Dept.

of Cardiology and Vascular Medicine

Universitas Indonesia
National Cardiovascular Center Harapan Kita
Case
• A woman, 63 yo admitted to NCCHK for dyspnea
and hemodynamic decompensation
• DVT at left ilio-femoro-popliteal and right femoro-
popliteal vein
Question
• Risk stratification?
• Initial therapy?
• What is the recommendation for
thrombolytic therapy?
• Choice of anticoagulant therapy ?
• How long is enough for anticoagulant
therapy?
 ♦ VTE refers to a continuum of
disease that begins with DVT and can
progress to PE1
Migration
♦ DVT is a condition in which a
thrombus typically forms in
Embolus one or more of the deep veins
of the calf or thigh1

♦ PE occurs when all or part of a

thrombus originating in the
Thrombus
deep veins detaches from the
vessel wall and travels in the
venous system as an embolus,
ultimately obstructing
pulmonary arteries1

Kroegel C, et al. Principle mechanisms underlying venous thromboembolism: Epidemiology,

Risk factor, pathophysiology and pathogenesis. Respiration. 2003.70:7-30.
Deep Vein Thrombosis and
Pulmonary Embolism
Trends in VTE: Prevalence to Double by 2050 

Deitelzweig SB, et al. American J Hematology. 2011 86:217-220.

 Pathogenesis :
Virchow’s triad
® Malignancy
® Pregnancy and
peripartum period ® Venous disorders

® Oestrogen therapy ® Venous valvular

damage
® Inflammatory bowel
disease ® Trauma or surgery

® Sepsis ® Indwelling
catheters
® Thrombophilia

® 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
Process for management of acute VTE
 Diagnostic Approach and
Treatment

Mazzolai, et al. European Heart Journal (2017) 0, 1–13

DVT treatment:
The initial treatment objective:

ü To prevent thrombus extention.

ü To prevent PE.
ü To prevent early & late recurrence of VTE.
ü To prevent or minimize the risk of the post
thrombotic syndrome (PTS).
The long-term treatment objective:

ü To complete of the acute episode of VTE.

ü To prevent of new episode VTE.

Kearon C, et al. Chest 2012; 133:454s-545s.

 PE: Risk-Adjusted Management in the Acute Phase and Over the
Long Term

Konstantinides, et al. 2014 ESC Guidelines on the diagnosis and

management of acute pulmonary embolism
 Anticoagulant therapy remains the mainstay of VTE treatment

The management of venous thromboembolism: A practical tool for the front-line clinician
Tammy J, et al. CPJ/RPC. 2017
 Parenteral Anticoagulants Used for PE

Konstantinides, et al. 2014 ESC Guidelines on the diagnosis and management of acute
pulmonary embolism
Anticoagulant therapy remains the mainstay of
DVT treatment

Streiff et al. J Thromb Thrombolysis (2016) 41:32–67

NOAC Used for VTE

ESC Guidelines 2014

Use of thrombolytic therapy for the
treatment of venous thromboembolism

The goals of thrombolytic therapy are to reduce

thrombus burden
üFor massive and submassive PE, to reduce
mortality and recurrent PE, relieve symptoms,
prevent CTEPH preserve functional capacity, and
improve quality of life; and
üFor acute iliofemoral DVT, to relieve symptoms,
prevent PTS, improve quality of life, and in selected
patients save life, limb, or organ.

Vedantham S, et al. Guidance for the use of thrombolytic therapy for the treatment
of venous thromboembolism. J Thromb Thrombolysis (2016) 41:68–80
Recommendation ACCP VTE 2016: PE
In patients with acute PE associated with hypotension and who have (i)
high bleeding risk, (ii) failed thrombolysis, or (iii) shock that is likely to
cause death before systemic thrombolysis can take effect (eg, within
hours), if appropriate expertise and resources are available, we suggest
catheter-assisted thrombus removal over no such intervention (Grade
2C).

In patients with acute PE who are treated with a thrombolytic agent, we

suggest systemic thrombolytic therapy using a peripheral vein over
catheter directed thrombolysis (CDT) (Grade 2C).

VTE: 2016 ACCP Update with Best Evidence and Best Practices
Konstantinides, et al. 2014 ESC
Guidelines on the diagnosis and
management of acute pulmonary
embolism
Recommendation of thrombolytic in acute
DVT

• Careful risk stratification is important to ensure that

only those patients who are most likely to benefit and
least likely to be harmed are treated.
ØProjected risk of bleeding
Systemic thrombolysis is not suggested for DVT therapy  CDT
ØClinical severity of DVT
preferrable
Urgent thrombolysis is indicated to prevent life-, limb-,
or organ-threatening complications of acute DVT in
situations such as phlegmasia cerulea dolens or
extensive IVC thrombosis
ØAnatomic extent of DVT: acute ilio-femoral
ØLife-expectancy baseline ambulatory capacity, and co-
morbidities.
Vedantham S, et al. Guidance for the use of thrombolytic therapy for the treatment
of venous thromboembolism. J Thromb Thrombolysis (2016) 41:68–80
Risk stratification
for patients with
acute lower
extremity proximal
DVT

Vedantham S, et al. Guidance for the use

of thrombolytic therapy for the treatment
of venous thromboembolism. J Thromb
Thrombolysis (2016) 41:68–80
The management of venous thromboembolism: A practical tool for the front-line clinician
Tammy J, et al. CPJ/RPC. 2017
Extend in high risk patients
Anticoagulation after acute PE
Duration, agents & dose
Duration of anticoagulation therapy
Risk of recurrence

Kearon, et al. Chest 2016

FONDAPARINUX FOR TREATMENT OF VTE
Fondaparinux treatment of DVT-
MATISSE DVT

Background

Current standard initial therapy

in DVT is body weight adjusted
LMWH s.c.

Objective
To evaluate whether
fondaparinux has efficacy
and safety similar to those
of enoxaparin in patients
with deep venous
thrombosis.

Ann Intern Med. 2004;140:867-873.

 Study Design
MATISSE DVT

 5 days Fondaparinux* 7.5 mg once-daily + VKA (INR 2-3)

patients with
DVT (N=2.205)
from 154 5 mg if body weight < 50 kg
centres of 23 R 10 mg if body weight > 100 kg
countries Double-blind

 5 days SC enoxaparin (1 mg/kg, bid) + VKA (INR 2-3)

90 ± 7 Days

Primary Efficacy Outcome (3 months) Principal Safety Outcome (initial

•Recurrent symptomatic non-fatal PE or treatment)
DVT • Major bleed
•Fatal PE / unexplained death • Clinically relevant non-major bleed
 The MATISSE- DVT
Treatment VTE ( DVT & PE )

Once-daily FONDAPARINUX ... With similar incidence of

was as effective as twice-daily major bleeding
enoxaparin for the treatment of DVT
Ann Intern Med. 2004;140:867-873.
Fondaparinux treatment of Pulmonary
Embolism – MATISSE PE

Background
The standard initial treatment of hemodynamically stable patients with
pulmonary embolism is I.V. UFH, requiring laboratory monitoring and
hospitalization

Objective
To compare the efficacy and safety of the synthetic antithrombotic agent
Fondaparinux with those of UFH

N Engl J Med 2003;349:1695-702.

 Study Design
MATISSE PE

 5 days Fondaparinux* 7.5 mg once-daily + VKA (INR 2-3)

patients with
PE + DVT
(N=2.213) R Open-Label
From 214
centres of 20
countries  5 days IV UFH (aPTT 1.5-2.5) + VKA (INR 2-3)

* 5 mg if body weight < 50 kg

90 ± 7 Days
10 mg if body weight > 100 kg

Primary Efficacy Outcome (3 months) Principal Safety Outcome (initial treatment)

•Recurrent symptomatic non-fatal PE or DVT • Major bleed
•Fatal PE / unexplained death • Clinically relevant non-major bleed
 The MATISSE- PE

Once-daily FONDAPARINUX With similar incidence of major

was as effective as a bolus plus bleeding
continuous infusion of UFH in the
treatment of PE
FONDAPARINUX FOR PREVENTION OF VTE
 ARixtra for ThromboEmbolism prevention in a
Medical Indications Study (ARTEMIS)

Objective:
vTo determine the efficacy and safety of the anticoagulant
fondaparinux in older acute medical inpatients at
moderate to high risk of venous thromboembolism

Method:
vARTEMIS, a randomized, double-blind, placebo-
controlled study, was carried out at 35 centers in 8
countries (Australia, Canada, Denmark, France, The
Netherlands, Poland, the United Kingdom, and the United
States) on 849 patients aged ≥ 60 years.
vAbout 36% of patients had been hospitalized with
congestive heart failure (NYHA class III/IV), 44% had
acute respiratory disease, and 50% had acute infection
or inflammatory disease.
vAll patients required ≥ 4 days of bed rest
 Study Design

n = 425
n=849 Fondaparinux 2.5 mg, SC, Once-daily
from 35 R
centers of 8 Double-blind randomized placebo controlled trial
countries
Placebo
n = 414
*

6 - 14 Days

Primary Efficacy outcome was venous

thromboembolism detected by routine Secondary outcomes were
bilateral venography along with bleeding and death. Patient
symptomatic venous thromboembolism were followed up at one month
up to day 15
Result

46.7%
58.1%
RRR* n=8
49
P=0.02
9

2.5 mg/day
2.5 mg/day n=420 n=429
n=323**
n=321**

Adapted from Cohen AT et al. The ARTEMIS™ investigator. Efficacy and safety of
fondaparinux for the prevention of venous thromboembolism in older acute medical
Use of Compression Stockings to Prevent Post-
Thrombotic Syndrome 

• Since the 2012 update, a larger multicenter,

placebo-controlled trial found that routine use of
compression stockings did not reduce the incidence
of PTS or have other important benefits
• This study also found that the use of compression
stockings did not reduce leg pain 3 months after
DVT diagnosis

Kahn et al. Lancet. 2014;383(9920):880-888.

 Conclusions
• VTE cause significant morbidity and mortality, especially in
hospitalized patient
• It is actually preventable, detectable and curable
• Anticoagulant therapy remains the mainstay of VTE treatment
• Thrombolytic therapy can be chosen in selective patients of VTE
• Fondaparinux is at least as effective and equally safe as UFH for the
initial treatment of PE
• The fondaparinux regimen is a once daily s.c. injection without body
weight adaptation and offers an uniform approach for both DVT and PE
patients
Thank You
Inpatient Prophylactic Anticoagulation

• Patients with critically ill, cancer and reduced

mobility, suggest using an anticoagulant
rather than mechanical prophylaxis or no
anticoagulation
• Studies have uniformly found a benefit from
LMWH or Fondaparinux in VTE prevention
for patients at high VTE risk
• Hospitalized cancer patients without
immobility may also benefit from
pharmacologic thromboprophylaxis based on
their increased VTE risk due to malignancy
alone.

Kenneth AB, Uptodate 2017

Outpatient Prophylactic Anticoagulation

• For most ambulatory outpatients with cancer,

suggest that routine anticoagulation not be used.
• Prophylactic anticoagulation may be appropriate
in condition with :
• Multiple myeloma – treated with thalidomide or
lenalidomide-containing regimens
• High Khorana score – Prophylactic
anticoagulation could be considered for selected
higher-risk ambulatory patients (eg, those with a
Khorana score ≥3).
• History of unprovoked VTE –with a prior history
of unprovoked VTE unrelated to their tumor who
are not already on chronic anticoagulation.
Kenneth AB, Uptodate 2017
Properties of an ideal anticoagulant

Oral Food/Drug Predictable No routine Fixed No risk of

interactions response monitoring dosing HIT
Ideal ü ü ü ü ü ü
LMWH ü ü ü ü
UFH ü
Fondaparinux ü ü ü ü ü
VKAs ü ü

Rivaroxaban ü ü ü ü ü ü
Dabigatran ü ü ü ü ü ü
Apixaban ü ü ü ü ü ü

Eerenberg ES et al. Circulation. 2011;124:1573-1579.