DIAGNOSIS AND TREATMENT

VENOUS THROMBOEMBOLISM

C. Suharti
Division of Hematology-Medical
Oncology,
Diponegoro University, Semarang
 Venous thromboembolism
(VTE): definition

DVT: thrombus forms in a vein (deep

veins legs/pelvis)

PE: Thrombus can breaks off - travels

through the circulatory embolism -lodges
in the a. pulmonary

VTE: DVT+ PE a leading cause of

morbidity and mortality)
 Epidemiology of VTE

Incidence in 70-110/100.000
population person/year
Age:
25-35 years old 30 /100.000 person
70-79 years old 300-500 /100.000 person
Relative Absent autopsy: 66% vs
incidence 33%
DVT vs PE With autopsy: 45% vs 55%
Risk factors 25%-50% idiopathic
15-25% cancer
20% surgery (3 months)
White RH. Circulation 2003
 VTE: an increasing problem
Europe : >500,000 deaths
every year1

US: 300,000
VTE-related
deaths
eachyear2

WORLDWIDE: 3 million deaths a year

1. Cohen AT et al. Thromb Haemost 2007; 2. Heit JA et al. Blood 2005
 Virchows triad revisited

Malignancy Venous disorders

Pregnancy and Venous valvular
peripartum period damage
Oestrogen therapy Trauma or
Inflammatory bowel surgery
disease Indwelling
Hypercoagu Endothelial
Sepsis catheters
Injury
Thrombophilia lable State

Circulatory
Stasis
Left ventricular dysfunction
Immobility or paralysis
udolf Virchow 1856
ied of PE after leg fracture
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
RISK FACTORS
 Predisposing Factors
for VTE

Strong Risk Factors (Odds ratio >10)

Fracture of lower Major trauma
limb
Hospitalization for Myocardial
heart failure/AF/ infarction (within
flutter (within previous 3 previous 3 months)
months)
Hip or knee Previous VTE
replacement
Spinal
European cord injury
Heart Journal
doi:10.1093/eurheartj/ehu283
 Predisposing Factors
for VTE
Moderate risk factors (odds ratio 2-9)
Arthroscopic knee surgery
Auto-immune disease
Blood transfusion (NEW)
Erythropoiesis stimulating
agents (NEW)
Chemotherapy
Congestive heart or
respiratory failure
Central venous lines
Hormone replacement
therapy (depends on
formulation)
In vitro fertilization (NEW)
Infection (specifically
pneumonia, UTI, HIV)
Inflammatory bowel disease
Cancer (higher risk in
metastatic disease)
Oral contraceptive therapy
Paralytic stroke
Postpartum period
Superfiscial vein thrombosis
Thrombophilia
 Predisposing Factors
for VTE

Weak risk factors (odds ratio <2)

Diabetes Mellitus
Bed rest > 3days
Hypertension
Immobility due to sitting (prolonged car or
air travel)
Increasing age
Laparoscope surgery (e.g. cholecystectomy)
Obesity
Pregnancy
Varicose veins
European Heart Journal
STRATEGY DIAGNOSIS FOR
DVT
 Signs and Symptoms of DVT:
unreliable

Swelling
Unilateral leg pain
Pitting oedema
Tenderness
Increased
temperature
Prominent superficial
veins
Only 15-20% DVT
 Alternative diagnosis for
DVT
superficial phlebitis external venous
obstruction (e.g., due
to tumor)
postphlebitic syndrome lymphangitis or
lymphedema
cellulitis popliteal (Bakers) cyst
muscle strain or tear hematoma
leg swelling in pseudoaneurysm
paralyzed limb
venous insufficiency knee abnormality.
edema due to systemic
cause: CHF or cirrhosis
 Pre-test Probability DVT (Wells
score)
Active cancer (treatment ongoing or within previous 6 +1
months or palliative)
Paralysis, paresis or recent leg plaster +1
Bedridden > 3 d or major surgery within 12 weeks +1
Tenderness (localized) along the deep venous system +1
Entire leg swollen +1
Calf swelling >3 cm than the asymptomatic leg +1
(measured 10 cm below tibial tuberosity
Pitting edema (symptomatic leg) +1
Collateral superficial veins (non-varicose) +1
Previous documented DVT +1
Alternative diagnosis more likely -2
DVT likely: 2
DVT unlikely: 1
VTE Diagnosis & Treatment Guideline Group Health.2010. ANTITHROMBOTIC THERAPY AND PREVENTION OF
THROMBOSIS, 9TH ED: ACCP GUIDELINE. Venous thromboembolic diseases: the management of venous
thromboembolic diseases and the role of thrombophilia test. NICE clinical guideline 2012.
 Tests for confirmation

CUS (compression
Ultrasonography)
D-dimer
Venography
COMPRESSION
ULTRASONOGRAPHY

NON INVASIVE

HIGHLYPOSITIVE
IN PROXYMAL
DVT

LESSACCURATE
FOR ISOLATED
CALF DVT AND
PELVIS
 Clinical probability

DVT unlikely: Wells DVT likely: Wells score

score 1 2

D-dimer CUS

Negative Positive Negative Positive

(No DVT) CUS D-Dimer (DVT)

Negative Positive Negative Positive

(No DVT) DVT (No DVT) Repeat CUS

Diagnostic strategy for DVT

STRATEGY DIAGNOSIS FOR
PE
 Clinical Features OF PE:
unreliable
Dyspnoe
Chest pain
Collapse
Hypotension
Hemoptysis
Tachypnoea
Tachycardia
Raised jugular venous pressure
Hypoxia/Cyanosis
Focal signs in chest
 Pre-test Probability PE (Wells
score)
Clinical Feature Points

Previous PE or DVT +1.5

Heart rate > 100 beats per minute +1.5
Surgery or immobilisation 3 days in the previous 4 +1.5
week
Clinical signs of DVT +3
PE is as likely or more likely than alternative diagnosis * +3
Hemoptysis +1
Cancer (on treatment, treated in the last 6 months, or +1
palliative)

PE likely >4
PE unlikey 4
*e.g., myocardial infarction, pericarditis, pneumonia, pneumothorax, chest wall pain, congestive heart failure,
pleuritis, pericardial tamponade)

E Diagnosis & Treatment Guideline Group Health.2010. ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS,
H ED: ACCP GUIDELINE Venous thromboembolic diseases: the management of venous thromboembolic diseases and the
rombophilia test. NICE clinical guideline 2012.
Likely >4 Unlikely:4
sPESI: Simplified Pulmonary Embolism
Severity Index
Parameter Simplified
version
Patient related
Age (if age >80 years) 1 point
Cancer 1 point
Chronic pulmonary disease 1 point
PE related
Pulse rate 110bpm 1 point
Systolic blood pressure <100mmHg 1 point
Arterial oxyhemoglobin saturation <90% 1 point
0 points: 1 point(s):
30 d mortality risk 30 d mortality risk
1.0% 10.9%
(95% CI 0.0%-2.1%) (95% CI 9.5%-13.2%)
 Biochemical markers

Non high-risk PE patients

(cardiovascularly stable) should be
assessed for markers of myocardial injury:
o BNP
o Troponin
o Right ventricular dysfunction

BNP, brain natriuretic peptide

TREATMENT OF
VTE
 Treatment of DVT

The goals of DVT treatment:

o Prevent increasing size of clot
o Reduce risk of PE
o Prevent recurring of DVT
o Relieve symptoms
 Initial Treatment
of DVT
Heparin
o Unfractionated Heparin
o Low Molecular Weight Heparin
o Fondaparinux
along with vitamin K antagonist
(Warfarin)
Novel Oral Anticoagulant
o Rivaroxaban, Dabigatran, Apixaban
 VTE: phases of the disease and
conventional treatment with anticoagulants

Acute Intermediate Long-term

UFH, VKA INR
VKA INR
LMWH, 2.0-3.0 >3
2.0-3.0, at
Fondaparin months,
least 3
ux)+ VKA at years,
months
least 5 d indefinite

*With re-assessment of the individual benefitrisk at periodic intervals; INR, international normalized ratio;
LMWH, low molecular weight heparin; UFH, unfractionated heparin; VKA vitamin K antagonist
Kearon C, et al. Chest 2008;133;454545; Schellong S, Bounameaux H, Bller HR. ESC Textbook of Cardiovascular
Medicine 2nd Edition 2009; Chapter 37 pp 13481349
Single-Drug Approach

Rivaroxaban 15 mg bid x
3 weeks then 20mg od
 NOACs treatment DVT and/or
haemodynamically stable PE
Rivaroxaban Dabigatran Apixaban
15mg bid 3 weeks 150mg bid 10mg bid 7d, then
then following parenteral 5mg bid (until 6
20mg od initial therapy 5d months)
2.5mg bid,
>6months

Factor Xa direct Thrombin direct Factor Xa direct

EINSTEIN DVT RE-COVER AMPLIFY

EINSTEIN PE RE-COVER II AMPLIFY-EXT
EINSTEIN EXT RE-MEDY
RE-SONATE
 EINSTEIN DVT: primary efficacy
outcome analysis
Rivaroxaban Enoxaparin/VKA
(N=1731) (N=1718)
n (%) n (%)
First symptomatic recurrent VTE 36 (2.1) 51 (3.0)
Recurrent DVT 14 (0.8) 28 (1.6)
Recurrent DVT + PE 1 (<0.1) 0 (0.0)
Non-fatal PE 20 (1.2) 18 (1.0)
Fatal PE/unexplained death where
4 (0.2) 6 (0.3)
PE cannot be ruled out
0.44 0.68 1.04

0 1.00 2.00
HR
Rivaroxaban Rivaroxaban Rivaroxaban
superior non-inferior inferior
p=0.08 for superiority (two-sided) p<0.001 for non-inferiority
(one-sided)
CI, confidence interval; HR, hazard ratio
ITT population The EINSTEIN Investigators. N Engl J Med 2010
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 analysis
Rivaroxaban Enoxaparin/VKA
HR (95% CI)
(N=1718) (N=1711)

n (%) n (%) p-value

First major or non-major clinically 0.97 (0.761.22)

139 (8.1) 138 (8.1)
relevant bleeding p=0.77
0.65 (0.331.30)
Major bleeding 14 (0.8) 20 (1.2)
p=0.21

Contributing to death 1 (<0.1) 5 (0.3)

In a critical site 3 (0.2) 3 (0.2)

Associated with fall in haemoglobin

2 g/dl and/or transfusion of 2 10 (0.6) 12 (0.7)
units

Non-major clinically relevant bleeding 126 (7.3) 119 (7.0)

Patients could have one or more bleeding events

Safety population
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
12 (N=1711)
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

 Duration of anticoagulant
treatment

2012 ACCP Guidelines:

o 3 months
o Extended : 6 months - 12 months -
indefinite
o Provoked Unprovoked - Cancer
o Risk of bleeding: low moderate
high
 Patient admitted to Hospital:

Assess
Assess bleeding
VTE risk, RFT,
LFT

nce risk of VTE and Bleeding Care path

 Long-term Complications
of DVT

o Recurrent VTE
o Post-thrombotic syndrome
o Chronic thromboembolic pulmonary
hypertension

Compression stockings (30-

40 mm Hg knee high), 2
years PTS 50% (2B)

Prandoni P, et al. Haematological 2007;92(02):199-205.

Mayo Clin Proc. March 2014.89(3):394-408.
http://dx.doi.org/10.1016/j.mayocp.2013.11.015
 Role of Inferior Vena Cava
Filters
Indications:
o Acute proximal lower extremeties DVT or PE who
have CI to anticoagulation (IB).
Preference a temporary IVC that can be removed
when the bleeding risk has resolved.

inferior filter vena cava

o Clin Proc. March 2014.89(3):394-408. http://dx.doi.org/10.1016/j.mayocp.2013.11.015

 Point of Messages
Clinical features unreliable; DD: many
Pre-test Probability (Wells score)
Confirmative tests: CUS, D-Dimer, Venography

Conventional: Vit K antagonist LMWH

NOACs: Rivaroxaban, Apixaban, Dabigatran

Rivaroxaban po 15mg bd 3 weeks followed 20mg od

Simple for acute and continued treatment
THANK YOU
EINSTEIN DVT: conclusions

Acute symptomatic proximal DVT (no

symptomatic PE):
Rivaroxaban po 15 mg bid for 3 weeks,
followed by rivaroxaban 20 mg od

Simple and single-drug approach

Acute and continued treatment
benefitrisk profile of anticoagulation