Diagnosis and Management of

Venous Thromboembolism

Muhammad Darwin Prenggono

Endocrine update 2015
Banjarmasin
There are two types of blood clot
Thrombosis
Arterial Venous

Platelet-rich clot Fibrin-rich clot

(platelets and coagulation) (coagulation)
 Mechanism of platelet action
TXA2 GPIa-IIa MGDF
PAF ADP
ADP TXA2

Epinefrin
Ribosome
MGDF Aktifasi sintesis 5HT
TXA2
GPIIb-IIIa ADP
aktifasi
Tyrosin kynase COX
P47 P47PO4 5HT
PK-C ATP
Serin/treonin kinase Arachidonat

aktifasi MLC-PO4 DAG PLA2

Ca++ Ca++
MLC-K PL
MLC Ca++
PI(PO4)2 I(PO4)3 myosin
PL-C
dense granule
G protein
MLC = myosin light chain
GPIb-IX Ca++
MLC-K = myosin light chain kinase vWF
Dinding sel
I(PO4)3 = inositol trifosfat
PI(PO4)2 = Fosfatidilinositol bifosfat
P47 = protein sitoplasma adhesi Aktifasi kontraksi myofibril
PK-C = protein kinase C (Tyrosine, serine, treonine)
PLA2 = fosfolipase A2
MGDF= Megakaryocytes Growth Developing thombocytes Factors
Adhesive Protein receptors on Platelet

Receptor Ligand

GPIa-IIa Collagen
GPIb-IX Ristocetin-vWF, and (Direct Platelet associated IgG)
GPIc-IIa Fibrinocetin, Laminin
Ristocetin-vWF, Collagen, Fibrinogen, Fibrinocetin,
GPIIb-IIIa
Vitronectin, Complemen.
GPIIIb Collagen, Trombospondin
ADP ADP
TXA2 Tromboksan A2
Epinefrin Epinefrin

Direct Platelet associated IgG : Sticky platelet syndrome

Agregasi trombosit

ADP PF2, PF3, PF4

granules

Seretonin agregasi
GPIIb-IIIa
cohesi
agregasi
Fibrinogen
TXA2
cohesi

Trombosit Trombosit
Arachidonat

GPIb-IX vWF Direct platelet associated IgG

adhesi
 PROSES HEMOSTASIS
Robekan vaskuler
Gangguan endothel
Hemostasis sekunder Hemostasis primer

Prekalikrein Aktifasi KBMT Kontrol Tissue factor VCAM-1 Reflek

Fletcher Fitzgerald Hemostasis released ECAM vasokonstriksi

Sticky platelet
Kalikrein Jalur Intrinsik Jalur Ekstrinsik collagen
Trombin
t-PA ADP, TXA2
Fibrinogen FPA+FPB released
PAI-1
Aggregasi
Fibrin trombosit
Plasminogen Plasmin FDP X,Y,D,E
polimer
Trombosit plug
Fibrin FDP X,Y,E
semipermiable
Cross link D-Dimer

Recanalisasi endothelial proliferation PD-ECGF, VEGF, bFGF

Coagulation is an important, complex
part of haemostasis
Coagulation is a normal
physiological process:
In response to vascular injury
To prevent haemorrhage
Coagulation is mediated through
both cellular (platelet) and
protein (coagulation factor)
components
A complex cascade of
enzymatic reactions occurs in
the coagulation cascade
Factor Xa and thrombin are
activated coagulation proteins
that play important roles in
the cascade
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
VTE: deep vein thrombosis and
pulmonary embolism

Migration
PE

Embolus

Thrombus

DVT
Classification of PE
The European Society of Cardiology (ESC) guidelines stratify PE
into levels of risk of early death
Defined as 30-day risk of death
PE and risk of early death
High-risk PE (>15% mortality risk)
Intermediate-risk PE (315% mortality risk)
Low-risk PE (<1% mortality risk)
Clinical markers are:
Shock or hypotension
Right ventricular dysfunction
Markers of myocardial injury

Torbicki A et al. Eur Heart J 2008

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
The diagnosis of symptomatic VTE is
often delayed
Patients enrolled in the MASTER registry (N=2,047)
>10 days from onset

25
of symptoms (%)
Diagnosis of VTE

20
15
10
5 23% 16%
0
DVT PE
DVT: multiple signs or symptoms, pain and previous VTE are associated
with earlier diagnosis
PE: only multiple signs or symptoms and transient risk factors are
associated with an earlier diagnosis

Agnelli G et al. Thromb Res 2008; Ageno W et al. Thromb Res 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
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

 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
 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
 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

Acute treatment of DVT and PE
In patients with acute DVT of the leg, LMWH or fondaparinux
together with early initiated VKA is recommended. Although
recommended in the abstract, in this section rivaroxaban is not
mentioned
In patients with acute PE, initial treatment with LMWH,
fondaparinux, i.v. UFH or s.c. UFH is recommended together with
early initiated VKA. Rivaroxaban is not mentioned here either

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

Vitamin K antagonists
Duration of VKA therapy

The optimal treatment duration should be based on the

underlying risk factors of VTE recurrence and the
benefitrisk of long-term anticoagulant therapy

Reduction
of VTE
recurrence Bleeding
Outcomes with prolonged VKA therapy

Prolonged VKA treatment showed consistent reduction in

VTE recurrence compared with shorter treatment
Major bleeding was increased with prolonged VKA
therapy versus shorter treatment

Hutten B, Prins M. Cochrane Database Syst Rev 2006;1:CD001367

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

UFH: dosing strategies

Standard practice
Continuous i.v. infusion (after initial bolus dose) with dose
adjustments based on aPTT results
Subcutaneous administration bid (fixed dose or aPTT dose-
adjusted)

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

Problems with UFH use

Parenteral administration
Injection site reactions (uncommon)
Risk of osteoporosis
Risk of HIT, although relatively rare, may have serious
consequences
Risk of accumulation with renal impairment
Weight-adjusted dosing and coagulation monitoring

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

Fixed-dose subcutaneous UFH compared
with LMWH for the acute treatment of VTE
FIDO: outcomes at 3 months
Recurrent VTE Major bleeding Total mortality
Treatment
n/N (%) n/N (%) n/N (%)

Fixed-dose UFH 13/345 (3.8) 6/348 (1.7) 18/348 (5.2)

Fixed-dose LMWH 12/352 (3.4) 12/352 (3.4) 22/352 (6.3)

Fixed-dose, subcutaneous UFH was as effective and safe as

fixed-dose, subcutaneous LMWH for the acute treatment of VTE

Kearon C et al. JAMA 2006;296:935942

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
 VTE: phases of the disease and treatment with
anticoagulants

Phases of the disease

Acute

Intermediate

Long term

Potential treatment schemes with the novel oral anticoagulants

A Switching

Single drug approach

B

44
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: 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 DVT: conclusions
In patients who had acute symptomatic proximal DVT, without
symptomatic PE, rivaroxaban showed:
Non-inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI 0.441.04;
p<0.001)
Similar findings for principal safety outcome between the two groups
(HR=0.97; 95% CI 0.761.22; p=0.77)
Consistent efficacy and safety results irrespective of age, body weight,
gender, creatinine clearance and cancer
No evidence of liver toxicity
Oral rivaroxaban, 15 mg bid for 3 weeks followed by rivaroxaban
20 mg od, could provide clinicians and patients with a simple,
single-drug approach for the acute treatment of DVT
that potentially improves the benefitrisk profile of anticoagulation

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension: study design
Randomized, double-blind, placebo-controlled, event-driven (n=30),
superiority study

Confirmed
symptomatic Treatment period of 6 or 12 months
DVT or PE
completing Day 1
6 or 12
months of ~53%
rivaroxaban or
VKA in Rivaroxaban 20 mg od

observation
EINSTEIN N=1197

30-day

period
programme
R
Placebo

Confirmed
symptomatic
DVT or PE ~47%
completing
6 or 12 months
of 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

EINSTEIN Extension:
non-major clinically relevant bleeding
Rivaroxaban Placebo
(N=598) (N=590)
n (%) n (%)
Non-major clinically relevant bleeding 32 (5.4)* 7 (1.2)
Urogenital/uterus 12 (2.0) 2 (0.3)
Nasal 8 (1.3) 1 (0.2)
Rectal/anal 7 (1.2) 2 (0.3)
Skin 4 (0.7) 2 (0.3)
Ear 1 (0.2) 0 (0)
Gastrointestinal 1 (0.2) 0 (0)
Related to tooth extraction 1 (0.2) 0 (0)
Safety population; some patients experienced more than one event. *p<0.01

The EINSTEIN Investigators. N Engl J Med 2010;

Buller HR, for the EINSTEIN Investigators. ASH, December 2009
EINSTEIN Extension: liver function
Observation/
Treatment Outcome Rivaroxaban Placebo
frequency

Liver failure/death 0 0

ALT >3 ULN 0 0

+ bilirubin >2 ULN
ALT >3 ULN Continued Improved n=6 n=1
(single
measurement)
ALT >3 ULN Continued Improved n=1 n=1
(3 measurements) Hepatic steatosis, Allopurinol/
8-year history of ALT statins/multiple drugs
ALT >3 ULN Discontinued Improved n=3 n=1
(single 1 liver haemangioma/ Unexplained
measurement) hepatic steatosis
2 unexplained
ALT >8 ULN Discontinued Improved n=1 0
(2 measurements) Alcohol abuse/allopurinol/
hepatitis A
Safety population
The EINSTEIN Investigators. N Engl J Med 2010; Buller HR, for the EINSTEIN
Investigators. ASH, December 2009
EINSTEIN Extension: conclusions
In patients who had completed 6 or 12 months of anticoagulation,
rivaroxaban showed:
An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001)
Absolute risk reduction 5.8%; hence 15 patients need to be treated to
prevent one recurrent venous thromboembolic event
Low incidence of major bleeding (0.7%; p=0.11;
NNH approximately 139)
Efficacy and safety results were consistent irrespective of bodyweight
and creatinine clearance
Modest increase in non-major clinically relevant bleeding
(5.4% versus 1.2%; p<0.01)
No signal for liver toxicity
Oral rivaroxaban 20 mg od could provide clinicians and patients with
a simple and effective option for continued anticoagulant treatment
The EINSTEIN Investigators. N Engl J Med 2010
 VTE treatment comparison:
pivotal phase III clinical trials
EINSTEIN EXT 1 EINSTEIN DVT1 EINSTEIN PE2 RE-COVER3 RE-COVER II* RE-MEDY**
NCT 00439725 NCT 00440193 NCT 00439777 NCT00291330 NCT00680186 NCT00329238

Study drug Rivaroxaban Rivaroxaban Rivaroxaban Dabigatran Dabigatran Dabigatran

Indication Long-term Acute treatment of Acute treatment of Acute treatment Acute treatment of Long-term
prevention of DVT (including initial PE (including of VTE (after VTE (after parenteral treatment and
recurrent phase) initial phase) parenteral treatment in initial secondary
symptomatic VTE treatment in phase) prevention of VTE
(after treatment of initial phase) (in patients who
index event) had been treated
for 36 months)
Design Double-blind, Open-label, Open-label, Double-blind Double-blind Double-blind
placebo-controlled assessor-blind assessor-blind

Superiority Non-inferiority Non-inferiority Non-inferiority Non-inferiority Non-inferiority

Dosing and 20 mg od for 6 to 15 mg bid for 15 mg bid for 150 mg bid for 150 mg bid for 150 mg bid for
duration 12 months 3 weeks followed by 3 weeks followed 6 months 6 months 18 months
20 mg od for 3, 6 or by 20 mg od for 3,
12 months 6 or 12 months

Control: dosing Placebo 612 Enoxaparin 1 mg/kg Enoxaparin 1 Enoxaparin/UFH Enoxaparin/UFH (5 Warfarin
and duration months bid for at least 5 mg/kg bid for at (mean 10 days), 10 days), followed by (INR 23) for
days plus VKA (INR least 5 days plus followed by dabigatran vs VKA 18 months
23) for 3, 6 or 12 VKA (INR 23) for dabigatran vs for 6 months
months 3, 6 or 12 months VKA for 6
months

1. The EINSTEIN Investigators. N Engl J Med 2010; 2. The EINSTEINPE Investigators. N Engl J Med 2012; 3. Schulmann S, Kearon C, Kakkar AK et al. N Engl J Med 2009;
*Schulman S, Kakkar AK, Schellong SM, et al. ASH Annual Meeting Abstracts. Blood 2011; **Schulmann S, Kearon C, Kakkar AK for the RE-MEDY and the RE-SONATE Trials Investigators.
N Engl J Med 2013
.
 VTE treatment comparison:
pivotal phase III clinical trials
EINSTEIN EXT 1 EINSTEIN DVT1 EINSTEIN PE2 RE-COVER3 RE-COVER II* RE-MEDY**
NCT 00439725 NCT 00440193 NCT 00439777 NCT00291330 NCT00680186 NCT00329238

Study drug Rivaroxaban Rivaroxaban Rivaroxaban Dabigatran Dabigatran Dabigatran

Status Completed and Completed and Completed and Completed and Completed and Completed and
presented at ASH presented at ESC presented at ACC presented at ASH presented at ASH presented at
2009; published Dec 2010; published Dec 2012; published Mar 2009; published 2011 ISTH 2011;
2010 2010 2012 Dec 2009 published Feb
2013
Number of 1197 3449 4832 2539 2589 2867
patients
Primary efficacy Symptomatic Symptomatic recurrent Symptomatic Recurrent Recurrent Double-blind,
variable recurrent VTE: VTE: composite of recurrent VTE: symptomatic symptomatic non-inferiority
composite of DVT, DVT, non-fatal PE or composite of DVT, objectively objectively
non-fatal PE or fatal fatal PE non-fatal PE or fatal confirmed VTE confirmed VTE and
PE PE and related deaths related deaths

Primary efficacy 1.3% rivaroxaban 2.1% rivaroxaban 2.1% rivaroxaban 2.4% dabigatran 2.4% dabigatran 1.8% dabigatran
results 7.1% placebo 3.0% LMWH/VKAs 1.8% LMWH/VKAs 2.1% warfarin 2.2% warfarin 1.3% warfarin
RRR 82% Non-inferiority reached Non-inferiority Non-inferiority Non-inferiority Non-inferiority
Superiority reached reached reached reached reached

Primary safety Major bleeding Composite of major Composite of major Bleeding events Bleeding events Major bleeding
0.7% rivaroxaban and clinically relevant and clinically relevant and other and other 0.9% dabigatran
non-major bleeding non-major bleeding Major bleeding: Major bleeding:
0% placebo 1.8% warfarin
8.1% rivaroxaban 10.3% rivaroxaban 1.6% dabigatran 1.2% dabigatran
8.1% LMWH/VKAs 11.4% LMWH/VKAs 1.9% warfarin 1.8% warfarin
1. The EINSTEIN Investigators. N Engl J Med 2010; 2. The EINSTEINPE Investigators. N Engl J Med 2012 3. Schulmann S, Kearon C, Kakkar AK et al. N Engl J Med 2009;
*Schulman S, Kakkar AK, Schellong SM, et al. ASH Annual Meeting Abstracts. Blood 2011; **Schulmann S, Kearon C, Kakkar AK et al. for the RE-MEDY and the RE-SONATE Trials
VTE treatment comparison: completed and
ongoing pivotal phase III clinical trials*
RE-SONATE** AMPLIFY* AMPLIFY EXT1 Hokusai-VTE Study*
NCT 00558259 NCT 00643201 NCT 00633893 NCT00986154

Study drug Dabigatran Apixaban Apixaban Edoxaban

Indication Long-term prevention of recurrent Acute treatment of Prevention of recurrent Treatment of DVT and/or
symptomatic VTE (after 6-18 symptomatic DVT and PE VTE and death (after PE
months treatment with VKA) (including initial phase) completion of their
intended treatment for
DVT or PE)

Design Double-blind, placebo-controlled Double-blind, active- Double-blind, placebo- Double-blind warfarin vs

ontrolled controlled edoxaban

Superiority Non-inferiority Superiority Parallel group

Dosing and 150 mg bid for 6 months 10 mg bid for 7 days 2.5 or 5 mg bid for 60 mg od for 12 months
duration followed by 5 mg bid for 12 months
6 months

Control: dosing Placebo for 6 months Enoxaparin plus VKA Placebo for 12 months Enoxaparin/UFH
and duration (INR 23) for 6 months (512 days) followed by
VKA or edoxaban for
12 months

*www.clinicaltrials.gov
1. Agnelli G, Buller HR, Cohen A et al. N Engl J Med 2013; 368:699-708
**Schulman S, Kearon C, Kakkar AK et al. for the RE-MEDY and the RE-SONATE Trials Investigators. N Engl J Med 2013
VTE treatment comparison: completed and
ongoing pivotal phase III clinical trials*
RE-SONATE** AMPLIFY* AMPLIFY EXT1 Hokusai Study*
NCT 00558259 NCT 00643201 NCT 00633893 NCT00986154

Study drug Dabigatran Apixaban Apixaban Edoxaban

Status Completed and presented at Ongoing Completed and published Ongoing
ISTH 2011; published Feb Feb 2013
2013

Number of 1353 patients Estimated: 4816 patients 2486 patients Estimated: 7500 patients
patients

Primary efficacy Symptomatic recurrent VTE, Venous thromboembolic Symptomatic recurrent Symptomatic recurrent
variable non-fatal or fatal PE recurrence or death within VTE or death from any VTE, non-fatal or fatal PE
treatment period cause

Primary efficacy 0.4% dabigatran Not yet reported 1.7% apixaban 2.5 mg bid Not yet reported
results 5.6% placebo 1.7% apixaban 5 mg bid
p<0.0001 8.8% placebo
Superiority reached p<0.001 for both
Superiority reached
Primary safety Clinically relevant bleeding Bleeding upon occurrence Major Bleeding Major and clinically
results 5.3% dabigatran during study treatment 0.2% apixaban 2.5 mg bid relevant non-major
bleeding occurring during
0.8% placebo 0.1% apixaban 5 mg bid treatment
p=0.001 0.5% placebo
*www.clinicaltrials.gov
1. Agnelli G, Buller HR, Cohen A et al. N Engl J Med 2013; 368:699-708
**Schulman S, Kearon C, Kakkar AK et al. for the RE-MEDY and the RE-SONATE Trials Investigators. N Engl J Med 2013
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