Anticoagulant Drug Use

1. Anticoagulant Drug Use • Knowledge of the commonly used anticoagulant drugs is important in reducing the likelihood of patient harm associated with their administration. • Common drugs used for therapeutic anticoagulation are warfarin (Coumadin), unfractionated heparin (commonly referred to as heparin) and low molecular weight heparin (LMWH, ex: Lovenox). • Newer oral anticoagulants include dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).

2. Warfarin • Objectives • Learn mechanism of action of warfarin • Explain warfarin dosing and monitoring parameters • Identify adverse drug events that can be caused by warfarin administration • Understand key patient counseling points

3. Warfarin - Pharmacology • Interferes with liver activation of vitamin K-dependent coagulation factors (II, VII, IX, X) • Warfarin has no effect on coagulation factors already present in the circulation and therefore it takes time to see the clinical effect of warfarin. • Onset of action (or clinical activity) varies from 36-72 hours

4. Warfarin - Dosing • The Initial Inpatient Warfarin Dose Order (WC) is to be used. • Most patients can be initiated with 5 mg given by mouth daily • Dosage adjustments are based on the target International Normalized Ratio (INR) as determined by patient’s indication

5. Warfarin - Monitoring • The INR result is to be obtained within the 48 hours prior to initiation. Then every 24, 48, or 72 hours INRs are to be drawn until goal is met. • It is NOT acceptable to give warfarin without INR result. • For most indications, the goal INR is 2-3. • Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at any site.

6. Warfarin – Drug Interactions Common drugs/classes known to increase warfarin effect: • Acetaminophen • Allpurinol • Amiodarone • Aspirin • Cephalosporins • Citalopram • Diltiazem • Fish oil • Fluconazole • Fluoroquinolones • Heparins • Isoniazid • Macrolides • Metronidazole • NSAIDS • Omeprazole • Propafenone • Quinidine • Sertraline • Thyroxine • Trimethoprim-Sulfa

7. Warfarin – Key Counseling Points • Provide patient with a printed “Warfarin Medication Guide” and verbal information about the medication The following points should be reviewed with patient/family: • Purpose of warfarin therapy • Identification of generic and brand name products • Warfarin administration and dosing (missed doses, duration of therapy) and importance of compliance • Purpose and need for INR testing • Drug interactions (Avoid aspirin, ibuprofen, alcohol, herbals) • Consistent intake of foods containing Vitamin K (green leafy vegetables) • Monitor for signs of bleeding (nose, mouth, GI, GU) and call MD if serious • Communicate warfarin use to other healthcare professionals • Consult with a pharmacist or other health care professional when taking any new medications (OTC, prescription or herbal) • Document patient education and their comprehension

8. Warfarin – How to treat an Elevated INR • Consider the patient’s future anticoagulation needs when planning the reversal of warfarin. Large doses of vitamin K do not reverse anticoagulation faster and may cause a period of warfarin resistance • See the Warfarin Reversal Protocol, which can be viewed on the BJC.net site, under Pharmacy and then Anticoagulation Resources. It may also be viewed in the order entry section of Compass under “warfarin reversal” or “phytonadione for elevated INR due to warfarin.

9. Question • The clinical effects of warfarin are seen within • 8 hours • 24 hours • 36-72 hours • 5 days

10. Answer • The clinical effects of warfarin are seen within 36-72 hours. Warfarin has no effect on coagulation factors already present in the circulation and therefore it takes time to see warfarin’s clinical effect.

11. Question • The major side effect of warfarin is • bleeding • skin necrosis • diarrhea • itching

12. Answer • These are all potential side effects of warfarin, but the major concern with this medication is bleeding. Warfarin may cause severe bleeding that can be life-threatening and even result in death. A new medication called Kcentra (4-Factor Prothrombin Complex Concentrate) may be used to treat severe life-threatening bleeds in conjunction with phytonadione (Vitamin K).

13. Question • Which of the following points should be included when counseling a patient on warfarin? • Drug interactions • Importance of INR monitoring • Compliance • Dietary precautions • Monitoring for signs of bleeding • All of the above

14. Answer • It is important to counsel patients about drug interactions, follow-up lab monitoring, compliance, dietary precautions, and how to monitor for signs of bleeding. All these points need to be addressed because they can impact therapeutic outcomes. • Patient education is essential for effective oral anticoagulation.

15. Question • Irma N Reynolds is an 86 y/o female who presents to the ED with complaints of frequent nose bleeds that are hard to stop since she was started on warfarin for atrial fibrillation. Which of the following is the most appropriate? • Tell Irma this is a known side effect of warfarin and to come back if it gets worse • Give patient fresh frozen plasma and 10mg Vitamin K IVPB • Check her INR • Tell her to hold her next 2 doses of warfarin and then continue taking as prescribed

16. Answer • In this situation, it would be appropriate to check the patient’s INR prior to making any changes in therapy. The INR value will give you an indication as to her risk of bleeding, and then adjustments in therapy. • The 2012 CHEST Guidelines recommend to hold the warfarin dose & “monitor” patient if INR is less than or equal to 10, and there is no evidence of bleeding, and there is no planned surgery/procedure within 24 hours. Vitamin K offers no advantage.

17. Unfractionated Heparin (Heparin) • Objectives • Learn mechanism of action of heparin • Explain heparin dosing and monitoring parameters • Identify adverse drug events that can be caused by heparin administration

18. Heparin - Pharmacology • Heparin enhances the action of antithrombin III, thereby blocking thrombosis through inactivation of Factor Xa and inhibition of prothrombin’s conversion to thrombin. This also prevents fibrin formation from fibrinogen during active thrombosis. • Its onset of action is immediate when administered intravenously and approximately 20-30 minutes when given subcutaneously • This drug is not for IM use

19. Heparin - Monitoring • An activated partial thromboplastin time (aPTT) should be ordered before initiation, 6 hours after initial heparin bolus/infusion, and 6 hours after any change in rate of the infusion • When 2 consecutive aPTTs are therapeutic (1.5-2.5 times the control aPTT, the aPTT should be monitored at least daily • BJWCH therapeutic aPTT range: 60-100 seconds • CBC with platelets (or hemogram) should be monitored before initiation and every 72 hours throughout therapy. PT/INR should be monitored before initiation.

20. Heparin - Contraindications • Hypersensitivity to heparin or any component of the formulation • Severe thrombocytopenia including heparin-induced thrombocytopenia • Uncontrolled active bleeding except when due to disseminated intravascular coagulation • Suspected intracranial hemorrhage

21. Heparin – Therapeutic Dosing • It should be given as a weight-based bolus dose followed by weight-based infusion rate which is adjusted according to the patient’s aPTT. • The indication for the use and patient’s risk of bleeding determines the initial starting heparin infusion rate. • For the treatment of deep vein thrombosis (DVT)/pulmonary embolism, heparin should be administered (with the initiation of warfarin) for at least 5 days and/or until there are 2 consecutive therapeutic INRs.

22. Heparin – Side Effects • Fever, headache, chills, erythrema/injection site ulcer after subcutaneous injection • Hyperkalemia, hematoma • Heparin-induced thrombocytopenia • Increase hepatic aminotransferase levels • Osteoporosis with long-term, high dose administration

23. HIT Treatment • Discontinuation of all forms of heparin including flushes for line maintenance • Alternatives to heparin in these patients include Argatroban , lepirudin (Refludan), and bivalirudin (Angiomax) if needed. • Warfarin therapy if needed is contraindicated until platelet count has recovered to at least > 100,000/mm3

24. Question • Which lab test should be ordered 6 hours after initial heparin bolus and start of heparin infusion and its result is used to make dosage adjustments? • PT • INR • Anti-Xa • aPTT

25. Answer • The aPTT is used to monitor heparin anticoagulation therapy. The PT and INR test is used to evaluate the effectiveness of warfarin therapy, while the anti-Xa test monitors patients on low molecular weight heparin (ex: Lovenox)

26. Question • Heparin can be given as a weight-based bolus dose followed by a weight-based infusion rate, which is adjusted according to the patient’s aPTT. • True • False

27. Answer • True

28. Question • Heparin is associated with which of the following side effects? • Purple toes syndrome • Hyponatremia • Thrombocytopenia • Dizziness

29. Answer • Heparin-induced thrombocytopenia is a serious side effect of heparin therapy. This is characterized by a decrease in platelets by more than 50% from baseline or an absolute platelet count of < 100,000/mm3 following exposure to heparin or low molecular weight heparin.

30. Question • Patients who develop heparin-induced thrombocytopenia (HIT) can be treated with all of the following except: • Argatroban • Enoxaparin • Bivalirudin • Lepirudin

31. Answer • Patients with heparin-induced thrombocytopenia should not be treated with enoxaparin. All forms of heparin products should be discontinued. Alternatives to heparin therapy include argatroban, bivalirudin, and lepirudin. • Only argatroban is available at BJWCH.

32. Low Molecular Weight Heparin (LMWH) • Objectives • Learn mechanism of action of LMWH • Explain LMWH dosing and monitoring parameters • Identify adverse drug events that can be caused by LMWH • Understand key counseling points

33. LMWH - Pharmacology • LMWH has a small effect on the activated partial thromboplastin time (aPTT) and is a strong inhibitor of factor Xa • Enoxaparin (Lovenox) has an onset of action of around 3-5 hours and is renally excreted • These drugs are not for IM use

34. LMWH - Monitoring • Anti-factor Xa level monitoring can be considered in patients with poor renal function and the morbidly obese • CBC with platelets (of hemogram) and serum creatinine should be monitored before initiation and throughout therapy every 3 days.

35. LMWH - Contraindications • Hypersensitivity to the drug, heparin, or pork products • Active major bleeding • Thrombocytopenia • The black box warning with these agents is as follows: • Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis

36. LMWH – Therapeutic Dosing • For the treatment of DVT/PE, LMWH should be administered (with the initiation of warfarin) for at least 5 days and/or until there are 2 consecutive therapeutic INRs • The dose of enoxaparin for treatment of DVT/PE, unstable angina and non-ST segment elevation myocardial infarction (UA/NSTEMI) is 1mg/kg subcutaneously every 12 hours (in patients with a CrCl < 30 ml/min the enoxaparin dose is 1mg/kg subcutaneously every 24 hours). Treatment of DVT/PE may also be given as 1.5mg/kg every 24 hours. • In patients with morbid obesity (BMI > 40) and normal renal function, a starting dose of 0.75mg/kg subcutaneously every 12 hours is recommended along with Anti-Xa monitoring.

37. LMWH – Side Effects • Hemorrhage (includes cases of intracranial, retroperitoneal, or intraocular hemorrhage) • Thrombocytopenia including HIT • Hypochromic anemia • Elevated transaminase levels • Injection site hematoma and local reaction (irritation, pain, ecchymosis, erythema)

38. Enoxaparin – Key Counseling Points • Lovenox kits/booklets are available from pharmacy to provide to patients. • Review and follow all of the steps to ensure proper administration and safe disposal of Lovenox pre-filled syringes. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. To minimize bruising, do not rub the injection site after completion of the injection. • Monitor for signs of bleeding • Periodic serum creatinine, CBC including platelet counts, and stool occult blood tests are recommended to monitor drug therapy

39. Question Which of the following statements are TRUE about enoxaparin? • Is a strong inhibitor of Factor VIIa • Is also known as unfractionated heparin • Can be administered intramuscularly (IM) • Should be renally dose adjusted

40. Answer • Enoxaparin dose should be adjusted in patients with decreased renal function since it is eliminated in the urine. This low molecular weight heparin is a strong inhibitor of factor Xa and cannot be administered IM.

41. Question • Low molecular weight heparins (LMWH) are not associated with thrombocytopenia. • True • False

42. Answer • Heparin-induced thrombocytopenia is a serious adverse event that can occur in any patient exposed to heparin. This drug reaction is associated with unfractionated and low molecular weight heparin.

43. Question • Which of the following patients should not receive a LMWH? • Patient with an allergy to heparin and pork products • Patient with active major bleeding • Patient with epidural anesthesia • All of the above

44. Answer • All of the above are contraindications to the use of low molecular weight heparins. In addition to patients with hypersensitivity, this medication should be avoided in patients with active bleeds because it can exacerbate their condition. Giving the medication in patients with epidural anesthesia increases the risk of spinal or epidural hematoma.

45. Direct Thrombin Inhibitor (DTI) • Objectives • Learn mechanism of action of dabigatran (Pradaxa) • Explain dosing and monitoring parameters • Identify adverse drug events that can be caused by DTI • Understand key counseling points

46. DTI – Pharmacology • Dabigatran (Pradaxa) is the only orally available DTI in the US • Dabigatran is only indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvularatrial fibrillation. • Dabigatran is a prodrug and it is a reversible and selective direct thrombin inhibitor. It inhibits thrombin and thrombin-induced platelet aggregation. • It has a fast onset of action with peak levels reached within 1-4 hours. Half-life is 8-17 hours depending on renal function.

47. DTI - Monitoring • A baseline serum creatinine is required prior to starting therapy. Serum creatinine should be monitored periodically throughout therapy • There are no requirements for coagulation monitoring.

48. DTI - Contraindications • Dabigatran should not be taken by patients with an active pathological bleed • Dabigatran should not be taken by patients with a serious hypersensitivity to carrageenan, FD&C blue #2, FD&C yellow #6, hypromellose, potassium chloride, titanium dioxide, or black edible ink.

49. DTI – Therapeutic Dosing • The recommended dose is 150mg po BID in patients with a CrCl > 30 ml/min and 75mg po BID if CrCl is 15-30 ml/min • Dabigatran capsules should be swallowed whole, without chewing, breaking, or opening • Dabigatran may be taken with or without food • A missed dose should be skipped if it cannot be taken at least 6 hours before the next schedule dose

50. DTI – Side Effects • Dabigatran can cause serious and potentially fatal bleeding. Bleeding risk increases with age and decrease renal function • Thrombosis may occur with abrupt discontinuation of dabigatran • Gastritis-like symptoms have occurred in 35% of patients taking dabigatran