Thrombosis Management in Cardiology:The relevance of direct Factor Xa inhibition

Prevention and Treatment of Venous Thromboembolism

Alexander G G TurpieProfessor of MedicineMcMaster University

Hamilton ONCanada

22

1.Goldhaber SZ Am Coll Cardiol. 1992;19:246-247 2.Heit JA,et al ASH Annual Meeting Abstracts 2005;106:9103.Cohen AT, et al. Thromb Haemost 2007;98:756−644.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

VTE is a Serious Disease that Affects Hundreds of Thousands People each Year

3

Known Consequences of VTE

Increased future risk of recurrent VTE

3-10% recurrent VTE at 1-year1

Chronic post-thrombotic syndrome (PTS)

Fatal Pulmonary Embolism (PE)

Chronic thromboembolic pulmonary hypertension

Markedly increased risk of disability and reduced quality of life for the patient

Costs of investigating and treating add considerable healthcare costs1,3

3

1. Kearon C. Circulation. 2003;107(23 Suppl 1):I22I30. 2. Cohen AT, et al. Thromb Haemost 2007;98:756–764.3. Ginsberg JS, et al. Arch Intern Med. 2000;160:669672.

Pulmonary embolus

Deep Venous Thromboembolism (DVT)

4

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: Pain Odema Hyperpigmentation Eczema Varicose collateral veins

Severe PTS can lead to intractable, painful venous leg ulcers requiring ongoing nursing and medical care4

4

© Diepgen TL, et al. Dermatology Online Atlas (Reprinted with permission).

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.

66

Prothrombin

FibrinFibrinogen

Thrombin Dabigatranand others

Factor Xa RivaroxabanApixaban, Endoxaban and others

Factor X

Prothrombinase-complex

PhospholipidsFactor Va – Factor XaCa2+

Factor IX Factor IXaFactor VIIaTissue factorPhospholipidsCa2+

Factor IXaFactor VIIIaPhospholipidsCa2+

Initiationphase

Propagation phase = thrombin-generation

phase

Thrombinphase

New Drugs in Phase III Development Directly Targeting Coagulation Factors

Adapted from: Kubitza & Haas. Expert Opin Investig Drugs 2006

8

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

Enoxaparin

Rivaroxaban 10 mg odMandatory

bilateralvenography

Mandatorybilateral

venographyR

6–8 hours post-surgery in all RECORD studies

Day 1

Double blind

Last dose, daybefore venography

StudyRivaroxaban therapy

Dose DurationEnoxaparin 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

*Followed by oral placebo for 3 weeks

RECORD1–3: Evening before surgery

RECORD4: 12–24 hours post-surgery

RECORD Phase III Programme: Study Design

SURGERY

FOLLOW

UP

8

9

Pooled analysis: Time points

Rivaroxaban Follow-upEnoxaparin Follow-up

Rivaroxaban

Enoxaparin Follow-up

Follow-up

Rivaroxaban

Follow up by: 30–35 days

after last dose

Follow up by: 30–35 days

after last dose

Day 12 (10–14)

Day 1 Day 35(31–39)

Enoxaparin Placebo

Follow-up

Day 12 (10–14)

Hip1

Hip2

Knee4

Total study duration

pool

Day 12±2 active treatment pool

Total treatment duration pool

Rivaroxaban

Rivaroxaban

Enoxaparin Follow-up

Follow-up

Follow-up

Knee3

91.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

10

RECORD1–4* Pooled Analysis: Summary

1.3%

0.6%0.4%

RRR 58%‡

p<0.001

p=0.076 (NS)

Endpoints in total treatment

duration pool#

0.2%

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

0

0.5

1.0

1.5

2.0

2.5

Major bleedingSymptomatic VTEand all-cause mortality

0.5%

0.3%0.2%

RRR 52%¶

p=0.001

p=0.175 (NS)

Endpoints in day 12±2 active

treatment pool

1.0%

Major bleedingSymptomatic VTEand all-cause mortality

Enoxaparin regimens

Rivaroxaban regimens

Inci

den

ce (

%)

10

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.

11

RECORD1–4*: PE and all-cause mortality#

HR = 0.61(95% CI: 0.39–0.98)p=0.039

0

0.5

1.0

2.0

1.5

Da

y 1

= d

ay

of

su

rge

ry

47 events

29 events

Enoxaparin regimens

Rivaroxaban regimens

Time-to-event relative to surgery (days)

0 10 20 30 40 50 60 70

Cu

mu

lati

ve e

ven

t ra

te (

%)

*RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin #Post-hoc analysis; safety population, n=12,383

Turpie et al. Blood (ASH Annual Meeting Abstracts) 200811

Total study duration pool

12

RECORD1–4*: Composite of Death, MI, Stroke, Symptomatic VTE, and Major Bleeding#

*RECORD2 compared extended-duration (35±4 days) rivaroxaban with short-duration (12±2 days) enoxaparin #Post-hoc analysis; safety population, n=12,383

HR = 0.69(95% CI: 0.53–0.89)p=0.004

Total study duration poolC

um

ula

tive

eve

nt

rate

(%

)

0 10 20 30 40 50 60 70

0.5

1.0

2.0

1.5

2.5

3.0

Da

y 1

= d

ay

of

su

rge

ry139 events

96 events

Time-to-event relative to surgery (days)

Enoxaparin regimens

Rivaroxaban regimens

0

12

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

MAGELLAN: Study Design

Enoxaparin 40 mg once daily for 10 days

Patients hospitalized

for acute medical

illness with decreased

level of mobility

Rivaroxaban 10 mg once daily for 35 days

Day 1

R

N = 8000

Fo

llo

w-u

p

Day 10 Day 90Day 35

En

d o

f tr

ea

tme

nt

Oral placebofor 25 days

Randomization

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

15

VTE – Phases of the Disease and Conventional Treatment with Anticoagulants

Phases of the disease

Long-term

Types and intensity of conventional anticoagulation treatment

Initial, parenteral therapeutic dose anticoagulation

Early maintenance anticoagulation / Secondary prevention

Long-term maintenance anti-coagulation / Secondary prevention

UFH, LMWH, Fondaparinux

VKA INR 2.0-3.0

VKA INR 2.0-3.0 or 1.5-2.0

At least 5 days

At least 3 months

> 3 months / years/ indefinite**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 Schellong S, Bounameaux H, Büller HR pp 1348-1349

Intermediate

Acute

16

VTE Treatment: Clinical Studies1 Phase II Phase III

Rivaroxaban Oral direct FXa inhibitor

EINSTEIN DVTRivaroxaban vs LMWH/UFH followed by VKA1

ODIXa DVTRivaroxaban vsenoxaparin 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

Dabigatran Oral direct thrombin inhibitor

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

ApixabanOral direct FXa inhibitor

Botticelli-DVTApixaban vs LMWH or fondaparinux followed by VKA3

AMPLIFY4

Apixaban 10 mg bid followed by 5 mg bid for 6 months vs enoxaparin followed by warfarinAMPLIFY-EXT4

Apixaban 2.5 mg bid or 5 mg bid for extended 12 months period vs placebo

1. Büller HR et al. Blood 2008;112:2242–22472. Agnelli GA et al. Circulation 2007;116:180–187

3. Büller HR et al. J Thromb Haem 2008;6:1313–13184. www.clinicaltrials.gov

17

Dabigatran Study Programme

Confirmed symptomatic DVT or PE completing

6 to18 months VKA

Dabigatran Etexilate 150 mg BID

Placebo/warfarin

Day 1

R

N=1448

RE-SONATE/REMEDYTreatment period of 6 months

Symptomatic VTE

RE-COVER

R

N=2,564

ParenteralAnticoagulant

Day 1 Day 5-10

VKA target INR 2.5 (INR range 2–

3)

Symptomatic VTE

RE-COVER II

RE-COVER Pre-defined treatment period of 6 months

N=2,554

Dabigatran Etexilate 150 mg BID

17

1. RECOVER Study Information. Trial ID: NCT00291330 Available at http://clinicaltrial.gov/ct2/show/NCT00291330 Accessed 15 November 20092. 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

ParenteralAnticoagulant

18

Events Dabigatran (n=1274) 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

Any bleeding (%) 207 (16.2) 280 (22.1)HR = 0.71

95% CI; 0.59 to 0.85

RE-COVER: Study Results

Source – ASH 2009 Abstract

19

Rivaroxaban: VTE Treatment Studies

Phase II Phase III

Finished ODIXa-DVT EINSTEIN-DVT

EINSTEIN EXT

Ongoing EINSTEIN DVT EINSTEIN PE

http://clinicaltrials.gov19

2020

Day 1 Days 5–7 Day 21 Day 84 Day 114

ODIXa-DVT1

R

Enoxaparin(1 mg/kg)

VKA

10 mg bid20 mg bid

40 mg od30 mg bid

DOUBLE BLIND

OPEN LABEL

613 patients

randomized

INR 2–3

Rivaroxaban CC

US

FO

LLO

W-

UP

CCUS+PLS

CC

US

and

P

LS

EINSTEIN-DVT2

Rivaroxaban

CUS+ PLS R

LMWH/heparin

VKA

20 mg od30 mg od40 mg od C

US

and

P

LS

FO

LLO

W-

UPDOUBLE BLIND

OPEN LABEL

543 patients

randomized

INR 2–3

Day 1 Days 5–7 Day 21 Day 84 Day 114

Phase II Study Designs: ODIXa-DVT and EINSTEIN-DVT

Agnelli et al. Circulation 2007; Büller et al. Blood 2008

21

Phase II: ODIXa-DVT and EINSTEIN-DVT: Efficacy Outcome1,2

21

ODIXa-DVT1: Rivaroxaban showed similar efficacy to standard therapy

Rivaroxaban total daily dose (mg)LMWH/VKA

Ra

te o

f th

rom

bu

s r

eg

res

sio

n

wit

ho

ut

rec

urr

en

t V

TE

(%

) 80

70

60

50

40

30

20

10

0

6040200

bid rivaroxaban dosesod rivaroxaban dose

EINSTEIN-DVT2: Rivaroxaban showed similar efficacy to standard therapy

Ra

te o

f d

ete

rio

rati

on

(%

)

Rivaroxaban total daily dose (mg)LMWH/VKA10 30 40

201816141210 8 6 4 2 0

20

Recurrent DVT or PE, VTE-related death, and deterioration in CUS or PLS

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

22

EINSTEIN Phase III: Study Designs

Confirmed symptomatic DVT or PE completing 6 or 12 months of

rivaroxaban or VKA

Rivaroxaban 20 mg od

Placebo

Day 1

R

N=1,147

EINSTEIN EXT:Treatment period of 6 or 12 months

30

-da

y o

bs

erv

ati

on

p

eri

od

15 mg bid

Objectively confirmed DVT

without symptomatic PE

R

N=3,465 Rivaroxaban

Day 1 Day 21

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)

Objectively confirmed PE

with or without symptomatic

DVT

EINSTEIN DVT/PE:Pre-defined treatment period of 3, 6, or 12 months

20 mg od

N=3,300

30

-da

y o

bs

erv

ati

on

p

eri

od

Rivaroxaban

22EINSTEIN DVT, PE, Extension Evaluation Study Information available at: http://clinicaltrials.gov. Accessed 15 November 2009

23

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

EINSTEIN DVT, PE Evaluation Study Information available at http://clinicaltrials.gov, Accessed 15 November 2009.23

Study design

Confirmed symptomatic DVT or PE

completing

6 or 12 months of rivaroxaban or

VKA in EINSTEIN VTE program

Rivaroxaban 20 mg od

PlaceboDay 1

R

N=1,197

Treatment period of 6 or 12 months

30-d

ay o

bse

rvat

ion

al p

erio

d

Confirmed symptomatic DVT or

PE completing

6 or 12 months

of VKA

~53%

~47%

Randomized, double-blind, placebo-controlled,

event-driven (n=30), superiority study

EINSTEIN Extension Trial ID: NCT00439725

Major outcomes

Primary efficacy outcome* Symptomatic recurrent VTE, i.e. composite of recurrent DVT, non-

fatal 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

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

Safety population

ITT population for primary efficacy

Placebo

595

594

590

602

602

598

Rivaroxaban

Randomized (n=1,197)

Primary efficacy outcome and individual components

Placebo (n=594)

Rivaroxaban (n=602)

Symptomatic recurrent VTE* 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

Number of subjects at risk

Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81

Placebo 594 582 570 554 521 467 444 164 138 133 110 93 85

ITT population

Primary efficacy outcome analysis(time to first event)

10

9

8

7

6

5

4

3

2

1

0

Cu

mu

lati

ve e

ven

t ra

te (

%)

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Rivaroxaban (n=602)

Placebo (n=594)

HR=0.184; p<0.0001

RRR=82%

Number needed to treat to prevent 1 primary efficacy outcome: 15

Placebo (n=590)

Rivaroxaban(n=598)

Major bleeding 0  4 (0.7%)*

Bleeding contributing to death 0 0

Bleeding in a critical site 0 0

Associated with fall in hemoglobin 2 g/dL and/or transfusion

Gastrointestinal bleeding 0 3 (0.5%)

Menorrhagia 0 1 (0.2%)

Principal safety outcome: major bleeding

Number needed to harm: approximately 139

*p=0.11

Safety population

Placebo (n=590)

Rivaroxaban(n=598)

Clinically relevant non-major bleeding 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%)

Other outcomes

Safety population; some patients experienced more than one event

*p<0.01

Placebo(n=594)

Rivaroxaban(n=602)

Cardiovascular outcomes 4 (0.7%) 4 (0.7%)

STEMI 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

ITT population

Other outcomes

Total mortality 2 (0.3%) 1 (0.2%)

PE 1 (0.2%)

Cancer 1 (0.2%)

Unexplained death including where PE cannot be excluded

0 1 (0.2%)

ALT >3 x ULN(single measurement)

Continued Improved

n=1 n=6

ALT >3 x ULN(3 measurements)

ContinuedImproved

n=1• Allopurinol/statins/ multiple drugs

n=1• Hepatic steatosis, 8-year history of ALT

ALT >3 x ULN(single measurement)

DiscontinuedImproved

n=1• Unexplained

n=3• 1 liver hemangioma/ hepatic steatosis• 2 unexplained

ALT >8 x ULN(2 measurements)

DiscontinuedImproved

0 n=1• Alcohol abuse/ allopurinol/ hepatitis A

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

Safety population

35

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 benefit-risk and simplify acute VTE treatment and secondary prevention

35

1. Schulman S: N Engl J Med 2003 Oct 30; 349(18):1713-212. 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.