Transcript DVT and PE Pharmacotherapy Teaching Slides

DVT and PE Pharamcotherapy
TEACHING SLIDES
Olavo Fernandes Pharm.D.
Pharmacy Practice Leader, University Health Network
Assistant Professor, University of Toronto
October 2002
UHN Residency Open House
• Monday October 21st, 2002 5:30 pm to 8:00 pm
• Princess Margaret Hospital 610 University Ave
5th Floor Cafeteria
• The evening will include:
• An information session on our residency program
 A question and answer period
 Tours of the department and the hospitals
• Food will be provided
• Please RSVP to Tamar / Nancy at 416-340-3611
• By October 18th, 2002
DEFINTIONS
DVT
• thrombus material
composed of cellular
material (RBC, WBC, Plts)
bound together with fibrin
strands
• forms in the venous
portion of the vasculature
PE
• thrombus from from systemic
circulation lodges in pulmonary
artery or branches causing
complete or partial obstruction of
pulmonary blood flow
• 95% originate from DVT
• Submassive
– <50 % of pulmonary vascular bed
occluded
• VTE= DVT + PE
• Massive
– <50 % of pulmonary vascular bed
occluded
EPIDEMIOLOGY
DVT
• 48 per 100, 000
PE
• 69 per 100, 000 (with our
without associated DVT)
• 100, 000 deaths annually
due to PE
• Mortality (30%
untreated; 8% with
treatment )
PATHOPHYSIOLOGY
• Virchow’s Triangle
– abnormalities in blood blow
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(bed rest, tumour obstruction)
– abnormalities in clotting function
• (malignancy, pregnancy, deficiencies in Anti-thrombin III, Ptn S or C)
– abnormal vascular surfaces
• (catheters, vascular injury, trauma)
• To form a clot: imbalance in triangle; activation of
intrinsic and extrinsic pathway and cascade
• Venous Thrombi (red)
• Arterial Thrombi (white)
RISK FACTORS for DVT
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surgery or trauma
MI
stroke
increasing age
prior VTE
estrogen use
Factor V leiden
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Anti-phospholipid syndrome
pregnancy
CHF
Cancer
obesity
prolonged immobilization
Smoking
Ptn C or S or antithrombin
deficiency
• HIT
CLINICAL PRESENTATION
DVT
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symptoms present when
– obstruction of venous flow
– inflammation of vein wall or
perivascular space
– embolization to lung
unilateral leg pain
leg tenderness
leg swelling
redness/ discolouration
palpable cord
venous distention
Homan sign (calf pain on
dorsiflexion of the foot)
SILENT presentation
PE
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*transient dyspnea (84%)
tachypnea (RR > 20) 85%
+pleuritic chest pain (74%)
*apprehension (63%)
tachycardia (HR > 100) (58%)
cough (50%)
+hemoptysis (28%)
*syncope (13%)
hypoxemia, hypotension, cardiogenic
shock
*more often assoc with massive PE
+more often assoc with submassive
PE
SILENT presentation
Endpoints: Outcome Assessment
• VTE endpoints
– Venography
– Duplex compression
ultrasonography
– Impedance
Plesmography
– Fibrinogen Uptake
– D-Dimer Testing
– PE (lung scanning,
angiography, autopsy)
• Safety endpoints
– Major and minor bleeds
– Thrombocytopenia
• Mortality
MANAGEMENT OPTIONS
DVT
• pharmacological
agents
• surgery (rarely
indicated)
PE
• pharmacological
agents
• thrombolytics
• surgery
(endarterectomy,
can be life saving,
specialized centres)
• Greenfield Filters
(px)
THERAPEUTIC OPTIONS
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Heparin
LMWH
Warfarin (oral)
Danaparoid
Hirudin/ Lepirudin
Ancrod
Thrombolytics (PE)
Pentasacharide Injection (phase 3)
Thrombin inhibitors (oral) (phase 3)
Pharmacologic Agents
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MOA
Place in Therapy
Dosing
Monitoring
Adverse Effects/ Limitations
Reversal Agents
HEPARIN
• MOA: binds to
antithrombin III
• Monitor: aPTT heparin inhibition of
thrombin (IIa) and
factors Xa and IXa
– platelets, bleeding
• target: 1.5 -2.5 x
control
• onset: immediate
• advantage: can stop if
bleeding (t 1/2 short)
• reversal: protamine
effective
• Unpredictable dose
response requires
monitoring
• complications: HIT,
long term
osteoporosis
• does not inactivate
clot bound thrombin
LMWH
– MOA:
preferentially
inhibit factor Xa
– Monitor: limited
requirement ; antiXa for renal failure
and obesity
• platelets, bleeding
– target: variable
– onset: immediate
– prolonged effectmore difficult to
immediately reverse
effect
– reversal: difficult :
protamine
– OD vs. BID
– as effective, same
incidence of
bleeds/ mortality
• wt based dosing
UFH and LMWH
• Continue therapy for at least 5 days
(Grade 1A)
• longer duration of UFH or LMWH if
massive PE
• Should overlap with warfarin for at least
4-5 days.
– D/C after 2 consecutive days of therapeutic
INR
Favourable properties of a LMWH
– increased plasma half life- once daily/ bid dosing
– reduced non-specific binding to plasma proteins
(predictable anticoagulant response, predictable
bioavialability)
– reduced binding to platelets : (less HIT, potential
for less bleeding)
– less need for monitoring/ SC outpatient option
– less daily injections
– reduced binding to osteoblasts (less bone loss)
Favourable properties of a LMWH
– less expensive
– short acting- desirable in patients at high
risk of bleeding - can quickly reverse
anticoagulation
WARFARIN
– MOA: inhibits vit K
dep coagn factors (II,
VII, IX, X)
– Monitor: INR ,
bleeding
– target: 2-3 unless
MVR
– onset: delayed
clotting factor half
lives (factor II 72 hrs)
– reversal: Vitamin K
• Bleeding risk
correlated to INR
– inc with INR > 4
– major bleeds <
3% INR 2-3
• Drug Interactions
Duration of Warfarin Therapy
• Reversible or time limited RFs - first
event (3-6 months)
• Idiopathic VTE- first event (> 6 months)
• 12 mos- lifetime
• first event with: cancer until resolved;
antithrombin deficiency; anticardiolipin Ab
• recurrent event, idiopathic or with thrombophilia
WARFARIN DRUG INTERACTIONS :
Increased INR
• TMP/ SMX
– inhibits hepatic
metabolism of S-warfarin
– increases response to
warfarin (even 3 day
course)
• Amiodarone
– dramatic increase
– rough estimation - 50%
decrease in therapeutic
warfarin maintenance
dose
• Metronidazole
– dramatic increase
• Acetaminophen
– interaction appears more
likely at doses > 2000 mg/
day for a week or more
• Ciprofloxacin
– case reports - monitor INR
• Fluconazole
– inc INR especially with
doses > 200 mg/ day
• Phenytoin
– can both increase or
decrease INR
WARFARIN DRUG INTERACTIONS :
Pharmacodynamic and dec. INR
Pharmacodynamic
• ASA
• NSAIDS
• clopidogrel, ticlopidine
Decreased INR
• carbamazepine
• Binding resins
• barbituates
WARFARIN COUNSELLING POINTS
• Indication
• How it works•
prevents abnormal clots; stop
existing clots from getting
larger, decreases risk of clot
breaking off
• Blood Test
Monitoring (INR)
• Administration
• Length of Therapy
• Risks: bleeding
(practical
discussion)
– advise dentist
• Drug interactions
– Rx and Herbal
– Diet
• Alcohol
• Missed pills
WARFARIN COUNSELLING POINTS
• When to contact MD:
blood in urine, stool,
persistent nose
bleed, increased
swelling in extremity
• When to go to ER:
– SOB, Chest pain,
coughing up blood,
black tarry stools,
severe HA of sudden
onset, slurred speech
Thrombolytics for PE
• Indicated only if massive PE, submassive with
hemodynamic compromise (or failure of heparin tx)
• can start 7-14 days after PE dx
• only when dx certain (V/Q scan, angiography)
• only if no contraindications
– absolute (active bleed; CVA or neurosurg in last 10 days)
– relative (sx in last 10 days; severe HTN, pregnancy, GI bleed in last 3
months), arotic aneurysm, diabetic retinopathy, serious recent trauma
• bleeding risks
• expensive
Indications for Exoxaparin
• Non-ST segment elevation ACS
– angina at rest lasting at least 10 min
– evidence of underlying IHD - specific ECG
changes
– inpatients
• Exclude:
– chest pain NYD, persistent ST segment
elevation; emergency intervention within 24
hrs