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An Update on Management of Venous

Thromboembolism & Chronic Venous Diseases

Suci Indriyani
Dept. of Cardiology and Vascular MedicineUniv. of Indonesia /
Harapan Kita National Cardiovascular Center
Venous Thromboembolism :
Definition

a term used to
include the
formation of
thrombus in a vein
which may dislodge
from its site of origin
to travel in the blood,
a phenomenon
called embolism.

NICE Guidelines 2010


♦ VTE refers to a continuum of disease that begins
with DVT and can progress to PE1
Migration
♦ DVT is a condition in which a
Embolus thrombus typically forms in one or
more of the deep veins of the calf or
thigh1

♦ PE occurs when all or part of a


thrombus originating in the deep
veins detaches from the vessel wall
and travels in the venous system as
Thrombus 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
Epidemiology

a major health care problem resulting in


significant mortality and morbidity.

The vast majority of these deaths occur in


untreated patients, where the diagnosis is
made post-mortem or undiagnosed

Cancer : 8 – 19 %
Non Cancer : 1,4 %

Heit JA. Atherioscler Thromb Vasc Biol.2008


Trendstoindouble
Prevalence VTE:by 2050

Projected VTE Rates (2006-2050)1


2.0
1.8
1.6
1.4
1.2
Adults with VTE
(millions)

1.0
0.8
0.6
0.4 P < 0.001
Total Males Females
0.2
0.0
'06 '08 '10 '15 '20 '25 '30 '35 '40 '45 '50

Deitelzweig SB, et al. AJH. 2011 86:217-220.


PE kills many people each year

Annual Deaths in the United States


– Up to 300,000 people a year 350,000 300,000
die from PE in the US 300,000
– It is the third most common 250,000
200,000
cardiovascular illness
150,000
– Direct annual payer cost in 100,000
40,500 34,500
the US have been estimated 50,000 9,600
at 1.5 billion 0
– No 1 cause of In Hospital Breast AIDS* Car PE**
Cancer* Accidents*
death that is actually
* CDC 2008
preventable ** Consensus Estimates range from 100,000 to 300,000

Tapson VF. N Engl J Med. 2008;358: 1037-1052.


Macdougall DA et al. Am J Health-Syst Pharm. 2006;63(20 suppl 6):S5-S15.
Chronic Complication of VTE
Pathogenesis : Virchow’s
triad
® Malignancy ®Venous disorders
® Pregnancy and ®Venous valvular
peripartum period damage
® Oestrogen therapy
®Trauma or surgery
® Inflammatory bowel disease
®Indwelling catheters
® Sepsis
® 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
The Wells Score

ESC Guidelines 2017


Diagnostic Approach and Treatment

ESC Guidelines 2017


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 Stratification

ESC Guidelines 2014


Risk Stratification

ESC Guidelines 2014


ESC Guidelines 2014
Catheter Directed Thrombolysis
Thrombus Fragmentation
AT Enhancers: Mechanism of Action
Unfractionated Heparin (UFH)
•Inhibits Thrombin (IIa), IXa, Xa, XIa
and XIIa
•Therapeutic action: Xa, thrombin

Low Molecular Weight Heparin


(LMWH)
•Predominantly inhibit factor Xa

Fondaparinux
•Purely inhibits factor Xa

Am J Health-Syst Pharm. 2002.


Anticoagulant therapy remains the mainstay of
DVT treatment

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


Parenteral Anticoagulants Used for PE

ESC Guidelines 2014


NOAC Used for VTE

ESC Guidelines 2014


FONDAPARINUX FOR PREVENTION OF VTE
ARixtra for ThromboEmbolism prevention in a
Medical Indications Study (ARTEMIS)
Objective:
v To 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. About 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. All patients required ≥ 4 days of bed rest
Study Design
n = 425
Fondaparinux 2.5 mg, SC, Once-daily
n=849
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 Secondary outcomes were bleeding and death.
detected by routine bilateral venography along with Patient were followed up at one month
symptomatic venous thromboembolism up to day 15
Result

n=849 n=849

46.7% 58.1%
RRR*
P=0.029

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


n=321** n=429
Adapted from Cohen AT et al. The ARTEMIS™ investigator. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute
medical patients; randomized placebo controlled trial. BMJ 2006; 332; 325-29
FONDAPARINUX FOR TREATMENT OF VTE
Fondaparinux treatment of 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

patients  5 days Fondaparinux* 7.5 mg once-daily + VKA (INR


with DVT 2-3)
5 mg if body weight < 50 kg
(N=2.205) R
from 154 Double- 10 mg if body weight > 100 kg

centres of 23 blind
countries
 5 days SC enoxaparin (1 mg/kg, bid) + VKA (INR
2-3)

90 ± 7 Days

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- 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.
Conclusion of the Study
v Once daily subcutaneous Fondaparinux was at least as effective (Non Inferior) and
safe as twice daily, body weight-adjusted enoxaparin in the initial treatment of
patients with symptomatic deep venous thrombosis
Fondaparinux treatment of Pulmonary Embolism

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
Conclusion of the Study
v Once daily, subcutaneous administration of Fondaparinux without monitoring is at
least as effective and is as safe adjusted-dose, intravenous administration of
unfractionated heparin in the initial treatment of hemodynamically stable patients
with pulmonary embolism.
Conclusions
• VTE cause significant morbidity and mortality, especially in
hospitalized patient

• It is actually preventable, detectable and curable

• 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

• Will allow for simplified treatment at home


• In selected cases endovascular intervention might be helpful
Thank you
VTE Prevention

Inpatient
Prophylactic
Anticoagulation
Prophylactic
Anticoagulation
Outpatient
VTE Prophylactic
Anticoagulation
Prophylaxis

Mechanical
Anticoagulation

Kenneth AB, Uptodate 2017


General rules

use short-term anticoagulation during periods of high risk (eg,


hospitalization for acute medical illness, following major
surgery)
LMWH and Fondaparinux are all reasonable options.
The choice depends on whether the patient is hospitalized or
outpatient, cost, availability, and patient-specific factors.
Mechanical prophylaxis is an option for hospitalized patients
for whom the risk of bleeding is considered high

Kenneth AB, Uptodate 2017


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


2016 Updated VTE Guidance Statements
VTE treatment consideration
 Cancer-associated vs No cancer
 Provoked vs Unprovoked
 Proximal vs Distal DVT
 Supervicial vs deep vein thrombosis
 Upper extremity vs Leg DVT

Choice of Anticoagulant

Kearon C, et al. Chest. 2012; 141(2)(Suppl):e419S–e494S


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.


VTE Treatment
In patients with acute DVT of the leg treated with VKA therapy,
we recommend initial treatment with parenteral anticoagulation
(LMWH, fondaparinux, UFH) over no such initial treatment
(Grade 1B).

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


UFH
LMWH
Fondaparinux
Fondaparinux
Initial treatment
Long term treatment
Extended treatment
5-10 At least 3 months indefinite
days
Kearon C, et al. Chest. 2012; 141(2)(Suppl):e419S–e494S
Parenteral Anticoagulants Dosing

UFH
80 U/kg IV bolus followed by 18 U/kg/hr
5000U IV bolus followed by 1000 U/hr

Enoxaparin
1 mg/kg SQ Q12H
1.5 mg/kg SQ QD
CrCl < 30: 1 mg/kg SQ Q24H

Fondaparinux
< 50kg: 5mg SQ QD
50-100kg: 7.5mg SQ QD
> 100kg: 10mg SQ QD

Alwquwaizini M, et al. Curr Emerg Hosp Med Rep (2013) 1:83–97


Oral Anticoagulants Therapy

Vitamin K Antagonist - warfarin


Started on day 1 or 2 of parenteral anticoagulation
Maintain overlap for at least 5 days.
INR goal = 2-3

OR

NOAC
Rivaroxaban, Apixaban, Edoxaban, Dabigatran
Contraindication of anticoagulation

Absolute
§ Active bleeding
§ Recent hemorrhagic CVA
§ History of heparin sensitivity
§ History of Heparin-induced thrombocytopenia (HIT)
§ Underlying bleeding diathesis
§ Intracranial pathology e.g subdural hematoma
Relative
§ Active peptic ulcer disease
§ Recent major trauma
Kakkos SK et al.2014.Eur j Vasc Endovasc Surg;48(5):565-575
Patient populations
potentially
at higher risk of bleeding

§ Elderly
§ Patients with renal impairment
§ Patients with hepatic impairment
§ Patients receiving certain co-medications
§ Genetic
§ Duration of use
§ Drug-drug interaction

Alexander Turpie et al. J Thromb Haemost 2012;108


Contraindications to
outpatient treatment of VTE

Active or high risk of bleeding

ü Recent surgery (within 7 days)


ü Cardiopulmonary instability
ü Severe symptomatic venous obstruction
ü High risk pulmonary embolism*
ü Thrombocytopenia (platelets \50,000/lL)
ü Other medical or surgical condition requiring inpatient management
ü Medical non-compliance
ü Geographical or telephone inaccessibility
ü Poor hepatic function (International Normalized Ratio (INR) C 1.5)
ü Unstable renal function (e.g. rising serum creatinine)
ü Poor home health care support environment

* High risk PE is characterized by systolic blood pressure \90 mmHg or a systolic blood pressure drop of
C40 mmHg for [15 min not due to an arrhythmia, hypovolemia or sepsis

J Thromb Thrombolysis (2016) 41:32–67


Summary
§ Anticoagulation options for acute VTE include unfractionated
heparin, low molecular weight heparin, fondaparinux and the
direct oral anticoagulants (DOACs).
§ Various clinical scenarios determine the choice of
anticoagulant therapy.
§ Fondaparinux has been proven to be at least as safe and
effective as treatment of DVT and pulmonary embolism (PE)
as LMWH and UFH.
§ The MATISSE DVT trial confirmed that fondaparinux and
enoxaparin have similar safety and efficacy for the initial
treatment of DVT.
SPECTRUM OF VTE

Deep Vein Thrombosis


• Distal (Calf) vein Thrombosis :
Thrombi remain confined to the deep calf vein
• Proximal vein Thrombosis :
Thrombosis involves the popliteal, femoral or Iliac Vein
v Provoked DVT : caused by a known event ( eg, surgery, hospital admission, Oral
Contraception, immobilitation)
v Unprovoked DVT : no identifiable cause or provoking event for DVT is evident
Acute Pulmonary Embolism

Kenneth et al. Up to date.2014


Role of Fondaparinux for
the treatment of VTE
Heparin, LMWH, Fondaparinux

• Antithrombin (AT) inhibits factor Xa and


thrombin
• UFH, LMWH, and Fondaparinux
bind to AT, causing a
conformational change.
• Activated complex increases
Factor Xa inactivation by several
fold over endogenous AT
• Longer chain polysaccharides:AT complexes irreversibly binds to an inhibits the
active site of thrombin

Am J Health-Syst Pharm. 2002.


Heparin, LMWH, Fondaparinux

Heparin LMWH (enoxaparin) Fondaparinux


Source Endogenous Derived from UFH Synthetic Polysaccharide
(small molecule) (bovine and porcine)

Chain Length ~45 saccharide units ~15 saccharide units 5 saccharide units
Route IV, Subcutaneous Subcutaneous, IV Subcutaneous, IV
Time to Cmax SC: 20-30 min SC: 3-4.5 hours SC: 2-3 hours
(erratic absorption) (predictable absorption) (predictable absorption)
Half Life 0.5 to 2 hours ~4 to 7 hours 15-17 hours
(Daily to BID dosing) (Daily SC dosing)
Dosing in Renal No adjustment needed; Adjust doses; Adjust doses;
Impairment Preferred agent for Not recommended for Contraindicated when
ESRD/dialysis patients dialysis patients CrCl<30 mL/min
Laboratory aPTT, ACT, Not routinely Not routinely
monitoring anti-factor Xa recommended; optional recommended; optional
Platelet monitoring anti-factor Xa assay anti-factor Xa assay
Platelet monitoring

Am J Health-Syst Pharm. 2002.


Heparin, LMWH, Fondaparinux
Heparin LMWH (enoxaparin) Fondaparinux
Additional Proteins, macrophages, Less protein, osteoblast, No additional binding
Binding platelets, osteoblasts platelet binding than UFH
Bleeding Higher than LMWHs 0-13% Any bleeding 2-3 % Minor bleeding
Incidence (rates vary based on 0-4% Major bleeding 1-3% Major bleeding
indication and patient)
Incidence of 1-5% HIT <1%HIT 0% HIT
thrombocytopenia 30% Non-HIT 3-5% Non-HIT 3% Non-HIT
Pregnancy Preferred anticoagulant Preferred anticoagulant Category B
(not routinely used)
Body Weight Caution with obese Caution in extremes of Treatment dose tiered
Initial doses often weight according to body capped,
and/or adjusted (<45kg and >~180kg) weight.
body weights are used Actual body weight used
for weight-based doses
Reversal Protamine (100%) Protamine (~60 to 75%) No specific reversal agent
available

Am J Health-Syst Pharm. 2002.