Meeting Abstracts) 2008
RECORD1–4*: Composite of Death, MI, Stroke,
Symptomatic VTE, and Major Bleeding#
Total study duration pool
Enoxaparin regimens
2.5
Day 1 = day of
surgery
Cumulative event rate (%)
3.0
2.0
1.5
139 events
HR = 0.69
(95% CI: 0.53–0.89)
p=0.004
Rivaroxaban regimens
96 events
1.0
0.5
0
0
10
20
30
40
50
60
Time-to-event relative to surgery (days)
70
*RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin
#Post-hoc analysis; safety population, n=12,383
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Turpie et al. Oral presentation at the XXII Congress of the ISTH. Boston, MA, USA. July 11–16, 2009.
Turpie et al. Blood 2008;112(11):Abstract 36.
VTE prevention in hospitalized medically ill
patients
http://clinicaltrials.gov/ct2/show/NCT00571649?term=rivaroxaban&rank=9
Day 10
Day 35
Day 90
Follow-up
Day 1
End of treatment
MAGELLAN: Study Design
Randomization
Patients
hospitalized
for acute
medical
illness with
decreased
level of
mobility
N = 8000
R
Rivaroxaban 10 mg once daily
for 35 days
Enoxaparin 40 mg
once daily for 10 days
Oral placebo
for 25 days
Primary efficacy endpoint
 Composite of asymptomatic proximal DVT detected by bilateral ultrasound, symptomatic DVT,
non-fatal PE and VTE-related death.
Primary safety endpoint
 Major bleeding and clinically relevant non-major bleeding
VTE – Phases of the Disease and
Conventional Treatment with Anticoagulants
Phases of the disease
Acute
Intermediate
Long-term
Types and intensity of conventional anticoagulation treatment
UFH, LMWH,
Fondaparinux
Initial, parenteral
therapeutic dose
anticoagulation
At least
5 days
VKA INR 2.0-3.0
Early maintenance anticoagulation /
Secondary prevention
VKA INR 2.0-3.0 or 1.5-2.0
At least 3 months
*With re-assessment of the individual benefit–risk at periodic intervals.
Kearon C, et al. Chest. 2008;133;454-545.
ESC Textbook of Cardiovascular Medicin 2nd Edition 2009; Chapter 37
15 Schellong S, Bounameaux H, Büller HR pp 1348-1349
Long-term maintenance anticoagulation / Secondary prevention
> 3 months / years/ indefinite*
VTE Treatment: Clinical Studies1
Rivaroxaban Oral
direct FXa inhibitor
Phase II
Phase III
EINSTEIN DVT
Rivaroxaban vs
LMWH/UFH followed by VKA1
ODIXa DVT
Rivaroxaban vs
enoxaparin followed by VKA2
EINSTEIN DVT/PE4
Rivaroxaban for 3, 6 or 12 months vs
enoxaparin for > 5 days followed by VKA for
3, 6, or 12 months
EINSTEIN EXT4
Pre-treatment with rivaroxaban or VKA for 6
or 12 months followed by rivaroxaban or
placebo for 6 or 12 months
RE-COVER4 & RE-COVER II4
5-10 days pre-treatment with LMWH bridging
to dabigatran or VKA for 6 months
RE-MEDY4
3-6 months treatment with approved
anticoagulant; switch to dabigatran or warfarin
RE-SONATE4
6-18 months VKA treatment followed by 6
months dabigatran or placebo
Dabigatran
Oral direct thrombin
inhibitor
Apixaban
Oral direct FXa
inhibitor
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Botticelli-DVT
Apixaban vs
LMWH or fondaparinux
followed by VKA3
1. Büller HR et al. Blood 2008;112:2242–2247
2. Agnelli GA et al. Circulation 2007;116:180–187
AMPLIFY4
Apixaban 10 mg bid followed by 5 mg bid for
6 months vs enoxaparin followed by warfarin
AMPLIFY-EXT4
Apixaban 2.5 mg bid or 5 mg bid for extended
12 months period vs placebo
3. Büller HR et al. J Thromb Haem 2008;6:1313–1318
4. www.clinicaltrials.gov
Dabigatran Study Programme
RE-COVER
Pre-defined treatment period of 6 months
Symptomatic
VTE
RE-COVER
Day 1 Day 5-10
Parenteral
Dabigatran Etexilate 150 mg BID
N=2,564 Anticoagulant
R
Symptomatic
VTE
RE-COVER II
N=2,554
Parenteral
Anticoagulant
Day 1
Confirmed
symptomatic DVT
or PE completing
6 to18 months
VKA
17
VKA target INR 2.5 (INR range 2–3)
RE-SONATE/REMEDY
Treatment period of 6
months
N=1448
R
Dabigatran Etexilate 150 mg BID
Placebo/warfarin
1. RECOVER Study Information. Trial ID: NCT00291330 Available at http://clinicaltrial.gov/ct2/show/NCT00291330 Accessed 15 November 2009
2. RECOVER Study Information. Trial ID: NCT00680186 Available at http://clinicaltrial.gov/ct2/show/NCT00680186 Accessed 15 November 2009
3. RESONATE Study Information. Trial ID: NCT00558259 Available at http://clinicaltrial.gov/ct2/show/NCT00558259. Accessed 15 November 2009
RE-COVER: Study Results
Events
Warfarin (n=1265)
Hazard ratios and
confidence intervals
Recurrent VTE (%)
30 (2.4)
27 (2.2)
Risk difference = 0.4% 95%
CI; -0.8 to 1.5 p<0.0001 for
prespecified non-inferiority
Recurrent VTE to the end
of follow-up period (%)
34 (2.7)
32 (2.5)
HR = 1 .05
95% CI; 0.065 to 1.70
Major bleeding (%)
20 (1.6)
24 (1.9)
HR = 0.82
95% CI; 0.45 to 1.48
207 (16.2)
280 (22.1)
HR = 0.71
95% CI; 0.59 to 0.85
Any bleeding (%)
18
Dabigatran (n=1274)
Source – ASH 2009 Abstract
Rivaroxaban: VTE Treatment Studies
Finished
Phase II
Phase III
 ODIXa-DVT
 EINSTEIN
EXT
 EINSTEIN
DVT
 EINSTEIN
PE
 EINSTEIN-DVT
Ongoing
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http://clinicaltrials.gov
Phase II Study Designs:
ODIXa-DVT and EINSTEIN-DVT
Rivaroxaban
10 mg bid
20 mg bid
30 mg bid
40 mg od
Day 1
Days 5–7
FOLLOW-UP
INR 2–3
Day 21
Day 84
Day 114
FOLLOW-UP
DOUBLE BLIND
VKA
CCUS
CCUS+ 613 patients
randomized R
PLS
CUS and PLS
OPEN LABEL
Enoxaparin
(1 mg/kg)
CCUS and PLS
ODIXa-DVT1
Day 21
Day 84
Day 114
EINSTEIN-DVT2
LMWH/heparin
OPEN LABEL
CUS+
PLS
543 patients
randomized
VKA
R
DOUBLE BLIND
Rivaroxaban
20 mg od
30 mg od
40 mg od
Day 1
20
20
INR 2–3
Agnelli et al. Circulation 2007; Büller et al. Blood 2008
Days 5–7
Phase II: ODIXa-DVT and EINSTEIN-DVT:
Efficacy Outcome1,2
Rate of thrombus regression
without recurrent VTE (%)
ODIXa-DVT1: Rivaroxaban showed similar efficacy to standard therapy
80
bid rivaroxaban doses
od rivaroxaban dose
70
60
50
40
30
20
10
0
0
20
40
Rivaroxaban total daily dose (mg)
60
LMWH/VKA
Rate of
deterioration (%)
EINSTEIN-DVT2: Rivaroxaban showed similar efficacy to standard therapy
20
18
16
14
12
10
8
6
4
2
0
Recurrent DVT or PE, VTE-related death, and
deterioration in CUS or PLS
10
21
21
20
30
Rivaroxaban total daily dose (mg)
40
LMWH/VKA
Agnelli et al (ESC Annual Meeting, Poster presentation) 2006; Buller et al (ESC Annual Meeting, Oral Presentation) 2006: Agnelli et al.
Circulation 2007; Büller et al. Blood 2008
EINSTEIN Phase III: Study Designs
EINSTEIN DVT/PE:
Pre-defined treatment period of 3, 6, or 12 months
N=3,465
Day 21
Rivaroxaban
15 mg bid
Rivaroxaban
20 mg od
R
Objectively
confirmed PE
with or without
symptomatic
DVT
N=3,300
Enoxaparin 1.0 mg/kg bid for at least 5 days, plus
VKA to start <48 hrs, target INR 2.5 (INR range 2–3)
EINSTEIN EXT:
Treatment period of 6 or 12 months
Day 1
Confirmed
symptomatic DVT
or PE completing
6 or 12 months of
rivaroxaban or
VKA
22
22
N=1,147
Rivaroxaban 20 mg od
R
Placebo
EINSTEIN DVT, PE, Extension Evaluation Study Information
available at: http://clinicaltrials.gov. Accessed 15 November 2009
30-day observation
period
Day 1
30-day observation
period
Objectively
confirmed DVT
without
symptomatic PE
Primary and Secondary Outcome Measures of
EINSTEIN DVT and EINSTEIN PE Evaluation

Primary outcome measures1,2
 Symptomatic recurrent VTE, i.e., the composite of (recurrent) DVT or fatal
or non-fatal PE

Principal safety outcome1,2
 Combination of major and clinically relevant non-major bleeding

Secondary outcome measures1,2
 All-cause mortality
 Vascular events
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EINSTEIN DVT, PE Evaluation Study Information
available at http://clinicaltrials.gov, Accessed 15 November 2009.
Study design
Randomized, double-blind, placebo-controlled,
event-driven (n=30), superiority study
Confirmed symptomatic DVT
or PE completing
6 or 12 months of
rivaroxaban or VKA in
EINSTEIN VTE program
N=1,197
Rivaroxaban 20 mg od
R
Day 1
Confirmed symptomatic DVT
or PE completing
6 or 12 months
of VKA
~47%
EINSTEIN Extension Trial ID: NCT00439725
Placebo
30-day observational period
Treatment period of 6 or 12 months
~53%
Major outcomes
Primary efficacy outcome*
 Symptomatic recurrent VTE, i.e. composite of recurrent DVT, nonfatal PE, or fatal PE, or unexplained death where PE cannot be
excluded
Principal safety outcome*
 Major bleeding, defined as overt bleeding associated with:
 A fall in hemoglobin of 2 g/dL or more, or
 A transfusion of 2 or more units of packed red blood cells or whole
blood, or
 Occurrence at a critical site: intracranial, intraspinal, intraocular,
pericardial, intra-articular, intramuscular with compartment syndrome,
retroperitoneal, or
 Death
*Adjudicated by the Central Independent Adjudication Committee
Patient flow
Placebo

Rivaroxaban
595
Randomized
(n=1,197)
602
594
ITT population for primary
efficacy
602
590
Safety population
598
Mean duration of therapy
 Before study entry: placebo 249 days; rivaroxaban 248 days
 During study: placebo 190 days; rivaroxaban 190 days

Last patient enrolled
 Treated for at least 3 months
Primary efficacy outcome and
individual components
Placebo
(n=594)
Symptomatic recurrent VTE*
Rivaroxaban
(n=602)
42 7.1%
8 1.3%
Recurrent DVT
31 5.2%
5 0.8%
Non-fatal PE
13 2.2%
2 0.3%
Fatal PE
1 0.2%
0
Unexplained death
(where PE cannot be excluded)
0
1 0.2%
ITT population; *some patients experienced more than one event
Primary efficacy outcome analysis
(time to first event)
Cumulative event rate (%)
10
Number needed to treat
to prevent 1 primary
efficacy outcome: 15
9
8
7
Placebo
(n=594)
HR=0.184; p<0.0001
6
5
RRR=82%
4
3
2
Rivaroxaban
(n=602)
1
0
0
30
60
90
Number of
subjects at risk
120 150 180 210 240 270
Time to event (days)
300 330 360
Rivaroxaban 602
590
583
573
552
503
482
171
138
132
114
92
81
Placebo
582
570
554
521
467
444
164
138
133
110
93
85
594
ITT population
Principal safety outcome: major bleeding
Placebo
(n=590)
Rivaroxaban
(n=598)
0
4 (0.7%)*
Bleeding contributing to death
0
0
Bleeding in a critical site
0
0
Gastrointestinal bleeding
0
3 (0.5%)
Menorrhagia
0
1 (0.2%)
Major bleeding
Associated with fall in hemoglobin
2 g/dL and/or transfusion
*p=0.11

Number needed to harm: approximately 139
Safety population
Other outcomes
Placebo
(n=590)
Rivaroxaban
(n=598)
7 (1.2%)
32 (5.4%)*
Urogenital/uterus
2 (0.3%)
12 (2.0%)
Nasal
1 (0.2%)
8 (1.3%)
Rectal/anal
2 (0.3%)
6 (1.0%)
Skin
2 (0.3%)
4 (0.7%)
Ear
0
1 (0.2%)
Gastrointestinal
0
1 (0.2%)
Surgical site
0
1 (0.2%)
Clinically relevant non-major bleeding
*p<0.01
Safety population; some patients experienced more than one event
Other outcomes
Placebo
(n=594)
Rivaroxaban
(n=602)
4 (0.7%)
4 (0.7%)
0
1 (0.2%)
Unstable angina
1 (0.2%)
3 (0.5%)
Transient ischemic attack
1 (0.2%)
0
Ischemic stroke
1 (0.2%)
0
Non-CNS systemic embolism
1 (0.2%)
0
2 (0.3%)
1 (0.2%)
Cardiovascular outcomes
STEMI
Total mortality
PE
1 (0.2%)
Cancer
1 (0.2%)
Unexplained death including
where PE cannot be excluded
ITT population
0
1 (0.2%)
Asymptomatic ALT rises, study treatment, clinical
history, and concomitant medication
Observation/
frequency
Treatment/
outcome
Placebo
Rivaroxaban
Liver failure/ death
0
0
ALT >3x ULN +
bilirubin >2x ULN
0
0
ALT >3 x ULN
(single
measurement)
Continued
Improved
n=1
n=6
ALT >3 x ULN
(3 measurements)
Continued
Improved
n=1
• Allopurinol/statins/
multiple drugs
n=1
• Hepatic steatosis, 8-year history of ALT 
ALT >3 x ULN
(single
measurement)
Discontinued
Improved
n=1
• Unexplained
n=3
• 1 liver hemangioma/ hepatic steatosis
• 2 unexplained
ALT >8 x ULN
(2 measurements)
Discontinued
Improved
0
n=1
• Alcohol abuse/ allopurinol/ hepatitis A
Safety population
Summary
VTE is a serious and potentially life-threatening condition
 Current standard of treatment usually requires initial parenteral
LMWH/UFH or fondaparinux followed by an oral VKA
 For many patients with VTE, secondary prevention with VKA is not
extended beyond 6 months since risk of VTE may be outweighed by
risk of major bleeding1
 Patients with VTE have a major risk of recurrent VTE that may
persist for years2,3
 New oral anticoagulants may have the potential to improve benefitrisk and simplify acute VTE treatment and secondary prevention

35
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1. Schulman S: N Engl J Med 2003 Oct 30; 349(18):1713-21
2. Prandoni P, Lensing AWA, Cogo A, et al. Ann Intern Med 1996; 125: 1–7.
3. Heit JA, Mohr DN, Silverstein MD, et al. Arch Intern Med 2000; 160: 761–768.