Algorithm: Sedation Protocol

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DVT and PE Pharamcotherapy TEACHING SLIDES
Olavo Fernandes Pharm.D. Pharmacy Practice
Leader, University Health Network Assistant
Professor, University of Toronto October 2002
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UHN Residency Open House

• Monday October 21st, 2002 530 pm to 800 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

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DEFINTIONS

• 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
• lt50 of pulmonary vascular bed occluded
• Massive
• lt50 of pulmonary vascular bed occluded

• DVT
• thrombus material composed of cellular material
  (RBC, WBC, Plts) bound together with fibrin
  strands
• forms in the venous portion of the vasculature
• VTE DVT PE

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EPIDEMIOLOGY

• PE
• 69 per 100, 000 (with our without associated DVT)
• 100, 000 deaths annually due to PE
• Mortality (30 untreated 8 with treatment )

• DVT
• 48 per 100, 000

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PATHOPHYSIOLOGY

• Virchows Triangle
• abnormalities in blood blow
• (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)

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RISK FACTORS for DVT

• Anti-phospholipid syndrome
• pregnancy
• CHF
• Cancer
• obesity
• prolonged immobilization
• Smoking
• Ptn C or S or antithrombin deficiency
• HIT

• surgery or trauma
• MI
• stroke
• increasing age
• prior VTE
• estrogen use
• Factor V leiden

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CLINICAL PRESENTATION

• PE
• transient dyspnea (84)
• tachypnea (RR gt 20) 85
• pleuritic chest pain (74)
• apprehension (63)
• tachycardia (HR gt 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

• DVT
• 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

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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

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MANAGEMENT OPTIONS

• PE
• pharmacological agents
• thrombolytics
• surgery (endarterectomy, can be life saving,
  specialized centres)
• Greenfield Filters (px)

• DVT
• pharmacological agents
• surgery (rarely indicated)

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THERAPEUTIC OPTIONS

• Heparin
• LMWH
• Warfarin (oral)
• Danaparoid
• Hirudin/ Lepirudin
• Ancrod
• Thrombolytics (PE)
• Pentasacharide Injection (phase 3)
• Thrombin inhibitors (oral) (phase 3)

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Pharmacologic Agents

• MOA
• Place in Therapy
• Dosing
• Monitoring
• Adverse Effects/ Limitations
• Reversal Agents

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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

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LMWH

• MOA preferentially inhibit factor Xa
• Monitor limited requirement anti-Xa for renal
  failure and obesity
• platelets, bleeding
• target variable
• onset immediate

• prolonged effect- more difficult to immediately
  reverse effect
• reversal difficult protamine
• OD vs. BID
• as effective, same incidence of bleeds/ mortality
• wt based dosing

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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

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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)

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Favourable properties of a LMWH

• less expensive
• short acting- desirable in patients at high risk
  of bleeding - can quickly reverse anticoagulation

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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 gt 4
• major bleeds lt 3 INR 2-3
• Drug Interactions

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Duration of Warfarin Therapy

• Reversible or time limited RFs - first event (3-6
  months)
• Idiopathic VTE- first event (gt 6 months)
• 12 mos- lifetime
• first event with cancer until resolved
  antithrombin deficiency anticardiolipin Ab
• recurrent event, idiopathic or with thrombophilia

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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 gt 2000
  mg/ day for a week or more
• Ciprofloxacin
• case reports - monitor INR
• Fluconazole
• inc INR especially with doses gt 200 mg/ day
• Phenytoin
• can both increase or decrease INR

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WARFARIN DRUG INTERACTIONS Pharmacodynamic and
dec. INR

• Pharmacodynamic
• ASA
• NSAIDS
• clopidogrel, ticlopidine

• Decreased INR
• carbamazepine
• Binding resins
• barbituates

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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

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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

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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

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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