Various Aspects in Deep Vein

Thrombosis : Cause, How Often

and Management

dr.Dadang Hendrawan, Sp.JP (K)

 Disclaimer
These slides are for scientific and educational purposes only and are the
copyright of Bayer HealthCare
The data contained within this slide deck do not support or recommend
the use of rivaroxaban in any countries or indications in which it is not
approved
In Indonesia, Xarelto is licensed for :
Prevention of venous thromboembolism (VTE) in adult patients undergoing
elective hip or knee replacement surgery
To reduce the risk of stroke and systemic embolism in patients with nonvalvular
atrial fibrillation
With previous history of stroke or TIA
With CHADS2 Score 2
The treatment of deep vein thrombosis (DVT) in which duration of treatment
should be based on the underlying disease
VTE: deep vein thrombosis and
pulmonary embolism
Thrombosis is the formation PE occurs when parts of the clot
or presence of a thrombus detach and travel in the blood
that may obstruct blood flow to block vessels in the lungs
PE
through a vein or artery1
VTE occurs when Migration Embolus
thrombosis obstructs blood
flow through a vein
The term VTE
encompasses:
Thrombus
DVT
PE As the venous
clot grows, it
VTE is a serious health extends along
issue2 the vein

DVT, deep vein thrombosis; PE, pulmonary embolism

1. Anderson FA, et al. Center for Outcomes Research, University of Massachusetts Medical Center; 1998
2. Goldhaber SZ. J Am Coll Cardiol 1992
There are two types of blood clot
Thrombosis
Arterial Venous

Platelet-rich clot Fibrin-rich clot

(platelets and coagulation) (coagulation)
VTE: deep vein thrombosis and
pulmonary embolism

Migration
PE

Embolus

Thrombus

DVT
Clinical presentations of DVT
DVT occurs when clots form in the deep veins within the muscles of
the leg1
Less commonly, clots may form in the upper extremities as well2
DVT-related symptoms may include:1,3
Leg pain
Tenderness of the leg
Cramping that intensifies over several days
Erythema
Warmth at the site of DVT
Edema
DVT is often asymptomatic, sometimes revealed only after
diagnostic tests4

1. Blann AD, Lip GY. BMJ 2006; 2. Spencer FA. J Gen Intern Med 2006 3. Goldhaber SZ, Morrison RB. Circulation 2002;
4. Anderson FA et al. Center for Outcomes Research, University of Massachusetts Medical Center 1998
Risk factors for VTE
Exposing risk factors Predisposing risk factors
(acute conditions or trauma, surgery) (patient characteristics)

History of VTE
Chronic heart failure
Advanced age
Surgery
Varicose veins
Trauma Cancer Obesity
Acute medical illness
Immobility or paresis
Acute heart failure* Inflammatory
Myeloproliferative disorders
Acute respiratory failure diseases
Pregnancy/peripartum period
Central venous
catheterization Inherited or acquired
thrombophilia
Hormone therapies
Renal insufficiency

*New York Heart Association classification III and IV

Risk factors from Geerts WH et al. Chest 2004
Virchows triad revisited
Malignancy Venous disorders
Pregnancy and Venous valvular
peripartum period damage
Oestrogen therapy Trauma or surgery
Inflammatory bowel disease Indwelling catheters
Sepsis Endothelial
Hypercoagulable
Thrombophilia Injury
State

Circulatory
Stasis
Left ventricular dysfunction
Immobility or paralysis
Venous insufficiency or varicose veins
Venous obstruction from tumour, obesity or pregnancy
Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856;
Blann AD, Lip GYH. BMJ 2006; Geerts WH et al. Chest 2004; Bennett PC et al. Thromb Haemost 2009
 Provoked and unprovoked VTE
Transient/
Continuing/
reversible factors No identifiable
irreversible factors
e.g. surgery or cause
e.g. cancer
hospitalization

Unprovoked
Provoked VTE (idiopathic)
VTE

ACCP guidelines recommend at least 3 months VKA therapy after

provoked VTE or longer after unprovoked (idiopathic) VTE3

ACCP, American College of Chest Physicians; VKA, vitamin K antagonist

1. Zhu T et al. Arterioscler Thromb Vasc Biol 2009; 2. Gensini GF et al. Semin Thromb Hemost 1997;
3. Kearon C et al. Chest 2012
Incidence of VTE increases with age
A population-based study shows Incidence rates of DVT and PE in
the incidence rate of VTE patients treated in short-stay hospitals1
increases exponentially 350
with age1 DVT

Rate per 100,000 patients

300
Risk increases by a factor of PE
~200 between the ages of 20 250
and 80 years1
200
Patients aged 60 years or
over represent ~65% of those 150
with PE2
100

50

Age

1. Anderson FA, Jr et al. Arch Intern Med 1991; 2. Torbicki A et al. Eur Heart J 2008
Distal or proximal

Proximal
DVT can be:
Distal External iliac
Below the knee in the deep
veins of the calf
Deep femoral
Proximal
Above the knee, primarily in the Great saphenous
popliteal and femoral veins
Popliteal
DVT usually begins distally

Distal
A thrombus may grow and extend to
the proximal veins Anterior tibial
and embolize1 Posterior tibial

Dorsal venous arch

1. Anderson FA, et al. Center for Outcomes Research, University of Massachusetts Medical Center; 1998
 Potential complications
and goal of treatment

DVT complications:1,2
PE
Damage to valves in the deep veins
Venous reflux
Post-thrombotic syndrome (PTS)
Goal of treatment
Prevent embolization to the lungs
Prevent extension into larger veins
Prevent recurrence
Avoid the chronic complications

1. Kearon C. Circulation 2003; 2. Ginsberg JS, et al. Arch Intern Med 2000
Pulmonary embolism
PE occurs when part of a dislodged thrombus (embolus) passes
into the pulmonary circulation blocking the main artery of the lung
or one of its branches
May lead to increased pulmonary vascular resistance, impaired
gas exchange (alveolar ventilation with hypoperfusion)
Increase in pressure on the right heart can cause dilation,
dysfunction, and ischemia of the right ventricular wall1
PE-related symptoms13
Shortness of breath
Chest pain, tachypnoe, tachycardia
Anxiety
Hemoptysis
Fever Medical Illustration Copyright 2007
Nucleus Medical Art. All rights reserved.

1. Goldhaber SZ. N Engl J Med 1998; 2. Goldhaber SZ, et al. Circulation 2002; 3. Stein PD et al. Chest 2001
Chronic thromboembolic
pulmonary hypertension
Serious complication of PE
Up to 5% of patients with PE are
reported to develop chronic
thromboembolic pulmonary
hypertension (CTPH)1
Initial phase of disease often
asymptomatic and followed by
progressive dyspnoea and
hypoxaemia2
Right heart failure can frequently
occur2
Progressive condition associated
with mortality rates of 420%2
Chest axial with a clot on the left (patients right side); a
tongue of white contrast can be seen extending into the
clot (PE)
Reproduced with permission from Professor AT Cohen
1. Kearon C. Circulation 2003; 2. Torbicki A et al. Eur Heart J 2008
Post-thrombotic syndrome
Occurs in nearly one-third of
patients within 5 years after
idiopathic DVT1
PTS is characterized by:2
Pain
Oedema
Hyperpigmentation
Eczema
Varicose collateral veins
Venous ulceration
Severe PTS can lead to
intractable, painful venous
leg ulcers requiring ongoing
nursing and medical care3
Reproduced with permission from Dr AT Cohen and Dr T Urbanek
1. Prandoni P et al. Ann Intern Med 1996; 2. Kahn SR. J Thromb Thrombolysis 2006;
3. Kahn SR, et al. J Gen Intern Med 2000
VTE is a leading cause of death worldwide
VTE is estimated to cause >500,000 deaths
Europe every year1

An estimated
300,000
VTE-related
deaths occur in
the US VTE is estimated to cause at least
each year2 3 million deaths a year worldwide
1. Cohen AT et al. Thromb Haemost 2007; 2. Heit JA et al. Blood 2005
VTE is a major cause of death in Europe
600,000 Deaths resulting from VTE
543,454
500,000
Number of deaths per annum

400,000

300,000
Combined deaths
209,926
200,000 Transport accident

Prostate cancer
100,000
Breast cancer
AIDS
0

AIDS, acquired immune deficiency syndrome

Cohen AT et al. Thromb Haemost 2007
Total hospitalization costs for recurrent DVT are
~20% higher compared with first DVT

p=0.38
16000 N=14,108
14000 $14,722
p=0.006 $14,146
Total average cost
per patient (US$)

12000
$11,862
10000
$9,805
8000
6000
4000
2000
0
First Recurrent First Recurrent
DVT DVT PE PE

No significant difference in hospitalization costs for recurrent versus first PE

Spyropoulos AC, Lin J. J Manag Care Pharm 2007

 Data From Asia
DVT Rates in Asia
Incidence is perceived as
low in Asian populations,
1
1988
2.7 but has increased
in some patient groups by
~ 6 fold in the past decade
19.3
2
1999

0 5 10 15 20 25
Incidence of DVT per 10,000 hospital patients

1 Woo KS, et all. Singapore Med J.1988 Aug:Aug29(4)357-359

2 Lee LH. New Insights and unresolved issue in the prevention of DVT/VTE in Asia. March 2001.Phuket.Thailand
VTE Incidence : Asian vs Caucasian

Cohen A, et al. Thromb Res 2012

In Asia

It is becoming evidence that Asians are at

much higher risk of VTE than was
supposed.

Cohen A, et al. Thromb Res 2012

What About Indonesia ?
Data From Indonesia From 13 Patients
Undergoing Major Orthopedic Surgery

Asymptomatic VTE was found in

69,2% patients at hospital discharge
Symptomatic VTE was found in 23,1%
patients
No thromboprophylaxis were given to
patients

Med J Indones 2009;18:249-56

 VTE is not merely a western disease
Data from Indonesia showed high rate of VTE,
when patients undergoing major orthopedic
surgery were not given thromboprophylactic.
Also high prevalence of VTE among cancer and
bedridden patients

VTE is a REAL DISEASE

Cancer-associated VTE
Patients with acute VTE Further characterization of patients with
enrolled in the SWIVTER II cancer (n=315) in the SWIVTER II registry
registry (N=1,247)
60
57%
50
Cancer 50%

(n=315),
Percentage (%)
40
25%

30
Non cancer
(n=932), 75% 26%
20
20%

10

0
Metastatic Prior/ongoing Prior cancer Recurrent VTE
disease chemotherapy surgery

Spirk D et al. Thromb Haemost 2011;105:962967

Cancer and VTE predict poor outcome
Patients with a diagnosis of cancer at the time of an episode of VTE were
more likely to have distant metastases and had poorer 1-year survival than
matched controls with cancer but no VTE

1-year survival in patients with cancer and VTE versus matched controls

Controls (cancer, no VTE)

Percentage of patients (%)

50
VTE at the same time
p<0.001
as cancer diagnosis
40
36%
30

20

10 12%

0
1-year survival

Sorensen HT et al. N Engl J Med 2000;343:18461850

VTE in special populations
Special population Problem
Renal insufficiency1 Risk of bleeding is increased with LMWH and in general for
all drugs eliminated primarily via the kidneys

Obesity1 Dose adjustment to ideal bodyweight not as effective as

adjustment to actual bodyweight
Once-daily dosing of enoxaparin not as effective as twice-
daily dosing

Pregnancy2 Potential for foetal and maternal complications, despite VTE

being a major cause of maternal morbidity

1. Rondina MT et al. Thromb Res 2007;119:391402; 2. Bates SM et al. Chest 2008;133:844S886S

Management of VTE in special populations
Special population Recommendation
Renal function Use aPTT-monitored UFH if CrCl <30 ml/min or decrease
insufficiency1 LMWH dose with peak anti-Factor Xa activity monitoring

Obesity1 Adjust doses to actual bodyweight according to

manufacturers recommendations

Pregnancy2 Adjusted-dose LMWH or UFH for 5 days, discontinue at

least 24 hours before elective induction of labour

1. Rondina MT et al. Thromb Res 2007;119:391402; 2. Bates SM et al. Chest 2008;133:844S886S

VTE in other clinical settings
Clinical setting Problem
Recurrent VTE1 VTE recurrence despite appropriate anticoagulant therapy

Heparin resistance1 aPTT testing does not correlate well with clinical efficacy of
UFH doses >35,000 units/day

1. Rondina MT et al. Thromb Res 2007;119:391402

Management of VTE in other clinical settings
Clinical setting Recommendation*
Recurrent VTE1 Either increase intensity of VKA therapy, indefinite LMWH
therapy. Consider vena cava filter (to prevent fatal PE)

Heparin resistance1 Adjust heparin doses according to anti-Factor Xa activity;

if this is not possible, administer LMWH or fondaparinux

*These recommendations are not evidence-based and vary between guidelines (international and national)
1. Rondina MT et al. Thromb Res 2007;119:391402
 Diagnostic investigations

If a patient presents with signs or symptoms of DVT carry out

the following to exclude other causes:
an assessment of their general medical history and
a physical examination

If DVT suspected use the two-level DVT Wells score

(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
Wells score DVT
Factor Points
Active cancer (treatment within last six months or palliative) 1
Calf swelling 3 cm compared to asymptomatic calf (measured 10 1
cm below tibial tuberosity)
Collateral superficial veins (non-varicose) 1
Pitting oedema (confined to symptomatic leg) 1
Swelling of entire leg 1
Localised tenderness along distribution of deep venous system 1

Paralysis, paresis, or recent cast immobilisation of lower extremities 1

Recently bedridden 3 days, or major surgery requiring regional or 1

general anesthetic in the previous 12 weeks
Previously documented deep-vein thrombosis 1
Alternative diagnosis at least as likely as DVT -2
Interpretation: For dichotomised evaluation (likely v unlikely)
score of 2 or higher - DVT is likely
score of less than 2 - DVT is unlikely (2)
(1) Tovey C, Wyatt S. Diagnosis, investigation, and management of deep vein thrombosis. BMJ. 2003;326(7400):1180-4
(2) Scottish Intercollegiate Guidelines Network (SIGN) 2010. Prevention and Management of Venous Thromboembolism
 1) Tovey C, Wyatt S. Diagnosis,
investigation, and management of
deep vein thrombosis. BMJ.
2003;326(7400):1180-4
(2) Scottish Intercollegiate
Guidelines Network (SIGN) 2010.
Prevention and Management of
Venous Thromboembolism
 Wells score = DVT unlikely
Offer a D-dimer test and if the result is positive offer either:
proximal leg vein ultrasound scan (within 4 hours of request) or
if proximal leg vein scan not available within 4 hours, interim 24-
hour dose of a parenteral anticoagulant followed by proximal leg
vein ultrasound within 24 hours of request

(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
 Wells score = DVT likely
Offer
proximal leg vein ultrasound scan (within 4 hours of request), if
negative, a D-dimer test or
if proximal leg vein scan not available within 4 hours, D-dimer test
and an interim 24-hour dose of a parenteral followed by proximal
leg vein ultrasound within 24 hours of request
Repeat proximal leg vein ultrasound scan 68 days later for all patients
with positive D-dimer test and negative proximal leg vein ultrasound
scan

(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
 Diagnose DVT and treat patients with positive proximal leg
vein ultrasound

Take into consideration alternative diagnoses in patients

with:
unlikely two-level DVT Wells score and negative D-dimer test or
positive D-dimer test and negative proximal leg vein ultrasound
scan.
likely two level DVT Wells score and negative proximal leg vein
ultrasound scan and negative D-dimer test or repeat negative
proximal leg vein ultrasound scan.

(http://guidance.nice.org.uk/CG144/EducationResource/DVTTrainingPlan/doc/English)
.
The risk of recurrent VTE
Events occurring subsequent to an acute episode are termed
recurrent VTE, and their prevention is termed secondary prevention
Chance of recurrent VTE in first 3 months

<2% 47%
If adequate anticoagulant response is
achieved1 (2-4% in subsequent 3 months) If proximal DVT inadequately treated1

Overall incidence of recurrent VTE at 6 months is 7%, despite anticoagulant

therapy
After an initial DVT, ~80% of the recurrences are DVTs2
After an initial PE, ~60% of the recurrences are PEs2
If treated with current therapies, most recurrent events can be avoided; however,
when treatment stops, risk continues for recurrent events3
After a course of treatment, patients with unprovoked (idiopathic) VTE or
persistent risk factors (e.g. cancer, prothrombotic biochemical abnormalities) have
the highest risk of recurrent thrombosis2 10% per patient-year
1. Line B. Semin Nucl Med; 2. Kearon C. Circulation 2003; 3. Agnelli G, Becattini C. J Thromb Thrombolysis 2008
Risk factors associated with VTE recurrence

Idiopathic presentation1,2
Thrombophilia1
Presentation of primary DVT1
Increasing age1
Proximal DVT2
Cancer2
Residual thrombus mass3
Male gender4

1. Prandoni P et al. Haematologica 2007; 2. Hansson PO et al. Arch Intern Med 2000;
3. Prandoni P et al. Ann Intern Med 2002; 4. Eichinger S et al. Circulation 2010
 Summary of 2012 ACCP guidelines:
duration of anticoagulant treatment
Condition
First provoked DVT or PE
First unprovoked proximal
DVT or PE with low to
moderate risk for bleeding
First unprovoked proximal
DVT or PE with high risk for
bleeding
First unprovoked proximal
DVT or PE in cancer patients
Second unprovoked
VTE
Choice of agent
Extended therapy
Kearon C et al. Chest 2012
ACCP recommendation Grade of recommendation
Therapy for 3 months 1B
2B (nonsurgical risk factor and
low or moderate bleeding risk)
Extended treatment 2B
Therapy for 3 months 1B
extended therapy 1B
2B (high bleeding risk)
with LMWH over VKA 2B
extended therapy in low to moderate 1B (2B moderate bleeding risk)
bleeding risk
3 months therapy in high bleeding risk 2B
VKA or LMWH over dabigatran or 2B
rivaroxaban
Reassessed at periodic intervals (eg,
annually)
Antithrombotic therapy for VTE disease
In their recent guideline on antithrombotic therapy of VTE disease,
ACCP has considered for the first time treatment with rivaroxaban
The ACCP treatment model is a 3-phase model. The three phases
are initial, long-term and extended treatment

Long-term Extended
Initial (07 days)
(7 days3 months) (3 monthsindefinite)

Abstract statement: For acute DVT or pulmonary embolism (PE),

we recommend initial parenteral anticoagulant therapy (Grade 1B)
or anticoagulation with rivaroxaban.

Kearon et al. Chest 2012

2012 ACCP guidelines: recommended
agents for VTEx

Phases of anticoagulation

Initial Long-term Extended

Recommended anticoagulants
0 to ~7 days

Therapeutic
UFH, LMWH,
Up to 3 months >3 months to indefinite with
fondaparinux or
periodic (eg. annual) risk assessment
rivaroxaban

VKA (INR2.0-3.0) VKA (INR2.0-3.0)

or LMWH, dabigatran or rivaroxaban or LMWH, dabigatran or rivaroxaban

Kearon C et al. Chest 2012

Long-term treatment of DVT and PE
For long-term treatment (7 days3 months) in patients with DVT
without cancer, ACCP suggests to use VKA therapy over LMWH.
For patients with DVT and no cancer who are not treated with
VKA therapy, ACCP suggests LMWH over dabigatran or
rivaroxaban
1. VKA
2. LMWH
3. New OACs

A similar approach is used for patients with DVT and cancer.

LMWH is suggested over VKA therapy. The suggestion for
patients who are not treated with LMWH is a VKA over dabigatran
or rivaroxaban
1. LMWH
2. VKA
3. New OACs
Kearon et al. Chest 2012
Prevention of recurrent VTE
Meta-analysis1 of 8 trials containing 2994 patients with
symptomatic VTE compared different durations of treatment with VKAs
Patients on prolonged treatment had

3-times higher risk of

bleeding complications

>5-times lower risk of

VTE recurrences

For many patients with VTE, secondary prevention with VKAs

is not extended beyond 6 months, as risk of recurrence
may be outweighed by the risk of major bleeding

1. Hutten BA, Prins MH. Cochrane Database Syst Rev 2000

Traditional anticoagulants: drawbacks
UFH1 Oral VKAs2
Parenteral administration Narrow therapeutic window
Monitoring and dose Interaction with food and drugs
adjustment required
Frequent monitoring and
Risk of heparin-induced dose adjustment required
thrombocytopenia (HIT)
LMWH1
Parenteral administration
Weight-adjusted dosing

1. Hirsh J et al. Chest 2008; 2. Ansell J et al. Chest 2008

Problems with VKAs
Narrow therapeutic window Warfarin thrombosis
Warfarin bleeding
Difficult to keep within
therapeutic range
Frequent INR monitoring/dose-
adjustment

Thrombosis
Narrow

Bleeding
therapeutic
Multiple drugdrug and window

fooddrug interactions
Slow onset/offset of action
Increased risk of bleeding
Dose

Ansell J et al. Chest 2004;126:204S233S

Problems with UFH use

Parenteral administration
Injection site reactions (uncommon)
Risk of osteoporosis
Risk of HIT, although relatively rare, may have serious
consequences
Requirement for platelet monitoring
Weight-adjusted dosing and coagulation monitoring

Warkentin TE et al. Chest 2008;133:340S380S

Problems with LMWH use

Subcutaneous injection
Injection site problems
Risk of osteoporosis (although less than with UFH)
A lower risk of HIT compared with UFH
Risk of accumulation with renal impairment

1. Hirsh J et al. Chest 2008;133:141S159S; 2. Warkentin TE et al. Chest 2008;133:340S380S

The promise of new oral anticoagulants
Simplified dosing regimen
No dietary restrictions Reduced potential
Predictable anticoagulation and no need for food and drug
for routine coagulation monitoring interactions
Can be given at fixed doses

Less Less impact on Improved

labour-intensive patients daily life compliance

Reduced Improved Improved

administrative quality of life efficacy
costs and safety
1. Raghaven N et al. Drugs Metab Dispos 2009; 2. Shantsila E, Lip GY. Curr Opin Investig Drugs 2008; 3. Mueck W et al.
Clin Pharmacokinet 2008; 4. Mueck W et al. Thromb Haemost 2008; 5. Mueck W et al. Int J Clin Pharmacol Ther 2007
New drugs in phase III development
directly targeting coagulation factors
TF VIIa

Initiation
X IX

Va
Propagation =
Xa IXa
thrombin-generation
phase
Rivaroxaban II Prothrombin
Prothrombinase
Inactive factor apixaban complex
edoxaban
Active factor and others
Dabigatran Thrombin
Transformation IIa
and others
Catalysis

Clot formation Fibrinogen Fibrin

TF, tissue factor
Adapted from: Kubitza D, Haas S. Expert Opin Investig Drugs 2006
Characteristics of New Oral Anticoagulants
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of Thrombin Factor Xa Factor Xa Factor Xa
action inhibitor inhibitor inhibitor inhibitor
T1/2 14-17 hours 5-9 hours 12 hours 6-12 hours

Regimen BID QD/BID BID QD

Peak to trough ~7 12 (QD) 3-5 ~3

Renal ~80% 36%-45% 25%-30% 35%
excretion of
absorbed drug
Potential for P-glycoprotein CYP3A4 CYP3A4 CYP3A4
drug inhibitor substrate and substrate and substrate
interactions P-glycoprotein P-glycoprotein and P-
inhibitor inhibitor glycoprotein
inhibitor
Single-drug approach vs switching in
treatment of VTE

CURRENT

Current VTE treatment LMWH* s.c.

regimens: 2 anticoagulants VKA

Day 1 Bridging 3 months

FUTURE

EINSTEIN DVT/PE:
rivaroxaban single drug Rivaroxaban 15 mg bid 3 wks, then 20 mg od
Single-drug approach
EINSTEIN DVT:
primary efficacy outcome time to first event
4.0
Cumulative event rate (%)

Enoxaparin/VKA (N=1718)
3.0
Rivaroxaban (N=1731)

2.0

HR=0.68; p<0.001 (non-inferiority)

1.0 RR=32%

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk

Rivaroxaban 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266
Enoxaparin/
1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264
VKA

RR, relative risk

The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN DVT:
primary efficacy outcome by subgroup
Symptomatic recurrent VTE
Rivaroxaban Enoxaparin/VKA HR (95% CI)
n/N (%) n/N (%)
Overall 36/1731 (2.1) 51/1718 (3.0)
Age
<65 years 26/1145 (2.3) 30/1111 (2.7)
6575 years 6/371 (1.6) 11/382 (2.9)
>75 years 4/215 (1.9) 10/225 (4.4)
Weight
70 kg 12/494 (2.4) 21/524 (4.0)
>7090 kg 13/740 (1.8) 19/707 (2.7)
>90 kg 11/491 (2.2) 11/486 (2.3)
Gender
Male 17/993 (1.7) 24/967 (2.5)
Female 19/738 (2.6) 27/751 (3.6)

0.1 1 10

Favours rivaroxaban Favours enoxaparin/VKA

ITT population

The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)

EINSTEIN DVT: principal safety outcome (composite
of major or non-major clinically relevant bleeding)
14 Enoxaparin/VKA (N=1711)
12
Cumulative event rate (%)

10

8 Rivaroxaban (N=1718)
6

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk
Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140
Enoxaparin/
1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118
VKA

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension:
primary efficacy outcome analysis time to first event
13
12
Cumulative event rate (%)

11 Number needed to treat Placebo (N=594)

10 to prevent 1 primary
9
8 efficacy outcome: 15
7 HR=0.18; p<0.001
6 RRR=82%
5
4 Rivaroxaban (N=602)
3
2
1
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)

Number of subjects at risk

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

Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85

RRR, relative risk reduction

The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN Extension: major bleeding
Rivaroxaban Placebo
(N=598) (N=590)
n (%) n (%)
Major bleeding 4 (0.7)* 0 (0)
Bleeding contributing to death 0 (0) 0 (0)
Bleeding in a critical site 0 (0) 0 (0)
Associated with fall in haemoglobin
4 (0.7) 0 (0)
2 g/dl and/or transfusion of 2 units
Gastrointestinal bleeding 3 (0.5) 0 (0)
Menorrhagia 1 (0.2) 0 (0)

Number needed to harm: approximately 139

Safety population; *p=0.11

The EINSTEIN Investigators. N Engl J Med 2010

Thrombolysis

First-line treatment for high-risk PE with haemodynamic

compromise1,2
e.g. recombinant tissue plasminogen activator, streptokinase
and urokinase
Local/catheter-directed thrombolysis can be used to treat
acute extensive DVT in some patients (e.g. iliofemoral
DVT) who have a low risk of bleeding (general/systemic
may only be used when local/catheter-directed
thrombolysis is not available)2
Care should be taken because of increased bleeding risk

1. Torbicki A et al. Eur Heart J 2008;29:22762315; 2. Kearon C et al. Chest 2008;133:454S545S

Compression therapy
Recommended for 2 years in patients with symptomatic proximal
DVT to prevent post-thrombotic syndrome1
Elastic compression stockings reduced the rate of post-thrombotic
syndrome after proximal DVT by ~50% compared with no stockings2

1. Kearon C et al. Chest 2008;133:454S545S; 2. Brandjes DP et al. Lancet 2009;349:759762;

3. Arpaia G et al. J Thromb Thrombolysis 2009;28:389393;
Vena cava filters

Permanent/retrievable inferior vena cava filters are

recommended when anticoagulants are contraindicated
Patients with an inferior vena cava filter as an alternative
to anticoagulant therapy should receive conventional
anticoagulation if their bleeding risk resolves

Kearon C et al. Chest 2008;133:454S545S

Surgical interventions

Thrombectomy can be used for selected patients

(e.g. life expectancy 1 year) with iliofemoral DVT to
alleviate symptoms and lower morbidity associated with
post-thrombotic syndrome

Kearon C et al. Chest 2008;133:454S545S

 Overall 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 a VKA is not extended
beyond 6 months1
Patients with VTE have a major risk of recurrent VTE that may persist for many
years2,3
In patients who had completed 6 or 12 months of anticoagulation, rivaroxaban
showed an 82% relative risk reduction in the recurrence of VTE (HR=0.18;
p<0.001) vs placebo (EINSTEIN EXT)4
Rivaroxaban demonstrated non-inferiority to LMWH/VKA for the treatment of
acute DVT, with a similar safety profile (EINSTEIN DVT)4
New oral anticoagulants may have the potential to improve benefitrisk and
simplify acute VTE treatment and secondary prevention

1. Schulman S. N Engl J Med 2003; 2. Prandoni P et al. Ann Intern Med 1996;
3. Heit JA et al. Arch Intern Med 2000; 4. The EINSTEIN Investigators. N Engl J Med 2010;
5. The EINSTEINPE Investigators. N Engl J Med 2012