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Management of DVT(and a little bit of PE, too)
Jeffrey P Schaefer MSc MD FRCPC
May 24, 2006
Objectives
• Management of Venothrombotic Disease– levels of evidence– epidemiology and diagnostics– initial management of suspected DVT– management of confirmed DVT– special populations– post-thrombotic syndrome
Data Sources - Therapy
American College of Chest Physicians
CHEST Supplement
September 2004
Volume 126(3)
**Uptodate & eMedicine are not recent ***
Grade 1 “Recommend”
IntermediateObservational studiesClear1C
Strong; most patientsRCTs with limitationsClear1B
Strong; most patients, circumstances
No RCTs; strong results extrapolated or strong observational studies
Clear1C+
Strong; applies to most patients and circumstances
RCTs w/o significant limitations
Clear1A
Strength of Recommendation
Methodologic StrengthRisk/
Benefit
Grade
Grade 2 “Suggest”
Very weakObservational studiesUnclear2C
Weak; alternatives likely better for some
RCTs with limitationsUnclear2B
Weak; action depends on circumstances, values
No RCTs; strong results extrapolated or strong observational studies
Unclear2C+
Intermediate; action depends on circumstances, values
RCTs w/o important limitationsUnclear2A
Strength of Recommendation
Methodologic StrengthRisk/
Benefit
Grade
Hierarchy of Evidence: therapy/prevention
• Systematic reviews of RCTs
• A single RCT
• Systematic review of observational
studies
• Physiological studies
• Unsystematic clinical observations
Randomized Clinical TrialPatients with DVT
Treatment A
Outcome among A
Treatment B
random allocation
Outcome among B
Venothrombotic disease (VTED)
• superficial thrombophlebitis
• deep vein thrombosis– lower limb– upper limb
• pulmonary thromboembolism
• post-thrombotic syndrome
Superficial Vein Thrombophlebitis
Potentially Lethal Misnomer SFV = deep
Deep Vein Thrombosis
Calgary Health RegionJan 1 to June 30, 2001
• 1,400 patients investigated for DVT – 33% inpatient– 40% emergency dept– 27% outpatient
• 3,175 patients investigated for PE– 60% inpatient– 25% emergency dept– 15% outpatient QIHI
Calgary Health RegionJan 1 to June 30, 2001
• DVT tests– 4,200 leg ultrasounds
• 2,500 bilateral• 1,700 unilateral
– 95 venograms
• PE tests– 1,400 V/Q scans– 130 CT scans– 100 pulmonary angiograms
• Estimated cost: $1,500,000 QIHI
DVT - diagnosis• Clinical Suspicion - any one feature performs poorly
D - dimer
• D-dimer Assay– D-dimer is breakdown product of fibrinolysis– high sensitivity (98%) & modest specificity (~50%)– useful for excluding DVT and PE– not useful for confirming diagnosis
– SHOULD NOT TO BE USED• post-operative patient• pregnant patient• patient with malignancy
Duplex Ultrasonography
• Duplex US – above knee DVT
• Sens = 96%
• Spec = 96%Haemostasis 23:61-7
• calf dvt– sens = 80%
Venography
• Gold standard (sens 100%, spec 100%)
CHR Protocol
Pulmonary Thromboembolism
PE - diagnosis (V/Q scan)
• high probability V/Q scan (2 defects)
PE - diagnosis (spiral CT scan)
PE - diagnosis
Venography
- gold standard
- (100% / 100%)
CHR Protocol
Overview of Prevention / Treatment
DVT PE
Prevent DVT
Patient at Risk
Death
Treat PE =Prevent
More PE
Treat DVT =Prevent PE
Treat PE
Overview of Prevention / Treatment
Prevent DVT
Patient at Risk
Risk of VTED among Non-prophylaxed Inpatients
VTED Prevention in Medical Pts
• Medical in-patients– heart failure, severe resp disease, bedridden,
cancer, prev VTE, sepsis, acute neurologic disease, or inflammatory bowel disease
• recommend LDUH (1A) or LMWH (1A)
• if heparin contraindication, use mechanical prophylaxis with GCS or IPC (1C+)
Heparins
• Dalteparin (Fragmin)– primarily used for prevention– 2,500 to 5,000 units sq od
• Tinzaparin (Innohep)– primarily used for DVT / PE therapy– 175 anti-Xa units / kg sq od
• Enoxaparin (Lovenox)– primarily used for acute coronary syndromes
How LMWHs Differ - Molecular Weight Distribution
UFHTinzaparin
Enoxaparin
Molecular Weight (KDa)
2 3 4.5
6.5 15 30
LMWH: Doses• Treatment: DVT or PE
– Tinzaparin 175 u/kg sc OD– Dalteparin 200 u/kg sc OD or 100 u/kg sc BID– Enoxaparin 1.5 mg/kg sc OD or 1 mg/kg sc BID
• Prophylaxis– Dalteparin 5000 u sc OD (2500 day of Orthopedic
surgery)– Enoxaparin 30 mg sc BID or 40 mg sc OD– Tinzaparin weight based or 4500 u sc OD
What of those pre-filled syringes
• “Pre-filled syringes” are not useful as they do not allow me to exactly dose the patient
• Dose adjustment is likely unneeded as these drugs have a wide therapeutic window
– e.g. if the predicted dose is 12764 U I would feel very comfortable treating with 14000 unit pre-filled syringe
• What if my assurances are not enough ?
– Heparin is stable for some days if drawn up into a syringe by clinic staff and given to the patient
Warfarin
• Inhibits the formation of Vitamin K dependent clotting factors 2, 7, 9, 10
• Inhibits formation of Protein C and S
• Overall, defective clotting proteins are formed
• Effect depends on depletion of previously made normal clotting proteins (2, 7, 9, 10)
• Not safe in pregnancy
THR, TKR, Hip#, No Prophylaxis
Prox DVT% PE% Fatal PE%
THR 23-36 0.7-30 0.1-0.4
TKR 9-20 9-20 0.2-0.7
Hip# 17-36 4-24 3.6-12.9
Recommendations: THR, TKR, Hip#
• LMWH started– 12 hr pre-op or (epidural hematoma risk)– 12-24 hr post-op or– 4-6 hr post-op at 1/2 dose
or• Warfarin started
– immediately pre-op– post-op
• Extended (post-discharge) may be acceptable
Other Surgical Settings
• Consult CHEST supplement
Take-Home-PointsDiagnosis of DVT and PE
• Prevention is standard of care.
• Guidelines are explicit.– medical– surgical
Overview of Prevention / Treatment
DVT PE
Prevent DVT
Patient at Risk
Death
Treat PE =Prevent
More PE
Treat DVT =Prevent PE
Treat PE
Overview of Prevention / Treatment
DVT PE
Treat PE =Prevent
More PE
Treat DVT =Prevent PE
Why Intervene?
• Risk of PE among untreated DVT ~ 15-25%
• Risk of death among PE ~ 20-30%
• Risk of death among untreated DVT ~5%
• Risk of death for treated PE ~ 1.5%/yr
• Risk of death for treated DVT ~ 0.4%/yr
• Risk of major bleed treated PE/DVT ~1.0%/yr
Suspected DVT
• If high clinical suspicion of DVT, treat with anticoagulants while awaiting the outcome of diagnostic tests (1C+).
Confirmed DVT/PE• Clinical assessment risk / benefit of intervetion.• Draw baseline CBC, PTT, and INR and start:
Low Molecular Weight Heparinor
Adjusted Dose Unfractionated Heparin IVor
Adjusted Dose Unfractionated Heparin SQ
Any one of the three are acceptableLow Molecular Wt Heparin is preferred
(dosing, slightly better efficacy and safety)
Duration of Heparin for acute DVT/PE
• Most Adults– minimum 5 days AND– until INR therapeutic for two consecutive days
• Active Cancer– minimum 3 – 6 months before converting to
‘indefinite’ warfarin
• Pregnant– therapeutic heparin until delivery– warfarin 4-6 weeks post-partum
Duration of Warfarin for DVT/PE
• Warfarin (if not pregnant)– start concurrently with heparin– target INR 2.0 - 3.0
• Duration of warfarin– time reversible risk factors: > 3 months*– first idiopathic DVT/PE: > 6 months– recurrent DVT/PE: > 12 months– continuing risk factor > 12 months
• cancer and thrombophilias
*local tendency to tx PE x 6 months
Thrombolysis for DVT?
Thrombolysis for DVT?
Thrombolysis for DVT?
Therapy: Do we need to anticoagulate patients with acute VTE ?
Barrit and Jordan, Lancet 1960:1:1309
• Randomized trial of no-therapy vs subcutaneous heparin for patients with suspected acute PE
• Established the precedent for randomized trials in this area
Untreated
Treated
DeathsNon-fatal
recurrences
5 5
0 0
Is this enough ?
Do you need a fast acting a/c up front ?Brandjes et al. NEJM 1992:327;1485
– Patients with objectively proven acute lower-limb DVT– Randomized trial of IV standard heparin + oral
anticoagulants or oral anticoagulants alone
OAC alone
Heparin + OAC
Symptomaticrecurrences
Asymptomaticrecurrences
12 / 60 39.6 %
4 / 60 8.2 %
Calf (below knee) DVT
• Below knee DVT extend proximally in 20% of patients treated with IV heparin for several days
• Recommend: treatment of below knee DVT is SAME AS proximal DVT
Arm DVT
• Many recommendations– anticoagulation– thrombolysis– surgical extraction– catheter embolectomy
Latter three interventions science not persuasive
JPS I treat these similar to leg DVT
Take-Home-PointsTreatment of DVT and PE
• Heparin– low molecular weight is preferred– duration is longer among cancer patients
• Warfarin– duration varies by clinical setting– implicit message that longer is better
Overview of Prevention / Treatment
DVT PE
Prevent DVT
Patient at Risk
Death
Treat PE =Prevent
More PE
Treat DVT =Prevent PE
Treat PE
Overview of Prevention / Treatment
PE Death
Treat PE
Massive PE
• Thrombolytic Therapy– highly individualized– ICU admission
– reserved for echocardiographic right heart failure
Thrombolysis for sub-massive PE
n = 238
Endpoint = escalation of therapy or death. NEJM 2002;347;1143
Thrombolysis for sub-massive PE
Post-Thrombotic Syndrome
• Variously defined– pain and swelling post-DVT– 20 – 50%
Post-Phlebetic Syndrome• elastic compression stocking (30-40) during
2 years after an episode of DVT (1A)
• intermittent pneumatic compression for severe edema (2B)
• elastic compression stockings for mild edema of the leg due to the PTS (2C).
--------------
• Rutosides for mild edema due to PTS (2B)
What are rutosides?
• A substance produced from leaves & flowers of the plant Sophora japonica
What to expect?
• Potential for post-phlebitic syndrome
• PE chest pain may come and go
• Hemoptysis may occur
• Elevate legs when not ambulating
• Okay to walk
What happens to the Thrombus?
Summary
• ACCP Guidelines– accessible– address most situations
• Other Topics– role of Anti-coagulation Management Clinics– perioperative care– travel– intolerance to heparin
Anticoagulation in Special Risk Populations
Mark Crowther, MD, MSc, FRCPC
Associate Professor, Medicine and Haematology Residency Training Program Director
Acting Vice President, Research and Head of Service, Haematology
St Joseph’s HealthcareHamilton, Ontario, Canada
Thanks to Borys Sydoruk
LEO Pharma Inc.
