DVT and PE Pharamcotherapy TEACHING SLIDES

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 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

3. 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 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 Massive <50 % of pulmonary vascular bed occluded DEFINTIONS

4. 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 ) EPIDEMIOLOGY

5. PATHOPHYSIOLOGY • Virchow’s 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)

6. surgery or trauma MI stroke increasing age prior VTE estrogen use Factor V leiden Anti-phospholipid syndrome pregnancy CHF Cancer obesity prolonged immobilization Smoking Ptn C or S or antithrombin deficiency HIT RISK FACTORS for DVT

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

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

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

12. 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 HEPARIN

13. 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 LMWH

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. 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 WARFARIN

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. 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 : Increased INR

20. Pharmacodynamic ASA NSAIDS clopidogrel, ticlopidine Decreased INR carbamazepine Binding resins barbituates WARFARIN DRUG INTERACTIONS : Pharmacodynamic and dec. INR

21. 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

22. 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 WARFARIN COUNSELLING POINTS

23. 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

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