Download Antithrombotic Therapy for Venous Thromboembolic Disease

ANTITHROMBOTIC THERAPY FOR
VENOUS THROMBOEMBOLIC DISEASE
OUTLINE
A. OVERVIEW
1. ANATOMY
2. DEFINITIONS
3. VENOUS THROMBO EMBOLISM (VTE)
- DEEP VENOUS THROMBOSIS (DVT)
and PULMONARY EMBOLISM (PE)
OUTLINE
B. ACCP GUIDELINE ON ANTITHROMBOTIC
THERAPY FOR VENOUS THROMBOEMBOLIC
DISEASE
1. RECOMMENDATIONS
2. DVT OF THE LEG: INITIAL THERAPY AND
LONG-TERM TREATMENT
3. PE: INITIAL THERAPY AND LONG-TERM
TREATMENT
A. OVERVIEW
1. ANATOMY
A. OVERVIEW
2. DEFINITIONS
2.1. Venous ThromboEmbolism (VTE):
Any radiologically confirmed thromboembolic event
occurring within the venous system. Includes:
2.2. Deep Vein Thrombosis (DVT): Thrombotic
occlusion of the deep venous system of the legs
causing pain/swelling:
A. OVERVIEW
2. DEFINITIONS
* Isolated Calf Vein Thrombosis
Confined to calf veins (fig 1)
* Proximal DVT – Above the knee –
Popliteal, femoral, iliac veins (fig 2)
* Pulmonary embolism (PE): Thromboembolic occlusion of
pulmonary arteries causing breathlessness and/or chest
pain (fig 4)
2.3. Post-Thrombotic Syndrome (PTS): Oedema, ulceration
and impaired viability of SC tissues of the leg occurring
after DVT
A. OVERVIEW
3. VTE and DVT- Background
- VTE: Most common disorder of the veins
- Most hospitalized pts have risk factors for
VTE
- 10% of hospital deaths are attributable to PE
- Hospital- acquired DVT and PE are ussually
clinically silent
A. OVERVIEW
3. VTE and DVT- Background
- Difficult to predict which at risk patients will
develop symptomatic thromboembolic
complications
- The pevention of DVT also prevents PE
- Thrombus formation associated with
inflammation
A. OVERVIEW
3. VTE and DVT- Incidence
A. OVERVIEW
3. VTE and DVT- Etiology
A. OVERVIEW
3. VTE and DVT- Etiology
* Circulatory Stasis
– Atrial fibrillation, obesity, immobility, pregnancy
* Endothelial Injury
– Trauma, external pressure, IV caustic substances
* Hypercoagulable State
– Hematologic disorders – polycythemia, severe
anemias, malignancies, sepsis, use of
contraceptives, smoking
A. OVERVIEW
3. VTE and DVT- Risk Factors
- Increasing age
- Varicose veins
- Immobility, paresis
- Heart or Respiratory failure
- Previous VTE
- Central venous catheterization
- Cancer and cancer therapy
- Inflammatory bowel disease
- Surgery
- Myeloproliferative disorders
- Trauma (*)
- Nephrotic syndrome
- Obesity
- Paroxysmal nocturnal
- Smoking
hemoglobinuria
- Acute medical illness
- Pregnancy or postpartum
- Inherited or acquired thrombophilia - Estrogen use
(*) Especcially fractures of the pelvis, hip or leg
A. OVERVIEW
3. VTE and DVT- Travel
• VTE may be associated with any form of travel
of four or more hours. Direct link with air travel
remains controversial
• Immobility is the major underlying risk factor
• Risk higher in people with known risk factors
• Vast majority need no medication – just keep
moving and drinking (water)!
• Simple exercises - getting up and walking
around regularly are advised
A. OVERVIEW
3. VTE and DVT- Diagnosis
Consider predisposing factors and suggestive
signs/symptoms:
DVT
PE
• Unilateral leg pain
• Breathlessness
• Swelling
• Faintness
• Tenderness
• Chest pain
• Increased temperature
• Tachycardia/tachypnoea
• Pitting oedema etc.
• Raised jugular venous
pressure
If VTE is clinically suspected  Refer to hospital
Clinical presentation influences diagnostic process
A. OVERVIEW
3. VTE and DVT- Complications
* Pulmonary Emboli
– Life threatening
* Chronic venous insufficiency
– Valvular destruction, retrograde blood flow
• Persistent edema, increased pigmentation,
secondary varicosities, ulceration, dependent
position cyanosis
– Phlegmasia cerulea dolens – rare
• Sudden occurrence - edematous cyanotic painful
leg
• May result in gangrene
The spectrum of clinical presentation of PE
PE-related shock
Mild clinical symptoms
The spectrum of clinical outcome of PE
>30%
Mortality
1%
Markers for risk stratification in acute PE
1. Clinical markers
Shock
Sustained hypotension
Implicit and explicit score assessment
2. Markers of myocardial dysfunction
RVD dilation at echocardiography or spiral CT
BNP or NT-proBNP elevation
3. Markers of myocardial injury
Elevated T or I troponin
Severity of Pulmonary Embolism
Definitions related to
severity of pulmonary embolism and risk stratification
MARKERS
CLINICAL
RV
dysfunction
Myocardial
Injury
Treatment
implications
RISK
HIGH
(Clinically Massive PE)
Thrombolysis
or
embolectomy
+
+
+
+
-
INTERMEDIATE
-
+
-
LOW
-
-
NON
HIGH
Hospital
treatment
consider
early
discharge or
ambulatory
treatment
2008 ESC Guidelines
B. ACCP Guideline for treatment of VTE
1. RECOMMENDATIONS: GRADE 1
Grade
Risk/
Benefit
Methodologic Strength
Strength of
Recommendation
1A
Clear
RCTs w/o significant
limitations
Strong; applies to most
patients and
circumstances
1C+
Clear
No RCTs; strong results
extrapolated or strong
observational studies
Strong; most patients,
circumstances
1B
Clear
RCTs with limitations
Strong; most patients
1C
Clear
Observational studies
Intermediate
RCT = randomized controlled trial
B. ACCP Guideline for treatment of VTE
1. RECOMMENDATIONS: GRADE 2
Grade
Risk/
Benefit
Methodologic Strength
2A
Unclear RCTs w/o important
limitations
Intermediate; action
depends on
circumstances, values
2C+
Unclear No RCTs; strong results
extrapolated or strong
observational studies
Weak; action depends on
circumstances, values
2B
Unclear RCTs with limitations
Weak; alternatives likely
better for some
2C
Unclear Observational studies
Very weak
RCT = randomized controlled trial
Strength of
Recommendation
B. ACCP Guideline for treatment of VTE
TREATMENT OF VTE
Initial treatment
Long term-treatment
Extended* treatment
≥ 5 days
at least 3 months
indefinite*
* With re-assessment of the individual risk-benefit at periodic interval
B. ACCP Guideline for treatment of VTE
2. INITIAL THERAPY FOR ACUTE DVT OF THE LEG
• We recommend that patients receive
anticoagulants as soon as the diagnosis of DVT
is confirmed
• Interim treatment should be started if suspicion
is high and confirmation is delayed
Initial Therapy
DRUG
DOSE
IV UFH
- 80 U/kg or 5.000 U (bolus IV); followed: 18
U/kg/h or 1.300U/h; aPTT
Monitored SC UFH
-17.500U or 250U/kg bid; aPTT
Unmonitored SC
UFH
- 333U/kg; followed 250U/kg, bid
SC LMWH
-Initiate once or twice daily, as an outpatient
or as an inpatient if possible, rather than with
IV UFH.
- Against routine monitoring with anti-factor
Xa
Fondaparinus or SC No difference in recurrent VTE, major
bleeding or death
UFH vs SC LMWH
Initial Therapy
THERAPY
RECOMMENDATIONS
Catheter-
- Against routine use (Grade 1C)
directed
-Confining use to selected patients* (Grade 2C)
thrombolysis -Reduce acute sts and postthrombotic morbidity
(CDT)
-After successful CDT, correct of underlying venous
lesions using balloon angioplasty and stents (Gr 2C).
-Pharmacomechanical thrombolysis (eg, with inclusion
of thrombus fragmentation and/or aspiration) in
preference to CDT alone to shorten treatment time
-After successful CDT, the same intensity and duration
of anticoagulant therapy as for comparable patients
who do not undergo CDT (Grade 1C).
(*): Extensive, acute proximal DVT (eg Iliofemoral DVT, symptoms for < 14 days, good
functional status, life expectancy > 1 year) who have a low risk of bleeding
Initial Therapy
THERAPY
RECOMMENDATIONS
IV thrombolytic therapy - Against routine use (Grade 1A)
- Use in selected patients* (Grade 2C) if CDT is
not available
Percutaneous Venous
Thrombectomy
Should not be treated alone (Grade 2C).
Operative Venous
Thrombectomy
- May be used to reduce acute symptoms and
postthrombotic morbidity
- No high risk of bleeding, CDT is referable .
- After success, the same intensity and duration of
anticoagulant therapy as for comparable patients
who do not undergo CDT (Grade 1C).
(*): Extensive, acute proximal DVT (eg Iliofemoral DVT, symptoms for < 14 days, good
functional status, life expectancy > 1 year) who have a low risk of bleeding
Initial Therapy
THERAPY
RECOMMENDATIONS
Placement of a - Against routine use in most patients during
vena cava
anticoagulant therapy (Grade 1A)
filter
- For patients with acute proximal DVT with a
contraindication for, or complication of, anticoagulant
therapy, and those with recurrent thromboembolism
despite adequate anticoagulant therapy (Grade 2C)
- Should subsequently receive a conventional course
of anticoagulant therapy if their risk of bleeding
resolves
Immobilization Early ambulation in preference to initial bed rest when
this is feasible (Grade 1A).
Long-term Therapy for DVT of the Leg
PATIENT CHARACTERISTICS
RECOMMENDED TREATMENT
First DVT episode, secondary
VKA therapy for 3 months, over use
to a transient risk
for shorter periods (Grade 1A)
Unprovoked DVT
VKA for at least 3 months (Grade 1A),
after 3 months, all patients should
be evaluated for the risk/benefit of
long-term therapy (Grade 1C)
* Proximal or Second episode
Long-term treatment if no risk of
bleeding and good monitoring
* First Isolated distal DVT
3 months of anticoagulant rather
than indefinite (Grade 2B).
Long-term Therapy for DVT of the Leg
PATIENT
RECOMMENDED TREATMENT
CHARACTERISTICS
DVT and cancer
LMWH for the first 3 to 6 months of long-term
(Grade 1A). Subsequent anticoagulant with VKA
or LMWH indefinitely or until the cancer is
resolved [Grade 1C].
-For pts with long-term anticoagulant, the risk/benefit ratio of continuing
treatment should be reassessed at periodic intervals (Grade 1C).
-Target INR: 2 – 3 for all treatment durations (Grade 1A).
-Patients with unprovoked DVT & a preference for less frequent INR test,
after the first 3 months of conventional- intensity anticoagulation (INR 2.0
to 3.0), we recommend low-intensity therapy (INR 1.5 to 1.9) with less
frequent INR monitoring over stopping treatment (Grade 1A).
Initial Therapy for PE
• We recommend that patients receive
anticoagulants as soon as the diagnosis of
PE is confirmed
• Interim treatment should be started if
suspicion is high and confirmation is
delayed
Initial Therapy for PE
CLINICAL SITUATION
Confirmed acute PE
RECOMMENDED TREATMENT
- Options: SC LMWH, IV UFH, monitored
SC UFH, fixed-dose SC UFH or SC
Fondaparinus (all Grade 1A)
- Initiate VKA together with LMWH or UFH
or Fondaparinux on the first day
High suspicion of PE
Anticoagulants, while awaiting the outcome
of diagnostic tests (Grade 1C)
Acute non-massive PE
SC LMWH over IV UFH (Grade 1A)
- Acute massive PE
IV UFH over SC LMWH, SC Fondaparinux
- Concern about SC absorption or SC UFH
- Thrombolytic therapy is planed
Acute PE and severe renal
failure
UFH over LMWH
Initial Therapy for PE
DRUG
DOSE
IV UFH
- 80 U/kg or 5.000 U (bolus IV); followed: 18
U/kg/h or 1.300U/h; aPTT
Monitored SC UFH
-17.500U or 250U/kg bid; aPTT
Unmonitored SC UFH - 333U/kg; followed 250U/kg, bid
SC LMWH
-Initiate once or twice daily, as an outpatient or as
an inpatient if possible, rather than with IV UFH.
- Against routine monitoring with anti-factor Xa
Initial Therapy for PE: Thrombolytic Agents
CLINICAL SITUATION
RECOMMENDATION
Most patients
Again use systemic thrombolytic therapy
Grade 1B)
All pts: risk stratification. Use of
thrombolytic  on PE severity, prognosic,
bleeding
Selected patients, eg,
hemodynamically unstable pts
Systemic thrombolytic therapy (Grade
1B)*
Patients receiving thrombolytic
therapy
Administered via a peripheral vein than
a pulmonary artery (Grade 1B)
Regimens with a short infusion time ( a 2h
infusion) over those with a prolonged
infusion time (Grade 1B)
Initial Therapy for PE:
Additional Recommendations
INITIAL TREATMENT OF PE
Most patients
Selected, highly
compromised patients
(those who are unable to
receive thrombolytic
therapy, or whose critical
status does not allow
enough time for infusion)
RECOMMENDATION
Against interventional
techniques (Fragmentation)
(Grade 1C)
Against pulmonary
embolectomy (Grade 1C)
Interventional techniques
may be used (Grade 2C)
Pulmonary embolectomy
may be used (Grade 2C)
Initial Therapy for PE:
Additional Recommendations, continued
INITIAL TREATMENT OF PE
Pts with a contraindication
for, or complication of,
anticoagulant treatment; or
patients with recurrent
thromboembolism, despite
adequate anticoagulation
therapy
RECOMMENDATION
We suggest clinicians place
an IVC filter (Grade 2C)
For pts who have an IVC
filter inserted as an
alternative to anticoagulation,
they should subsequently
receive a conventional
course of anticoagulant
therapy if the risk of bleeding
resolves (Grade 1C).
Long-term Therapy for PE
PATIENT CHARACTERISTICS
RECOMMENDED TREATMENT
PE episode, secondary to a
VKA therapy for 3 months, over use
transient risk
for shorter periods (Grade 1A)
Unprovoked PE
VKA for at least 3 months (Grade
1A), after 3 months, all patients
should be evaluated for the risk/
benefit of long-term therapy (Gr 1C)
* First unprovoked episode
of VTE that is a PE or
Long-term treatment if no risk of
second episode of
bleeding and good monitoring
unprovoked VTE
Long-term Therapy for PE
PATIENT
RECOMMENDED TREATMENT
CHARACTERISTICS
PE and cancer
LMWH for the first 3 to 6 months of long-term
(Grade 1A). Subsequent anticoagulant with VKA
or LMWH indefinitely or until the cancer is
resolved (Grade 1C).
-For pts with long-term anticoagulant, the risk/benefit ratio of continuing
treatment should be reassessed at periodic intervals (Grade 1C).
-Target INR: 2 – 3 for all treatment durations (Grade 1A).
-Patients with unprovoked PE & a preference for less frequent INR test,
after the first 3 months of conventional- intensity anticoagulation (INR 2.0
to 3.0), we recommend low-intensity therapy (INR 1.5 to 1.9) with less
frequent INR monitoring over stopping treatment (Grade 1A).
Chronic Thromboembolic Pulmonary
Hypertension (CTPH)
- CTPH: a minority of patients after acute PE,
underdiagnosed
- Unknown exact cause,  deficiencies of
antithrombin, protein C, or protein S
- The diagnosis is usually not made until the degree
of pulmonary hypertension is advanced
- Following this asymptomatic period, from months
to years, worsening exertional dyspnea, hypoxemia,
and right ventricular failure ultimately ensue.
Chronic Thromboembolic Pulmonary
Hypertension (CTPH)
- Currently, pulmonary angiography/angioscopy
remain the cornerstone for the diagnosis of
CTPH and confirm the surgical accessibility of
lesions.
- CT can be useful in determining whether a
mediastinal process (eg, fibrosing mediastinitis,
malignancy) is responsible for the angiographic
findings, and arch aortography may be useful if
an arteritis is being considered
Chronic Thromboembolic Pulmonary
Hypertension (CTPH)
In selected patients with CTPH, such as those with
central disease under the care of an experienced
surgical/medical team, we recommend pulmonary
thromboendarterectomy (Grade 1C).
All patients with CTPH, we recommend life-long
treatment with a VKA targeted to an INR of 2.0 to
3.0 (Grade 1C).
Postthrombotic Syndrome (PTS )
- PTS is a long-term complication,
development of venous insufficiency after
DVT
- Characterized by chronic, persistent pain,
swelling and other signs in the affected limb.
- The severity of symptoms may vary over
time, and the most extreme manifestation is a
venous ulcer of the lower leg.
Postthrombotic Syndrome
THERAPEUTIC GOAL
Prevent PTS
RECOMMENDATION
GCS (ankle pressure 30 to 40 mm Hg)
for 2 yr after a DVT episode (1A)
Treat severe edema of the leg
A course of therapy with an IPC
(without ulcer)
device (Grade 2B)
Treat mild edema of the leg
GCS (Grade 2C)
(without ulcer)
Postthrombotic Syndrome
THERAPEUTIC GOAL
RECOMMENDATION
Venous ulcers resistant to healing
1. + IPC
with wound care & compression
2. Pentoxifylline (Torental) , 400
mg po tid, in addition to local care
and compression and/or IPC
(Grade 2B)
3. Rutosides, in the form of MPFF
adminstered orally, or sulodexide
administered intramuscularly and
then orally, be added to local care
and compression (Grade 2B).
Hyperbaric O2 not be used (G 2 B)
Rutoside- Dx flavonoid (Rutin)
Sulodexide is a highly purified mixture of glycosaminoglycans composed of low
molecular weight heparin (80%) and dermatan sulfate (20%).
Superficial Vein Thrombosis (SVT)
PATIENT
CHARACTERISTICS
RECOMMENDED TREATMENT
Pts with
thrombophlebitis as a
complication of IV
infusion
- Oral diclofenac or another NSAIDS [Grade 2B],
topical diclofenac gel (Grade 2B), or heparin gel
(Grade 2B) until symptoms  or for up to 2 weeks.
-- Against use of systemic anticoagulation (Gra.
1C).
Pts with spontaneous
superficial vein
thrombosis
- Prophylactic or intermediate doses of LMWH
(Grade 2B) or intermediate doses of UFH (Grade 2B)
for at least 4 weeks.
- An alternative: VKA (target INR, 2.5; range, 2.0 to
3.0) can be overlapped with 5 days of UFH and
LMWH and continued for 4 weeks (Grade 2C).
- Oral NSAIDs should not be used in addition to
anticoagulation (Grade 2B).
- Medical treatment with anticoagulants over
surgical treatment (Grade 1B).
Acute UEDVT
PATIENT
CHARACTERISTICS
Acute UEDVT
RECOMMENDED TREATMENT
- Initial treatment with therapeutic doses
of LMWH, UFH, or fondaparinux as
described for leg DVT [Grade 1C].
- Against the routine use of systemic or
catheter-directed thrombolytic therapy
(Grade 1C).
Selected pts with
CDT may be used for initial treatment if
acute UEDVT (eg,
appropriate expertise and resources are
those with a low
available (Grade 2C).
risk of bleeding and
severe symptoms of
recent onset)
Acute UEDVT
PATIENT
CHARACTERISTICS
RECOMMENDED TREATMENT
Most pts with acute
UEDVT
Against the routine use of catheter
extraction, surgical thrombectomy,
transluminal angioplasty, stent placement,
staged approach of lysis followed by
interventional or surgical procedure, or SVC
filter placement (Grade 1C).
Selected pts with acute
UEDVT (eg, those with
primary UEDVT and
failure of anticoagulant
or thrombolytic treatment
who have severe
persistent symptoms),
Catheter extraction, surgical thrombectomy,
transluminal angioplasty, or a staged
approach of lysis followed by a vascular
interventional or surgical procedure may be
used if appropriate expertise and resources
are available (all Grade 2C).
Acute UEDVT
PATIENT
CHARACTERISTICS
Selected pts with
acute UEDVT (eg,
those in whom
anticoagulant
treatment is
contraindicated and
there is clear
evidence of DVT
progression or
clinically significant
PE)
RECOMMENDED TREATMENT
Placement of an SVC filter (Grade
2C).
Long-term Treatment of UEDVT
PATIENT
CHARACTERISTICS
RECOMMENDED TREATMENT
Pts with acute UEDVT
VKA for > 3 months (Grade 1C).
Most pts with UEDVT in
association with an
indwelling central venous
catheter
Catheter not be removed if it is functional
and there is an ongoing need for the
catheter (Grade 2C).
Pts who have UEDVT in
association with an
indwelling central venous
catheter that is removed
Do not recommend that the duration of
long-term anticoagulant treatment be
shortened to < 3 months (Grade 2C).
PTS of the Arm
PATIENT
CHARACTERISTICS
RECOMMENDED TREATMENT
Pts at risk for PTS
after UEDVT
Do not suggest routine use
of elastic compression or
venoactive medications
(Grade 2C).
Elastic bandages or elastic
compression sleeves to
reduce symptoms of PTS of
the upper extremity (Grade
2C).
Pts with UEDVT
who have
persistent edema
and pain
Mechanical Methods of Thromboprophylaxis
Mechanical Methods of Thromboprophylaxis
Graduated Compression Stockings
Intermittent Pneumatic Compression
Venous Foot Pump
Elastic Bandages
Elastic Compression Sleeve
Summary
• DVT and PE are responsible for a large
number of preventable deaths
• Urgently refer all with suspected DVT/PE
• LMWHs are the preferred initial treatment in
most
• Warfarin is used for maintenance
anticoagulation for at least 3 months in
most
Treatment of venous thromboembolism
UHF (iv, SQ, SQ fixed doses)
LMWH
Fondaparinux
Thrombolysis
Initial treatment
vitamin K antagonists
INR 2.0-3.0
2.0-3.0 or 1.5-1.9
Long term-treatment
Extended* treatment
≥ 5 days
at least 3 months
indefinite*
* With re-assessment of the individual risk-benefit at periodic interval
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