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Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and Radiology Division of Vascular and Endovascular Surgery.

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Presentation on theme: "Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and Radiology Division of Vascular and Endovascular Surgery."— Presentation transcript:

1 Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and Radiology Division of Vascular and Endovascular Surgery

2 Outline Available anticoagulants Surgical prophylaxis DVT and pulmonary embolus Atrial fibrillation Perioperative management of patients on chronic anticoagulation Arterial thromboembolism –Cerebral –Visceral –Extremity Anticoagulation in pregnancy

3 The Coagulation Cascade X Xa + Va + Ca ++ Intrinsic system XII XIIa XIIX Xia IXa + VIIa + Ca ++ Extrinsic system Injury Tissue thromboplastin + VII Prothrombin Thrombin FibrinogenFibrin

4 Available anticoagulants Unfractionated heparin Low Molecular Weight Heparins Oral Anti-coagulants Alternative agents

5 Unfractionated Heparin- Mechanism of Action Binds anti-thrombin III 1:1 Inactivates thrombin and F Xa Secondary effect on F V Effects not first order kinetics Effective after subcutaneous and intravenous administration Short half life (90 min) Reversed with protamine (1mg per 100 U circulating heparin)

6 Unfractionated Heparin- Limitations Significant protein binding Response is unpredictable (close monitoring required) <25% of patients in therapeutic range 12 hours after starting Rx Inaccessibility of clot-bound thrombin

7 Unfractionated Heparin- Dosing Loading U/ kg IV Then IV infusion at 18 U/kg/hr Normogram available for most hospitals Therapeutic range X control PTT

8 Unfractionated Heparin- Complications Major bleeding complications 0-7% HIT 1-5% Osteoporosis Alopecia Hypoadrenalism Anaphylaxis

9 Heparin – Induced Thrombocytopenia Incidence 1-5% Can occur with all methods of administration No known risk factors Increased incidence with Bovine preparations Dx- plt count < /uL

10 Heparin – Induced Thrombocytopenia I HIT IHIT I –Heparin induced platelet aggregation –Platelet sequestration and consumption –Mild –Thrombocytopenia in first few days of therapy –Plt count usually > /uL –Asymptomatic –Resolves spontaneously without d/c heparin

11 Heparin – Induced Thrombocytopenia II HIT II (HITT)HIT II (HITT) –Immunologically mediated –Ab to Heparin-PF 4 complex –More severe but less common –5-7 days after initiating Tx –PLT << /uL –Bleeding complications unusual –Diffuse thrombotic events –Separate and distinct from initial event requiring heparin Rx

12 Heparin – Induced Thrombocytopenia II Thrombotic events arterial and venous Associated skin necrosis Global amnesia Prosthetic valve thrombosis 29% mortality and 21% amputation rate

13 Heparin – Induced Thrombocytopenia – Treatment ALLWithdrawal of ALL heparin and heparin products Plasmapheresis - anecdotal success Further treatment should await confirmation of Dx Start anti-platelet therapy ? LMWH Thrombin inhibitors Ancrod Conversion to Warfarin

14 Available Anticoagulants Unfractionated heparin Low Molecular Weight Heparins Oral Anti-coagulants Alternative agents

15 Characteristics of UFH and LMWH Chains Molecular weight (daltons) 10,000 15,000 20,000 5,000 5,400 Anti-XaAnti-IIa and anti-Xa Resistant to PF4Sensitivity to PF4 Little non-specific bindingNon-specific binding Inhibition of thrombin generationLess inhibition thrombin generation Hirsh J, Levine MN. Blood. 1992; 79: 1-17.

16 Low Molecular Weight Heparins Effect through AT III Inhibits Factor Xa More predictable anticoagulant response Longer half-life Better bioavailability at low doses Renal clearance Lower incidence of HIT No need to monitor PTT in most cases

17 FDA-Approved Indications (May 2001) for Available LMWHs

18 Advantages of LMWH Over UFH Less platelet activation Less vascular permeability Smaller size Increased release of TFPI from vascular endothelium Less plasma protein binding Less interaction with PF4 Less osteoclast activation Less binding to VWF Stimulates megakaryopoiesis Less thrombin, growth factor production May limit tumor movement into intravascular space More potent anti-angiogenesis activity More potent anticoagulant and anti-cancer activity Predictable PK, safety, once daily dosing Lower incidence of HIT Less osteoporosis with long term use Less bleeding May attenuate chemotherapy - induced thrombocytopenia

19 Low Molecular Weight Heparins- Dosing 1mg/kg q12H Can monitor anti-factor Xa levels

20 Available Anticoagulants Unfractionated heparin Low Molecular Weight Heparins Oral Anti-coagulants Alternative agents

21 Oral Anticoagulation- Mechanism of Action Inhibition of Vitamin K-dependant coagulation factors II, VII, IX, X Inhibition of Vitamin K- dependant carboxylation of Protein C and S

22 Oral Anticoagulation- Limitations May create initial hypercoaguable state 3-5 days for anticoagulant effect 3-5 days to reverse effects –Reversed rapidly by FFP –Can reduce time of reversal with supplemental Vit K (10mg IV or 3-5mg PO)

23 Oral Anticoagulation- Complications Hemorrhage Skin necrosis –Protein C deficiency –Malignancy Teratogenic

24 Oral Anticoagulation- Dosing Loading 5mg PO QD Adjust daily dose to reach goal INR

25 Available Anticoagulants Unfractionated heparin Low Molecular Weight Heparins Oral Anti-coagulants Alternative agents

26 Alternative Anticoagulants Danaproid Thrombin Inhibitors –Hirudin –Lepirudin –Argatroban Ancrod

27 Alternative Anticoagulants- Danaproid Heparinoid Mixture heparin-like glycosaminoglycans and chondroitins Anti-factor Xa and anti-factor IIa activity Can be used in patients with HIT Approved for DVT prophylaxis Longer duration than UF heparin Measure by anti-factor Xa levels Weight based dosing

28 Alternative Anticoagulants- Thrombin Inhibitors Hirudin –Protein isolated from salivary gland of leech –Irreversible binding to thrombin –High incidence of bleeding complications –Monitor by PTT and ACT –Substitute for heparin in patients with HIT –Efective DVT prophylaxis

29 Alternative Anticoagulants- Thrombin Inhibitors Lepirudin –Recombinant Hirudidn derivative –Reduced mortality and morbidity in HIT patients –Renally excreted –Dosing - 0.4mg/kg IV loading and 0.15mg/kg maintenance –Monitor PTT –Therapeutic range: 1.5 – 2.5 X normal

30 Alternative Anticoagulants- Thrombin Inhibitors Argatroban –Competitive thrombin inhibitor –Univalent thrombin inhibitor (less specificity and affinity) –Short plasma life- no adj. for RF –2ug/kg/min IV –Monitor by PTT or ACT (2-3.5 X baseline)

31 Alternative Anticoagulants- Ancrod Venom of Malaysian Pit Viper Defibrinating agent Converts fibrinogen to soluble aggregate removed by plasmin and RES Increases FDP – augments anticagulant effect Indirect micro-fibrinolytic by increasing TPA release Monitor fibrin levels

32 Venous Thromboembolism Virchows Triad Stasis Intimal injury Activation of coagulation (hypercoaguable state)

33 Venous Thrombosis- Epidemiology Venous thromboembolism is the 3rd most common vascular disease in the United States Mortality and morbidity associated with VTE is enormous Average cost per admission in the US: –PE = $12,595 –DVT = $9,337 –Additional long-term costs of morbidity > 75% of initial therapy costs

34 Venous Thrombosis- Rationale for Prophylaxis Clinically silent disease High prevalence in hospitalized patients Dire consequences of missed DVT –First manifestation may be fatal PE –Most deaths within 30 min of acute event –Long term morbidity from post-phlebitic syndrome Wide variations in practice of physicians –Only 1/3 of at risk patients receive adequate prophylaxis –58% of fatal PE patients not prophylaxed in spite of risk factors

35 Venous Thrombosis- Risk Factors Obesity Varicose Veins Cardiac dysfunction Indwelling vascular catheter IBD Nephrotic syndrome Pregnancy or estrogen use Advanced age Prolonged immobility Stroke or Paralysis Previous VTE Cancer and its treatment Major Surgery –esp. abdomen, pelvis, and lower extremities Trauma –esp. fractures of pelvis, hip, or leg

36 Surgical Prophylaxis- Low Risk Patient Risk Factors Age under 40 years Minor surgery No other risk factors Event rate Calf DVT 2.0% Proximal DVT0.4% Clinical PE0.2% Fatal PE0.002% Recommended Regimens No specific measuresNo specific measures Aggressive mobilizationAggressive mobilization

37 Surgical Prophylaxis- Moderate Risk Patient Risk Factors Major surgery in patients with additional risk factors Non-major surgery in patients with no additional risk factors Major surgery in patients < 40 with no additional risk factors Event Rates Calf DVT10-20% Proximal DVT2-4% Clinical PE1-2% Fatal PE % Recommended Regimens LMWHLMWH Low dose UFHLow dose UFH Elastic stockingsElastic stockings Intermittent Pneumatic CompressionIntermittent Pneumatic Compression

38 Surgical Prophylaxis- High Risk Patient Risk Factors Non-major surgery in patients > 60 or additional risk factors Major surgery in patient < 40 or additional risk factors Event Rate Calf DVT20-40% Proximal DVT4-8% Clinical PE2-4% Fatal PE % Recommended Regimen LMWHLMWH Low dose UFH q8hLow dose UFH q8h IPCIPC

39 Surgical Prophylaxis- Highest Risk Patient Risk Factors Major surgery in patients > 40 plus prior VTE, cancer, hypercoaguable state Hip or knee arthroplasty Major trauma Spinal cord injury Event Rate Calf DVT40-80% Proximal DVT10-20% Clinical PE4-10% Fatal PE % Recommended Regimen LMWH Oral Anticoagulants IPC/ES + LMWH/LDUFH Adjustable dose UFH

40 Deep Venous Thrombosis- Treatment Start LMWH (SC enoxaparin 1mg/kg q12h or 1.5mg/kg q24) and warfarin Stop LMWH after 4-5 days when INR > 2.0 for 2 consecutive days Continue warfarin for at least 90 days at INR

41 LMWH vs. UFH In Acute Treatment of VTE In Favor of LMWHIn Favor of UFH Venous Thromboembolism Pulmonary Embolism Major Bleeding Thrombocytopenia Total Mortality Minor Bleeding Pooled Relative Risk Dolovich L, et al. Arch Intern Med. 2000:160:

42 LMWH: Fewer Deaths Meta-Analysis: N=3,566 LMWH UFH P Mortality 5.1% 6.7% 0.02 Overall 30% mortality reduction from: Recurrent Thromboembolism, Bleeding, and Cancer Gould, et al. Ann Intern Med. 1999; 130:

43 Study Design Enoxaparin sodium 1mg/kg q12h SC Adjusted-dose heparin infusion Documented acute, proximal DVT without PE Warfarin therapy initiated on 2nd day Warfarin 90 days post randomization Clinical endpoints Outpatient Treatment of DVT Enoxaparin q12h vs. Heparin

44 Embolic Event Total VTE * DVT only Proximal DVT PE 13 (5.3) 11 (4.5) 10 (4.0) 2 (0.8) 17 (6.7) 14 (5.5) 12 (4.7) 3 (1.2) Enoxaparin sodium n=247 (%) Heparin n=254 (%) Outpatient Treatment of DVT Enoxaparin q12h vs. Heparin Results: Recurrences of Thromboembolism * VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]). 95% CI = -5.6 to 2.7. Two died during the study.

45 Treatment Group & Event Enoxaparin sodium (n=5) Soft-tissue hematoma of hip Abdominal-wall hematoma Abdominal-wall hematoma Subdural hematoma Hematemesis Heparin (n=3) Hematuria Gastrointestinal bleeding Hematemesis Study Day INR* *International Normalized Ratio. P = Patient had cancer and associated thrombocytopenia due to chemotherapy and radiation. Outpatient Treatment of DVT Enoxaparin q12h vs. Heparin Results: Episodes of Major Bleeding aPTT (sec)

46 Atrial Fibrillation Most common arrythmia in adults Responsible for 15% CVA Better survival with combined rate control and anticoagulation IV heparin/ LMWH + coumadin Administer anticoagulation before and weeks after cardioversion

47 Atrial Fibrillation Age < 65 >65-75Any Risk Factors For Stroke* NoneNone 1 or more * Mitral stenosis, HTN, previous TIA or stroke, CHF, LV dysfunction, or age > 75 Therapy ASA or none ASA or Warfarin Warfarin

48 Perioperative Management Of Patients on Chronic Anticoagulation Patients at low risk VTE adequatelt treated for > 3 months, no predisposing factors Nonvalvular A. Fib without embolic events Most bioprosthetic and mechanical heart valves without thromboembolism

49 Perioperative Management Of Patients on Chronic Anticoagulation Recommendations Hold warfarin 4 days before surgeryHold warfarin 4 days before surgery Recheck PT day of surgeryRecheck PT day of surgery Resume warfarin on post-op day 2Resume warfarin on post-op day 2

50 Perioperative Management Of Patients on Chronic Anticoagulation Patients at intermediate risk Venous or arterial embolism –In 2 nd to 3 rd month of Tx, no predisposing factors –Recurrent VTE tx for 12 months Valvular heart disease, A. Fib, prosthetic heart valve with distant h/o embolism

51 Perioperative Management Of Patients on Chronic Anticoagulation Recommendations Hold warfarin 4 days surgeryHold warfarin 4 days before surgery Prophylactic SC UFH or LMWH pre-opProphylactic SC UFH or LMWH pre-op Recheck PT day of surgeryRecheck PT day of surgery Continue prophylaxis in peri-operative periodContinue prophylaxis in peri-operative period Restart warfarin at pre-operative dose on post-op day 2Restart warfarin at pre-operative dose on post-op day 2 Stop heparin when INR > 2Stop heparin when INR > 2

52 Perioperative Management Of Patients on Chronic Anticoagulation Patients at highest risk Venous thromboembolism with specific circumstances (consider IVC filter) –Onset within last month –Idiopathic, last 6 months –Recurrent VTE, within last 12 months Documented hypercoaguable state Recent embolism from A. Fib, prosthetic or diseased heart valve Acute arterial embolism within 1 month

53 Perioperative Management Of Patients on Chronic Anticoagulation Recommendations Hold warfarin 4 days prior to surgeryHold warfarin 4 days prior to surgery Begin IV heparin or SC LMWH 2 days prior to surgeryBegin IV heparin or SC LMWH 2 days prior to surgery Recheck PT day of surgeryRecheck PT day of surgery Hold heparin 6-12 hrs before surgeryHold heparin 6-12 hrs before surgery Resume heparin 12 hours after surgery if adequate hemostasisResume heparin 12 hours after surgery if adequate hemostasis Resume warfarin on post-op day 2Resume warfarin on post-op day 2 D/C heparin when INR > 2D/C heparin when INR > 2

54 Arterial Thromboembolism- Goals of Therapy Prevent recurrent thrombosis or embolism Adequate anticoagulation reduces in- hospital recurrence from 31% to 9% Decrease mortality from 25% to 4% Does result in increased wound complications (without major bleeding episodes) UFH first choice in therapy –Increased flexibility in monitoring and control

55 Arterial Thromboembolism- Extremity Patient with suspected ALI HistoryPEDoppler HEPARIN Diagnosis confirmed

56 Arterial Thromboembolism- Extremity IV HEPARIN 5000 u bolus Titrate to PTT sec Protection against clot propagation Prevent embolus

57 Arterial Thromboembolism - Cerebral No benefit to anticoagulation in completed stroke May benefit stroke-in-progress if < 25 hrs and submaximal Need to eliminate other causes of neurologic deterioration

58 Arterial Thromboembolism - Cerebral Cardioembolic stroke –Risk of recurrence 10-20% within 2-4 weeks –Evaluate for cardiac source (13-34%) No clear consensus Cerebral embolism study group –Anticoagulation in normotensive patients with small – moderate strokes after 24 hrs –Larger strokes after 5-7 days Recommendations IV heparin without loading dose Start Warfarin after 24 hrs INR Long-term therapy in patients with Atrial Fibrillation

59 Arterial Thromboembolism- Visceral Acute mesenteric ischemia –Embolic –Thrombotic –Non-occlusive –Venous thrombosis

60 Arterial Thromboembolism- Visceral Diagnosis requires high index of suspicion Angiography diagnostic Treatment –Initiate IV heparin at time of diagnosis (bolus and titrate to PTT sec) –Thrombolysis if no evidence of peritonitis –Surgical thrombectomy/revascularization with bowel resection

61 Arterial Thromboembolism- Visceral Non-occlusive mesenteric ischemia Multi-system organ failure, low-flow states, and visceral vasoconstriction Rarely exists without severe cardiac dysfunction Abdominal pain – 75%

62 Arterial Thromboembolism- Visceral Arteriography demonstrate mesenteric arterial spasm Reversible with intra-arterial papaverine infusion or other vasodilating agents Adjunctive use of IV heparin recommended

63 Arterial Thromboembolism- Visceral Venous thrombosis Hypercoaguable state Intraabdominal infection or inflammation Asymptomatic state to catastrophic illness –Generalized abdominal pain out of proportion to physical exam Diagnosis by CT, angiography Treatment –Rigorous resuscitation –IV heparin anticoagulation (PTT 60-80) –Surgical exploration for peritonitis –Long-term therapy with warfarin (life-time if hypercoaguable state identified)

64 Anticoagulation in Pregnancy Sixfold risk of venous thrombembolism PE most common cause of maternal mortality in US Gravid uterus compressing Vena Cava Pregnancy related hypercoagulability (increase II, VII, VIII, X) Decreased fibrinolytic activity and AT III

65 Anticoagulation in Pregnancy Coumadin during first trimester associated with specific malformations in > 25% of births Fetal Warfarin Syndrome (nasal hypoplasia, stippled epiphyses) Increase CNS anomalies if used during other time during pregnancy

66 Anticoagulation in Pregnancy Drugs with molecular weight < 1000 daltons pass through placental membranes Fetus has already low levels of Vit-K dependant factors- further depleted by warfarin effect

67 Anticoagulation in Pregnancy- Recommendations Initiate anticoagulation with intravenous heparin Continue Tx with subcutaneous heparin or LMWH Continue Tx through delivery and post-partum period After delivery coumadin for 6 months Prophylaxis (LMWH) recommended during subsequent pregnancy Acute iliofemoral DVT – consider thrombectomy or vena Caval filter placement

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