1. Anticoagulation By: Charita Marthone, PharmD Candidate 4 th Year PharmD Candidate Fall Seminar Disease State Presentation Professor: Dr. Charlie Colquitt, PharmD, PhD

2. Learning Objectives Identify accurate diagnosis of venous thromboembolism Identify treatment of venous thromboembolism Develop understanding of how to prevent progression or recurrence of thromboembolic disease Knowledge of how to improve safe use of anticoagulants to reduce potential harm and complications

3. Key Terms Venous Thromboembolism (VTE) Pulmonary Embolism (PE) Deep Vein Thrombosis (DVT) Low-molecular weight heparin (LMWH) Unfractionated heparin (UF) Activated partial thromboplastin time (aPTT) Heparin induced thrombocytopenia (HIT) International normalization ratio (INR)

4. Conditions Requiring Anticoagulation Venous thromboembolism (VTE) Antiphospholipid syndrome (APS) Atrial fibrillation (AF) Conditions requiring cardioversion Valvular heart disease and prosthetic valves Peripheral vascular disease Myocardial infarction and cardiomyopathy Pulmonary embolism (PE) Deep vein thrombosis (DVT), including cancer-associated DVT

5. Prevalence Venous Thromboembolism (VTE): One of the leading causes of morbidity and mortality in US Presents as either DVT or PE PE is leading cause of preventable in-hospital mortality

6. Epidemiology Every year:  Nearly 2 million develop VTE  600,000 are hospitalized  60,000 people die Men at increased risk African Americans and European Americans at higher risk

7. Risk assessment Age >50 Cigarette smoking Prior VTE Venous Stasis Injury to vasculature Hypercoagulability Medication therapy Nephrotic Syndrome

8. Pathophysiology Coagulation Cascade:  Intrinsic  Extrinsic  Common Pathway

9. \

10. Pathophysiology Thrombosis vs. Embolism Accessed October 9, 2013 http://doctoryonehiro.com/deep-venous-thrombosis/

11. Signs and Symptoms DVT: Swelling, pain and/or tenderness in one or both legs Warmth in the skin of the affected leg Red or discolored skin in the affected leg Visible surface veins Leg fatigue Accessed Oct 9, 2013: http://www.dvtforum.com/index.asp?action=start

12. Signs and Symptoms PE: Sudden shortness of breath Sharp chest pain that is worse when you cough or take a deep breath. A cough that brings up pink, foamy mucus

13. Diagnosis Deep Vein Thrombosis (DVT)  Physical examination, and patient history  Clinical pretest probability  D-dimer assays  Duplex ultrasound  Serial ultrasonography or venography  Computed tomographic  Contrast

14. Diagnosis Venograph of superficial femoral vein (lateral vein) containing a chronic linear thrombus Venograph outlining of an acute DVT in the popliteal vein (lower extremity) w/ contrast

15. Diagnosis PE Clinical pretest to include:  Chest X-ray  Arterial blood gases  EKG

16. Treatment Goals of therapy: Prevent PE Reduce morbidity Prevent post-thrombotic syndrome (PTS) Minimize adverse affects Minimize cost

17. Pharmacological Treatment Inpatient vs. Outpatient  Most patients can be treated on outpatient basis EXCEPT for patients with the following conditions: Suspected or proven PE Significant cardiovascular comorbidity Contraindications to anticoagulation Familial d/o of coagulation and/or bleeding Pregnancy Morbid Obesity Renal failure Personal (i.e. homeless, no telephone, etc)

18. Pharmacological Treatment Anticoagulant therapy:  Mainstay of medical therapy for DVT: Noninvasive Treats most patients (~90%) Low risk of complications Outcome of improved morbidity and mortality

19. Initial treatment of VTE NameDosingAnticoagulation Effects Monitoring Parameters Special Considerations LMWH: Dalteparin (Fragmin) Enoxaparin (Lovenox) Tinzaparin (Innohep) 200units/kg SC q24h 1mg/kg q12 OR 1.5mg/kg q 24h SC 175 anti-Xa IU/kg SC qd Prevents extension of thrombus Reduces incidence of fatal and nonfatal PE and recurrent thrombosis Renal function, active major bleeding, hypersensitivity, CBC,LFTs, BP Caution in hx of HIT, avoid in neuraxial anesthesis/spinal puncture, avoid NSAIDs, hemmorhagic stroke Heparin80 units/kg IV bolus THEN 18units/kg Infusion OR 5000units IV bolus THEN 1300units/hr Augments activity of antithrombin III; prevents fibrinogen to fibrin conversion, helps prevent reaccumulation of clot APTT, platelet counts, hematocrit, s/sxs of bleeding Caution in hx of HIT, consider benzolyl alcohol use, avoid in GI ulcers, carefully examine correct vials prior to use

20. Initial treatment of DVT NameDosingAnticoagulation Effects Monitoring Parameters Special Considerations Foundaparinux (Arixtra) SC qd by weight: <50kg: 5mg 50-100kg: 7.5mg 100kg: 10mg Inhibits factor Xa. Longer half- life than LMWH and UFH CBC, BP, Liver function, renal function Caution in high risk bleeding, elderly, renal insufficiency, pts <50kg, Rivaroxaban (Xarelto) 15mg po BID with food x21 days Inhibits platelet activation by blocking factor XA without requiring cofactor Renal function, hypersensitivity, blood loss, neurologic impairment Do not abruptly d/c, no antidote available, avoid in renal impairment, d/c 24hrs prior to surgical procedure

21. Maintenance therapy for DVT/PE NameDosingAnticoagulation Effects MonitoringSpecial Considerations Jantoven, Warfarin, Coumadin Initial: 2-5mg PO qd x2 days Adjust based on INR Typical Maintenance: 2-10mg/day Interferes with hepatic synthesis of vitamin K- dependent coagulation factors INR daily until stabilized then q1-4 weeks based on need Target INR is 2.5 unless mechanical valve, then target INR is 3 s/sxs of necrosis and/or gangrene Narrow therapeutic index therefore increased risk of bleeding in patients with: anemia, CV disease, INR >4.0, trauma, DM, diarrhea, hepatic disorders/impairm ent, vitamin K deficiency, protein C and S deficiency CYP450 inducers/inhibitors

23. Maintenance therapy for DVT/PE NameDosingAnticoagulation Effects MonitoringSpecial Considerations Dabigatran (Pradaxa) 150mg po bidDirect thrombin inhibitor; prevents thrombus development Inhibits both free and clot bound thrombin as well as thrombin- induced platelet aggregation Renal function, serum creatinine, aPTT DO NOT use in patients with mechanical valve Conversion from warfarin: d/c warfarin and initiate dabigatran at INR <2 Conversion from parenteral anticoagulation: give 0-2hrs prior to initiation

24. Pharmacological Treatment Thrombolytics: LAST RESORT!!  Used to dissolve a pathologic intraluminal thrombus or embolus that has not been dissolve by endogenous fibrinolytic system Alteplase, tPA (Activase) Tenecteplase (TNKase) Streptokinase (Kabikinase, Streptase) Urokinase (Abbokinase) Reteplase (Retevase)

26. Pharmacological Treatment CONTRAINDICATIONS: Absolute:  Active severe hemorrhage  Recent intracranial hemorrhage Relative:  recent or imminent surgery or trauma  anemia (hematocrit less than 30)  renal/liver disease  history of gastrointestinal hemorrhage  active peptic ulcer disease

27. Pharmacological Treatment Therapeutic outcome considerations: Recurrent DVT or PE Major bleeding All-cause mortality QOL Post-thrombotic Syndrome Length of hospital stay or ICU Symptom relief Ulceration Complications of surgical procedures or acute complications

28. Pharmacological Treatment Duration of Anticoagulation:  Transient risk (i.e. surgery, estrogen use, trauma) 3 months  Idiopathic risk (i.e. protein C, S deficiency) 3-6 months Consideration for indefinite therapy  Recurrent disease or continued risk factors (i.e cancer) Indefinite therapy

29. Non-pharmacological Treatment Mechanical and Surgical Management: Ambulation Elastic compression stockings, bandages, and sleeves Intermittent pneumatic compression (IPC) Catheter-directed thrombolysis (CDT) Catheter-assisted embolectomy Surgical pulmonary embolectomy Inferior vena cava (IVC) filter Pulmonary thromboendarterectomy

30. Special Populations Pregnancy Familial bleeding disorders Severe Renal dysfunction History of HIT

31. Role of the Pharmacist Inpatient: Monitor patients' INR on Coumadin Monitor CrCl in patients on LMWH and UFH Ensure therapeutic appropriateness Risk vs Benefit

32. Role of the Pharmacist Outpatient: Interview new patients on anticoagulation therapy Counsel patients about risks associated with anticoagulation therapy Follow-up with non-compliant patients Stay up to date on latest anticoagulation therapy Certified Anticoagulation Care Provider (CACP)

33. References Dupras D, Bluhm J, Felty C, et al. Venous thromboembolism diagnosis and treatment. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2013 Jan. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet. May 31 2013. Haeger K. Problems of acute deep venous thrombosis. I. The interpretation of signs and symptoms. Angiology. Apr 1969;20(4):219-23. Kearon C, Akl EA, Comerota AJ, Prandoni P, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb. Meignan M, Rosso J, Gauthier H, Brunengo F, Claudel S, Sagnard L, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med. Jan 24 2000;160(2):159-64. Tapson VF. Acute pulmonary embolism. N Engl J Med. Mar 6 2008;358(10):1037-52.

34. Questions?