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Drugs and Coagulation at Point-of-Care

Drugs and Coagulation at Point-of-Care. Stacie Krick Evans, Pharm.D. Orlando Regional Medical Center. Objectives. Review the mechanisms of action between oral and parenteral antiplatelet drugs.

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Drugs and Coagulation at Point-of-Care

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  1. Drugs and Coagulation at Point-of-Care Stacie Krick Evans, Pharm.D. Orlando Regional Medical Center

  2. Objectives • Review the mechanisms of action between oral and parenteral antiplatelet drugs. • Explain the differences in mechanisms of action between vitamin K antagonists, factor Xa inhibitors, indirect thrombin inhibitors, and direct thrombin inhibitors (DTIs). • Discuss the impact of multiple antiplatelet and anticoagulant drugs on point of care testing. • Discuss the limitations associated with unfractionated heparin. • Identify opportunities for collaboration among pharmacists and laboratory personnel in the healthcare setting.

  3. Antiplatelet Drugs

  4. Oral antiplatelet drugs • Aspirin • Clopidogrel (Plavix®) • Ticlopidine (Ticlid®) • Aspirin/Dipyridamole (Aggrenox®)

  5. Oral antiplatelet drugs • Aspirin • Irreversible inhibitor of cyclooxygenase (COX) which prevents formation of the platelet-aggregating substance thromboxane A2. • Monitoring • Clopidogrel • Blocks platelet aggregation by inhibition of ADP receptor on the platelet membrane. • Monitoring

  6. Parenteral antiplatelet drugs • Glycoprotein IIb/IIIa Inhibitors • Abciximab (Reopro®), eptifibatide (Integrilin®), tirofiban (Aggrastat®) • Prevent fibrinogen binding to Gly IIb/IIIa receptor and block platelet aggregation producing profound platelet inhibition. • Used in conjunction with percutaneous coronary interventions (PCI).

  7. Parenteral antiplatelet drugs • Often administered with ASA, heparin/LMWH, clopidogrel. • Monitoring • ACT • Platelet count

  8. Antithrombin Drugs • Vitamin K Antagonists - Warfarin (Coumadin®) • Recent clinical uses and applications: • Development of clinical guidelines for management of oral anticoagulants; the 7th ACCP Consensus Conference on Antithrombotic Therapy to be released Summer 2004. • Standardization of laboratory monitoring • New indications and treatment protocols • Point-of-care testing.

  9. Antithrombin Drugs • Warfarin interferes with vitamin-K dependent carboxylation of several coagulation factors including II, VII, IX, and X, as well as anticoagulant proteins C and S. • Full anticoagulant effect is delayed • Average daily dose 4-5mg.

  10. Warfarin - monitoring • International Normalized Ratio (INR) • The need for frequent testing and dose adjustments detracts from warfarin’s ease of use in clinical practice. • Anticoagulation Clinics • Coagucheck S ®

  11. Unfractionated Heparin • Complex glycosaminoglycan isolated and purified from animal tissues (porcine intestinal mucosa). Bovine lung heparin no longer available. • Binds to endothelial cells and macrophages, as well as plasma proteins (platelet factor 4 and von Willebrand factor).

  12. Unfractionated Heparin (UFH) • Exerts its anticoagulant effect via antithrombin • Heparin binds to and produces a conformational change in antithrombin. • Anticoagulant effect reversed with protamine.

  13. UFH - monitoring • Activated partial thromboplastin time (aPTT) - most commonly used test to monitor heparin therapy. • Activated clotting time (ACT) – bedside test most often used when high doses of heparin are required. • The laboratory-based aPTT has a stronger correlation to heparin concentration than the bedside-based aPTT and ACT. (Ann Pharmacother 2002;36:7-11)

  14. Heparin Resistance(Lab Hematol. 2003;9:125-131) • Definition: An inadequate response to heparin at a standard dose for achieving a therapeutic goal. • Need for heparin doses > 500 units/kg to prolong an ACT > 400 seconds. • An ACT < 480 seconds after > 400 units/kg of heparin.

  15. Heparin Resistance(Lab Hematol. 2003;9:125-131) • Proposed mechanisms of heparin resistance: • Heparin-induced thrombocytopenia • Up to 38% of patients with HIT may develop subsequent heparin resistance. • Decreased antithrombin (AT) level • Acquired or hereditary • Heparin therapy is thought to induce deficiency of AT in the first 12 hours of therapy. • Elevated factor VIII level

  16. Low Molecular Weight Heparin • Low molecular weight heparins (LMWH) are prepared from UFH by enzymatic or chemical hydrolysis. Available products • Fragmin® (dalteparin) • Lovenox® (enoxaparin) • Innohep® (tinzaparin)

  17. LMWH • Binds to antithrombin and inactivates thrombin to a lesser extent than UFH because the smaller molecule fragments cannot bind thrombin and antithrombin simultaneously.

  18. LMWH • Advantages • Better bioavailability • Longer half-life • Administered subcutaneously either once or twice daily • More predictable dose response • HIT Type II occurs less often with LMWH • Disadvantages • Protamine only partially reverses anticoagulant response.

  19. LMWH – Monitoring(Thromb Haemost 2002;87:163-164) • Debate over need to monitor LMWH in certain subgroups (i.e., children, pregnant women, morbidly obese, patients with renal failure). • Anti-Xa assay is generally used.

  20. LMWH – Monitoring(Thromb Haemost 2002;87:163-164) Limitations to Anti-Xa Assay: • Anti-Xa level has not been demonstrated to be a good predictor of bleeding during treatment with LMWH. The clinical status of the patient and dose administered are more informative. • Ani-Xa level has not been demonstrated to be a good predictor of bleeding risk and antithrombotic efficacy in thrombophylaxis with LMWH. • Relative anti-Xa and anti-IIa activities vary between preparations, and the antithrombin activity appears to be the more important in kinetic studies. • The comparability between commercially available anti-Xa chromogenic assays is poor. Assays should preferably be LMWH, method and equipment specific.

  21. Factor Xa Inhibition • Arixtra ® (fondaparinux) • Synthetic version of the pentasaccharide sequence of UFH and LMWH that binds to antithrombin and modifies its confirmation, inhibiting factor Xa.

  22. Arixtra® (fondaparinux) • FDA approved for prophylaxis of venous thromboembolism in patients undergoing hip fracture, hip replacement, or knee replacement surgery.

  23. Arixtra® (fondaparinux) • Does not affect platelet function • In vitro studies suggest that fondaparinux does not react with platelet factor 4 antibodies, potentially eliminating the risk of HIT. • No monitoring indicated; only fondaparinux can be used to calibrate the anti-Xa assay; the international standards of heparin or LMWH are not appropriate for this use.

  24. Direct Thrombin Inhibitors (DTI) Available Agents • Refludan® (lepirudin) • Argatroban • Angiomax® (bivalirudin) • Exanta® (ximelagatran)* *Awaiting FDA approval

  25. Direct Thrombin Inhibitors • Thrombin is the central effector of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. • Target sites on the thrombin molecule responsible for substrate recognition and/or cleavage. • By blocking either the active site alone or both the active site and exosite I, DTIs specifically inhibit thrombin activity.

  26. Refludan® (lepirudin) • First DTI to become available. • Potent and specific thrombin inhibitor. • Due to the almost irreversible nature of the bond between lepirudin and thrombin, bleeding problems have occurred. • No antidote is available to reverse the effect.

  27. Refludan® (lepirudin) • Therapeutic Use • Patients with HIT or HIT with thrombosis. • Monitoring • aPTT • aPTT ratio of 1.5-2.5 is used because the bleeding risk increases above this range with no increase in efficacy.

  28. Refludan® (lepirudin) Ecarin Clotting Test (ECT) • Pharmanetics has received an Humanitarian Device Exemption (HDE) for its Ecarin Clotting Time (ECT) test card from FDA www.fda.gov/cdrh/ode/h990012sum.html . • ECT has been studied in patients with HIT receiving lepirudin and bivalirudin undergoing coronary artery bypass grafting (CABG). • Anesth Anal 2003;96:283-286 • Am J Cardiol 2003;91:1110-1113 • J Cardiothorac Vasc Anesth 2000 Jun;14(3):249-252

  29. Argatroban • Small molecule that binds reversibly to the active site of the thrombin molecule. • Approved for patients with HIT or HIT with thrombosis and patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin. • No reversal agent available.

  30. Argatroban - Monitoring • aPTT with a ratio of 1.5 to 3.0 times the mean normal value is used. • Argatroban synergistically interferes with the INR; the PT or INR cannot always be reliably used to monitor warfarin therapy in patients receiving argatroban. Effect dependent on argatroban dose and ISI of thromboplastin used. • Argatroban alone also interferes with the INR and is dependent upon the ISI of the thromboplastin used.

  31. Angiomax® (bivalirudin) • Synthetic molecule designed on the basis of structural studies of hirudin; formerly known as hirulog. • Undergoes reversible binding may lead to less bleeding. • No antidote available for reversal.

  32. Angiomax® (bivalirudin) • Therapeutic use • FDA- approved • Anticoagulation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin. • Other • Treatment of patients with HIT and unstable angina. • Anticoagulation for patients with HIT undergoing CABG (on pump or off-pump).

  33. Angiomax® (bivalirudin) • Monitoring • ACT for patients undergoing PTCA. • ACT for patients undergoing CABG. • aPTT for patients with HIT or unstable angina.

  34. Ximelagatran • Prodrug administered orally and transformed after absorption into active drug melagatran. • Selective, competitive reversible active-site inhibitor of both free and clot-bound thrombin. • The stable and reproducible pharmacokinetic profile of ximelagatran suggests that coagulation monitoring should not be required. • Will be marketed as Exanta®

  35. Ximelagatran vs. Warfarin

  36. Ximelagatran • Potential uses • Prophylaxis for VTE in orthopedic patients • Treatment of Acute DVT • Prevention of stroke in AFIB patients • Prevention of recurrent coronary events

  37. Pharmacists and Point of Care • Point of care testing provides immediate availability of lab results that are beneficial in clinical decision making. • Point-of-care testing allows pharmacists to increase their participation in the provision of health care.

  38. Pharmacists and the Lab • Areas for opportunity • Education regarding new drugs. • Collaboration in research. • Participation in performance improvement teams.

  39. Summary • New anticoagulant therapeutic agents continue to be studied; including antiplatelet agents, direct Xa inhibitors, and direct thrombin inhibitors. • Heparin resistance should be considered in certain populations. • Opportunities for pharmacists and laboratory personnel include both inpatient and outpatient settings.

  40. QUESTIONS ?

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