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DVT and PE Pharamcotherapy TEACHING SLIDES Olavo Fernandes Pharm.D. Pharmacy Practice Leader, University Health Network Assistant Professor, University.

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Presentation on theme: "DVT and PE Pharamcotherapy TEACHING SLIDES Olavo Fernandes Pharm.D. Pharmacy Practice Leader, University Health Network Assistant Professor, University."— Presentation transcript:

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

2 UHN Residency Open House Monday October 21 st, 2002 5:30 pm to 8:00 pmMonday October 21 st, 2002 5:30 pm to 8:00 pm Princess Margaret Hospital 610 University Ave 5 th Floor CafeteriaPrincess Margaret Hospital 610 University Ave 5 th 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 period  Tours 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 18 th, 2002By October 18 th, 2002

3 DEFINTIONS DVT thrombus material composed of cellular material (RBC, WBC, Plts) bound together with fibrin strandsthrombus material composed of cellular material (RBC, WBC, Plts) bound together with fibrin strands forms in the venous portion of the vasculatureforms in the venous portion of the vasculature VTE= DVT + PEVTE= DVT + PE PE thrombus from from systemic circulation lodges in pulmonary artery or branches causing complete or partial obstruction of pulmonary blood flow thrombus from from systemic circulation lodges in pulmonary artery or branches causing complete or partial obstruction of pulmonary blood flow 95% originate from DVT 95% originate from DVT Submassive Submassive –<50 % of pulmonary vascular bed occluded Massive Massive –<50 % of pulmonary vascular bed occluded

4 EPIDEMIOLOGY DVT 48 per 100, 00048 per 100, 000 PE 69 per 100, 000 (with our without associated DVT) 69 per 100, 000 (with our without associated DVT) 100, 000 deaths annually due to PE 100, 000 deaths annually due to PE Mortality (30% untreated; 8% with treatment ) Mortality (30% untreated; 8% with treatment )

5 PATHOPHYSIOLOGY Virchow’s TriangleVirchow’s Triangle –abnormalities in blood blow (bed rest, tumour obstruction) (bed rest, tumour obstruction) –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 (catheters, vascular injury, trauma)(catheters, vascular injury, trauma) To form a clot: imbalance in triangle; activation of intrinsic and extrinsic pathway and cascadeTo form a clot: imbalance in triangle; activation of intrinsic and extrinsic pathway and cascade Venous Thrombi (red)Venous Thrombi (red) Arterial Thrombi (white)Arterial Thrombi (white)

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

7 CLINICAL PRESENTATION DVT symptoms present whensymptoms present when –obstruction of venous flow –inflammation of vein wall or perivascular space –embolization 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 dorsiflexion of the foot)Homan sign (calf pain on 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 shock hypoxemia, hypotension, cardiogenic shock *more often assoc with massive PE *more often assoc with massive PE +more often assoc with submassive PE +more often assoc with submassive PE SILENT presentation SILENT presentation

8 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

9 MANAGEMENT OPTIONS DVT pharmacological agents surgery (rarely indicated) PE pharmacological agents thrombolytics surgery (endarterectomy, can be life saving, specialized centres) Greenfield Filters (px)

10 THERAPEUTIC 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)

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

12 HEPARIN MOA: binds to antithrombin IIIMOA: binds to antithrombin III Monitor: aPTT - heparin inhibition of thrombin (IIa) and factors Xa and IXaMonitor: aPTT - heparin inhibition of thrombin (IIa) and factors Xa and IXa –platelets, bleeding target: 1.5 -2.5 x controltarget: 1.5 -2.5 x control onset: immediateonset: immediate advantage: can stop if bleeding (t 1/2 shortadvantage: can stop if bleeding (t 1/2 short) reversal: protamine effective reversal: protamine effective Unpredictable dose response requires monitoring Unpredictable dose response requires monitoring complications: HIT, long term osteoporosis complications: HIT, long term osteoporosis does not inactivate clot bound thrombin does not inactivate clot bound thrombin

13 LMWH –MOA: preferentially inhibit factor Xa –Monitor: limited requirement ; anti- Xa for renal failure and obesity platelets, bleedingplatelets, 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 wt based dosing

14 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

15 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)

16 Favourable properties of a LMWH –less expensive –short acting- desirable in patients at high risk of bleeding - can quickly reverse anticoagulation

17 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 Bleeding risk correlated to INR –inc with INR > 4 –major bleeds < 3% INR 2-3 Drug Interactions Drug Interactions

18 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

19 WARFARIN DRUG INTERACTIONS : Increased INR TMP/ SMXTMP/ SMX –inhibits hepatic metabolism of S-warfarin –increases response to warfarin (even 3 day course) AmiodaroneAmiodarone –dramatic increase –rough estimation - 50% decrease in therapeutic warfarin maintenance dose MetronidazoleMetronidazole –dramatic increase Acetaminophen Acetaminophen –interaction appears more likely at doses > 2000 mg/ day for a week or more Ciprofloxacin Ciprofloxacin –case reports - monitor INR Fluconazole Fluconazole –inc INR especially with doses > 200 mg/ day Phenytoin Phenytoin –can both increase or decrease INR

20 WARFARIN DRUG INTERACTIONS : Pharmacodynamic and dec. INR Pharmacodynamic ASAASA NSAIDSNSAIDS clopidogrel, ticlopidineclopidogrel, ticlopidine Decreased INR carbamazepine carbamazepine Binding resins Binding resins barbituates barbituates

21 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

22 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

23 Thrombolytics for PE Indicated only if massive PE, submassive with hemodynamic compromise (or failure of heparin tx)Indicated only if massive PE, submassive with 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) –relative (sx in last 10 days; severe HTN, pregnancy, GI bleed in last 3 months), arotic aneurysm, diabetic retinopathy, serious recent trauma bleeding risksbleeding risks expensiveexpensive

24 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


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