DVT and PE PharamcotherapyDVT and PE PharamcotherapyTEACHING SLIDES

Olavo Fernandes Pharm.D.Olavo Fernandes Pharm.D.Pharmacy Practice Leader, University Health NetworkPharmacy Practice Leader, University Health Network

Assistant Professor, University of TorontoAssistant Professor, University of TorontoOctober 2002October 2002

UHN Residency Open UHN Residency Open HouseHouse

• Monday October 21Monday October 21stst, 2002 5:30 pm to 8:00 pm, 2002 5:30 pm to 8:00 pm• Princess Margaret Hospital 610 University Ave Princess Margaret Hospital 610 University Ave

55thth Floor Cafeteria Floor Cafeteria

• The evening will include:The evening will include:• An information session on our residency programAn information session on our residency program A question and answer periodA question and answer period Tours of the department and the hospitalsTours of the department and the hospitals

• Food will be providedFood will be provided

• Please RSVP to Tamar / Nancy at 416-340-3611Please RSVP to Tamar / Nancy at 416-340-3611 • By October 18By October 18thth, 2002, 2002

DEFINTIONSDEFINTIONS

DVTDVT• thrombus material thrombus material

composed of cellular composed of cellular material (RBC, WBC, Plts) material (RBC, WBC, Plts) bound together with fibrin bound together with fibrin strandsstrands

• forms in the venous forms in the venous portion of the vasculatureportion of the vasculature

• VTE= DVT + PEVTE= DVT + PE

PEPE• thrombus from from systemic thrombus from from systemic

circulation lodges in pulmonary circulation lodges in pulmonary artery or branches causing artery or branches causing complete or partial obstruction of complete or partial obstruction of pulmonary blood flow pulmonary blood flow

• 95% originate from DVT95% originate from DVT• SubmassiveSubmassive

– <50 % of pulmonary vascular bed <50 % of pulmonary vascular bed occludedoccluded

• MassiveMassive– <50 % of pulmonary vascular bed <50 % of pulmonary vascular bed

occludedoccluded

EPIDEMIOLOGYEPIDEMIOLOGY

DVTDVT• 48 per 100, 00048 per 100, 000

PE PE • 69 per 100, 000 (with our 69 per 100, 000 (with our

without associated DVT)without associated DVT)• 100, 000 deaths annually 100, 000 deaths annually

due to PEdue to PE• Mortality (30% Mortality (30%

untreated; 8% with untreated; 8% with treatment )treatment )

PATHOPHYSIOLOGYPATHOPHYSIOLOGY• Virchow’s TriangleVirchow’s Triangle

– abnormalities in blood blowabnormalities in blood blow• (bed rest, tumour obstruction)(bed rest, tumour obstruction)

– abnormalities in clotting function abnormalities in clotting function • (malignancy, pregnancy, deficiencies in Anti-thrombin III, Ptn S or C)(malignancy, pregnancy, deficiencies in Anti-thrombin III, Ptn S or C)

– abnormal vascular surfaces abnormal vascular surfaces • (catheters, vascular injury, trauma)(catheters, vascular injury, trauma)

• To form a clot: imbalance in triangle; activation of To form a clot: imbalance in triangle; activation of intrinsic and extrinsic pathway and cascadeintrinsic and extrinsic pathway and cascade

• Venous Thrombi (red)Venous Thrombi (red)• Arterial Thrombi (white)Arterial Thrombi (white)

RISK FACTORS for DVTRISK FACTORS for DVT

• surgery or traumasurgery or trauma• MIMI• strokestroke• increasing ageincreasing age• prior VTEprior VTE• estrogen useestrogen use• Factor V leidenFactor V leiden

• Anti-phospholipid syndromeAnti-phospholipid syndrome• pregnancypregnancy• CHFCHF• CancerCancer• obesityobesity• prolonged immobilizationprolonged immobilization• SmokingSmoking• Ptn C or S or antithrombin Ptn C or S or antithrombin

deficiencydeficiency• HITHIT

CLINICAL PRESENTATIONCLINICAL PRESENTATIONDVT• symptoms present whensymptoms present when

– obstruction of venous flowobstruction of venous flow– inflammation of vein wall or inflammation of vein wall or

perivascular spaceperivascular space– embolization to lungembolization to lung

• unilateral leg painunilateral leg pain• leg tendernessleg tenderness• leg swellingleg swelling• redness/ discolourationredness/ discolouration• palpable cordpalpable cord• venous distentionvenous distention• Homan sign (calf pain on Homan sign (calf pain on

dorsiflexion of the foot)dorsiflexion of the foot)• SILENT presentationSILENT presentation

PE• *transient dyspnea (84%)*transient dyspnea (84%)• tachypnea (RR > 20) 85%tachypnea (RR > 20) 85%• +pleuritic chest pain (74%)+pleuritic chest pain (74%)• *apprehension (63%)*apprehension (63%)• tachycardia (HR > 100) (58%)tachycardia (HR > 100) (58%)• cough (50%)cough (50%)• +hemoptysis (28%)+hemoptysis (28%)• *syncope (13%)*syncope (13%)• hypoxemia, hypotension, cardiogenic hypoxemia, hypotension, cardiogenic

shock shock • *more often assoc with *more often assoc with massive PEmassive PE• +more often assoc with +more often assoc with submassive PEsubmassive PE• SILENT presentationSILENT presentation

Endpoints: Outcome AssessmentEndpoints: 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 OPTIONSMANAGEMENT OPTIONSDVT• pharmacological

agents• surgery (rarely

indicated)

PE• pharmacological

agents• thrombolytics• surgery

(endarterectomy, can be life saving, specialized centres)

• Greenfield Filters (px)

THERAPEUTIC OPTIONSTHERAPEUTIC OPTIONS• HeparinHeparin• LMWHLMWH• Warfarin (oral)Warfarin (oral)• DanaparoidDanaparoid• Hirudin/ LepirudinHirudin/ Lepirudin• AncrodAncrod• Thrombolytics (PE)Thrombolytics (PE)• Pentasacharide Injection (phase 3)Pentasacharide Injection (phase 3)• Thrombin inhibitors (oral) (phase 3)Thrombin inhibitors (oral) (phase 3)

Pharmacologic AgentsPharmacologic Agents

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

HEPARINHEPARIN• MOA: binds to MOA: binds to

antithrombin IIIantithrombin III• Monitor: aPTT - heparin Monitor: aPTT - heparin

inhibition of thrombin inhibition of thrombin (IIa) and factors Xa and (IIa) and factors Xa and IXaIXa– platelets, bleedingplatelets, bleeding

• target: 1.5 -2.5 x controltarget: 1.5 -2.5 x control• onset: immediateonset: immediate• advantage: can stop if advantage: can stop if

bleeding (t 1/2 shortbleeding (t 1/2 short)

• reversal: protamine reversal: protamine effectiveeffective

• Unpredictable dose Unpredictable dose response requires response requires monitoringmonitoring

• complications: complications: HIT, HIT, long term long term osteoporosisosteoporosis

• does not inactivate does not inactivate clot bound thrombinclot bound thrombin

LMWHLMWH– MOA: MOA:

preferentially preferentially inhibit factor Xainhibit factor Xa

– Monitor: limited Monitor: limited requirement ; anti-requirement ; anti-Xa for renal failure Xa for renal failure and obesityand obesity• platelets, bleedingplatelets, bleeding

– target: variabletarget: variable– onset: immediateonset: immediate

– prolonged effect- prolonged effect- more difficult to more difficult to immediately reverse immediately reverse effecteffect

– reversal: difficult : reversal: difficult : protamineprotamine

– OD vs. BID OD vs. BID – as effective, same as effective, same

incidence of incidence of bleeds/ mortalitybleeds/ mortality

• wt based dosingwt based dosing

UFH and LMWHUFH 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 LMWHFavourable properties of a LMWH– increased plasma half life- once daily/ bid dosingincreased plasma half life- once daily/ bid dosing– reduced non-specific binding to plasma proteins reduced non-specific binding to plasma proteins

(predictable anticoagulant response, predictable (predictable anticoagulant response, predictable bioavialability)bioavialability)

– reduced binding to platelets : (less HIT, potential reduced binding to platelets : (less HIT, potential for less bleeding)for less bleeding)

– less need for monitoring/ SC outpatient optionless need for monitoring/ SC outpatient option– less daily injectionsless daily injections– reduced binding to osteoblasts (less bone loss)reduced binding to osteoblasts (less bone loss)

Favourable properties of a LMWHFavourable properties of a LMWH

– less expensive– short acting- desirable in patients at high

risk of bleeding - can quickly reverse anticoagulation

WARFARINWARFARIN– MOA: inhibits vit K MOA: inhibits vit K

dep coagn factors (II, dep coagn factors (II, VII, IX, X)VII, IX, X)

– Monitor: INR , Monitor: INR , bleedingbleeding

– target: 2-3 unless MVRtarget: 2-3 unless MVR– onset: delayed onset: delayed

clotting factor half clotting factor half lives (factor II 72 hrs)lives (factor II 72 hrs)

– reversal: Vitamin Kreversal: Vitamin K

• Bleeding risk Bleeding risk correlated to INRcorrelated to INR– inc with INR > 4inc with INR > 4– major bleeds < major bleeds <

3% INR 2-33% INR 2-3• Drug InteractionsDrug Interactions

Duration of Warfarin TherapyDuration 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 : WARFARIN DRUG INTERACTIONS : Increased INRIncreased INR• TMP/ SMXTMP/ SMX

– inhibits hepatic inhibits hepatic metabolism of S-warfarinmetabolism of S-warfarin

– increases response to increases response to warfarin (even 3 day warfarin (even 3 day course)course)

• AmiodaroneAmiodarone– dramatic increasedramatic increase– rough estimation - 50% rough estimation - 50%

decrease in therapeutic decrease in therapeutic warfarin maintenance dosewarfarin maintenance dose

• MetronidazoleMetronidazole– dramatic increasedramatic increase

• AcetaminophenAcetaminophen– interaction appears more interaction appears more

likely at doses > 2000 mg/ likely at doses > 2000 mg/ day for a week or moreday for a week or more

• CiprofloxacinCiprofloxacin– case reports - monitor INRcase reports - monitor INR

• FluconazoleFluconazole– inc INR especially with inc INR especially with

doses > 200 mg/ daydoses > 200 mg/ day• PhenytoinPhenytoin

– can both increase or can both increase or decrease INRdecrease INR

WARFARIN DRUG INTERACTIONS : WARFARIN DRUG INTERACTIONS : Pharmacodynamic and dec. INRPharmacodynamic and dec. INR

Pharmacodynamic• ASAASA• NSAIDSNSAIDS• clopidogrel, ticlopidineclopidogrel, ticlopidine

Decreased INRDecreased INR• carbamazepinecarbamazepine• Binding resinsBinding resins• barbituatesbarbituates

WARFARIN COUNSELLING POINTSWARFARIN 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 POINTSWARFARIN 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 PEThrombolytics for PE• Indicated only if massive PE, submassive with Indicated only if massive PE, submassive with

hemodynamic compromise (or failure of heparin tx)hemodynamic compromise (or failure of heparin tx)• can start 7-14 days after PE dxcan start 7-14 days after PE dx• only when dx certain (V/Q scan, angiography)only when dx certain (V/Q scan, angiography)• only if no contraindicationsonly if no contraindications

– absolute (active bleed; CVA or neurosurg in last 10 days)absolute (active bleed; CVA or neurosurg in last 10 days)– relative (sx in last 10 days; severe HTN, pregnancy, GI bleed in last 3 relative (sx in last 10 days; severe HTN, pregnancy, GI bleed in last 3

months), arotic aneurysm, diabetic retinopathy, serious recent traumamonths), arotic aneurysm, diabetic retinopathy, serious recent trauma

• bleeding risksbleeding risks• expensiveexpensive

Indications for ExoxaparinIndications 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