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 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 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 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 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) 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 reversal: protamine effective Unpredictable dose response requires monitoring complications: HIT,
platelets, bleeding long term target: 1.5 -2.5 x control osteoporosis onset: immediate does not inactivate advantage: can stop if clot bound thrombin bleeding (t 1/2 short) short MOA: binds to antithrombin III Monitor: aPTT - heparin inhibition of thrombin (IIa) and factors Xa and IXa LMWH MOA: preferentially
inhibit factor Xa Monitor: limited requirement ; antiXa 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 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 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
