DVT and PE Pharamcotherapy TEACHING SLIDES Olavo Fernandes

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 21 st, 2002 5: 30 pm to 8: 00 pm • Princess Margaret Hospital 610 University Ave 5 th 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 18 th, 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 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 • (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 • • 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

CLINICAL 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 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

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

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

HEPARIN • MOA: binds to antithrombin III • Monitor: a. PTT 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) 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 ; anti. Xa 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 1 A) • 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