Anticoagulation, Antiplatelets and Fibrinolytics.pdf

1 ANTICOAGULANT, ANTIPLATELET, AND FIBRINOLYTIC AGENTS Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 2 Objectives Discuss commonly used laboratory tests that are used to monitor for coagulation disorders and anticoagulant /antiplatelet/fibrinolytic agents...

1 ANTICOAGULANT, ANTIPLATELET, AND FIBRINOLYTIC AGENTS Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 2 Objectives Discuss commonly used laboratory tests that are used to monitor for coagulation disorders and anticoagulant /antiplatelet/fibrinolytic agents Discuss indications, pharmacology, adverse events, contraindications of various anticoagulant, antiplatelet, thrombolytic, and reversal agents Discuss surgical and anesthesia implications for patients who are receiving anticoagulant, antiplatelet, and thrombolytic agents 3 Definition of Terms Anticoagulant agents are medications that delay or prevent the clotting of blood by direct or indirect actions on the coagulation cascade system Antiplatelet agents are medications that prevent the formation of thrombus by interfering with the normal adhesive and aggregation activity of platelets Fibrinolytic agents are medications that possess inherent fibrinolytic effects or enhance the body’s fibrinolytic system aka “clot busters” 4 Prothrombin Time (PT) Determines the function of the extrinsic system and the common pathway of the coagulation system Prothrombin time test measures the activity of 3 specific vitamin K dependent clotting factors (factors II, VII, X) The PT tests yields evidence about the current synthetic capacity of the liver, the adequacy of vitamin K absorption, and the inhibition on the clotting factor synthesis of warfarin Normal Range is 12-14 seconds International normalized ratio (INR) is the ratio of a patient’s prothrombin time to a normal (control) sample and standardizes the results of the prothrombin time since different reagents are used when calculating a prothrombin time 5 activated Partial Thromboplastin Time (aPTT) Measures the activity of the intrinsic and common pathway of the coagulation system Measures the time it takes for a fibrin clot to form after calcium and an activating agent are added to the patient’s plasma Sensitive to levels of thrombin (factor IIa), factor IXa, Xa and XIIa The aPTT test cannot be used and is not reliable in those patients with documented lupus anticoagulant (LAC) because LAC interferes with the aPTT The aPTT is widely used for monitoring unfractionated heparin and injectable direct thrombin inhibitors 6 Activated Clotting Time (ACT) The activated clotting time (ACT) is commonly used to monitor treatment high heparin doses and concentrations given before, during and shortly after certain medical procedures such as cardiopulmonary bypass surgery, cardiac angioplasty/catheterization and dialysis The ACT measures the onset of clot formation and is performed by mixing whole blood with an activating substance that has a large surface area, such as celite or kaolin. This is a contact activation through the intrinsic pathway of the clotting cascade where factor XII initiates activation of the clotting cascade and ultimately a clot is formed Measures the activity of the intrinsic and common pathway of the coagulation system 7 Activated Clotting Time (ACT) Normal ACT range is 100-150 seconds, depending on the timing device used Goal ACT for most procedures is typically between 300-450 seconds, but this may vary from institution to institution Being within the goal ACT means that there is adequate anticoagulation to perform the procedure The ACT response to heparin is not linear and several factors can influence the ACT such as hypothermia, thrombocytopenia, presence of aprotinin or preexisting coagulation deficiencies (fibrinogen, factor XII, factor VII to name a few) therefore the ACT needs to be checked frequently during surgical procedures 8 Thrombin Time (TT) Helps to assess the clotting of plasma by thrombin (factor IIa) and is affected by quantitative and qualitative abnormalities of fibrinogen The TT tests the time it takes for the formation and the appearance of a fibrin clot This test bypasses all earlier steps of the coagulation pathway and assesses the final common pathway Prolongation indicates a deficiency of fibrinogen or inhibition of thrombin Is used to monitor the effects of systemic fibrinolytic therapy, unfractionated heparin and direct thrombin inhibitor agents Normal range is < 30 seconds 9 Anticoagulants and Spinal/Epidural Hematoma Warning Epidural or spinal hematomas may occur in patients who are anticoagulated with unfractionated heparin, low molecular weight heparins, heparinoids, fondaparinux, and other anticoagulants and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, NSAID’s, platelet inhibitors or other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis 10 Unfractionated Heparin Chemistry UFH is a highly sulfated mucopolysaccharide molecule that is heterogeneous with respect to molecular size, anticoagulant activity and pharmacokinetic properties UFH is a large, negatively charged acidic molecule with molecular sizes ranging from 3,000 to 30,000 daltons Is also present endogenously in the secretory granules of mast cells, basophils and the liver Is derived from porcine intestinal mucosa (Heparin is a biologic source) 11 Unfractionated Heparin: Mechanism of Action Heparin acts by FIRST binding to and forming a complex with antithrombin (formally called antithrombin III, AT-III) causing a conformational change in antithrombin which accelerates the action of antithrombin by 1,000 fold or more. The AT/Heparin complex then irreversibly inhibits the activated coagulation factors IIa, IXa, Xa, XIa and XIIa Antithrombin is a required cofactor for UFH anticoagulant effects By inactivating thrombin (factor IIa), heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factor V and factor VIII A specific portion of heparin, called the pentasaccharide sequence, binds to AT forming the AT/Heparin complex Only 1/3rd of the heparin molecule contains this high-affinity pentasaccharide sequence required for anticoagulant activity AT = Antithrombin 12 Unfractionated Heparin: Mechanism of Action (cont.) Thrombin (Factor IIa) and Factor Xa are the most sensitive to inhibition by the AT/Heparin complex UFH must form a bridge between AT and thrombin in order to inactivate thrombin (see picture) UFH need only bind to AT in order to inhibit factor Xa (see picture) Heparin catalyzes the rates of factor Xa and thrombin (IIa) to a similar extent, has an anti-factor Xa to anti-factor IIa inactivated ratio of 1:1 In addition to antithrombin, UFH also binds to various plasma proteins (ie; PF4), endothelial cells, macrophages and also inhibits platelet function. Heparin is a very non-specific agent Binding to all of these substances contributes to the variable anticoagulant response among patients 13 Unfractionated Heparin: Mechanism of Action (cont.) Heparin need only bind to AT via its high-affinity pentasaccharide sequence in order to inactivate factor Xa Factor Xa Thrombin Heparin must bind to BOTH AT and thrombin to form a Ternary Heparin/AT/Thrombin Complex in order for thrombin to be inactivated 14 Unfractionated Heparin: Mechanism of Action (cont.) Heparin blocks the intrinsic and common pathways of the coagulation cascade Intrinsic Pathway: Surface contact/Vessel Injury Extrinsic Pathway: Tissue Damage/Cell Damage THE COAGULATION CASCADE XII XIIa XI Tissue Factor XIa IX VIIa VII IXa VIII Thrombin (IIa) X VIIIa Heparin + AT V XIII Xa Thrombin (IIa) Va Ca2+ 2+ Thrombin (IIa) II Ca XIIIa Ca2+ Common Pathway Fibrinogen (I) AT = Antithrombin Soluble Fibrin (Ia) Stabilized 15Fibrin 16 Unfractionated Heparin: Pharmacokinetics Absorption Heparin is a poorly lipid-soluble, high-molecular weight substance that cannot cross lipid barriers in significant amounts Heparin is not absorbed orally and therefore must be administered parenterally Absorption varies when administered subcutaneously Is administered either subcutaneously or continuous IV infusion Onset of action is variable with SQ but is generally 1-2 hours Onset of action is immediate with IV administration NEVER give UFH via IM route due to potential for large hematoma formation 17 Unfractionated Heparin: Pharmacokinetics (cont.) Biologic t1/2 of heparin is dose-dependent and ranges from 1-3 hours 25U/kg IV = 30 min 100u/kg IV = 60 min 400U/kg IV = 150 min The anticoagulant response of heparin is non-linear at therapeutic doses, with both the intensity and duration of effect rising disproportionately with increasing dose Hepatic disease and renal dysfunction can prolong the biologic t1/2 of heparin The response to heparin varies among patient to patient! 18 Unfractionated Heparin: Pharmacokinetics (cont.) Unfractionated heparin is physiologically cleared by 2 distinct mechanisms First, heparin is cleared and degraded primarily by the reticuloendothelial system, this is a rapid and saturable process At therapeutic doses, a large proportion of heparin is cleared through this mechanism A second slow and non-saturable process involves renal clearance of undegraded heparin and this predominates at very higher doses Does not cross the placenta and is not excreted in breast milk 19 Unfractionated Heparin: Anticoagulant Monitoring Heparin requires close monitoring due to its unpredictable anticoagulant response The anticoagulant activity of heparin can be monitored using any of the following tests: 1. 2. 3. aPTT (activated Partial Thromboplastin Time) ACT (Activated Clotting Time) Heparin anti-factor Xa assay In general, low-dose subcutaneous heparin (< 5000 units twice daily or three times daily) does not effect the aPTT, ACT or Heparin anti-factor Xa levels There are some exceptions to this general rule 20 Unfractionated Heparin: Anticoagulant Monitoring aPTT (activated Partial Thromboplastin Time) Sensitive to levels of thrombin (IIa), factor IXa, Xa and XIIa aPTT ratio of 1.5 to 2.5 times the control reagent/normal values is the goal for anticoagulation Control reagent values that are used to calibrate lab equipment vary from institution to institution, therefore, when the above goal aPTT range is converted into seconds, the goal range in seconds will vary from institution to institution! aPTT is measured at baseline then 6 hours after start of therapy then 6 hours after any rate change aPTT assesses the intrinsic and final common pathway 21 Unfractionated Heparin: Anticoagulant Monitoring (cont.) ACT (Activated Clotting Time) Used to monitor higher heparin doses and concentrations given to patients undergoing PCI or CABG procedures Goal typically reported between 300-450 seconds Some cardiac institutions target an ACT of 400 seconds For cardiac surgery, a baseline value is obtained before heparin administration, then 3-5 minutes after the initial bolus and then once in goal range, checked at 30 minute intervals during surgery ACT assesses the intrinsic and final common pathways Heparin anti-factor Xa assay This is the most accurate assay for monitoring UFH therapy Expected therapeutic range is 0.3-0.7 anti-Xa units/mL PCI = Percutaneous Coronary Intervention CABG = Coronary Artery Bypass Graft 22 Unfractionated Heparin: Other Monitoring Platelet count, Hgb/Hct, CBC Signs and symptoms of bleeding Risk of bleeding increases with heparin dose and with concomitant use with other agents that increase bleeding risk (i.e.: thrombolytics, glycoprotein IIb/IIIa inhibitors, warfarin, aspirin, clopidogrel, prasugrel, etc.) 23 Unfractionated Heparin: Clinical Uses VTE treatment and prophylaxis DVT/PE ACS Treatment Unstable Angina, NSTEMI, STEMI (acute MI) Ischemic Stroke Anticoagulant during CABG procedure Anticoagulant “bridge” during initiation of warfarin therapy in patients such as those with atrial fibrillation or in VTE treatment ACS = Acute Coronary Syndrome, CABG = Coronary Artery Bypass Graft, DVT = Deep Vein Thrombosis, NSTEMI = Non-ST Segment Elevation Myocardial Infarction, VTE = Venous thromboembolism, PE = Pulmonary Embolism, STEMI = ST Segment Elevation Myocardial Infarction 24 Unfractionated Heparin: Dosing VTE Prophylaxis Heparin 5000 units SQ q 8 - 12 hours prophylaxis doses Treatment Dosing Weight based IV dosing nomogram that is adjusted based on either the aPTT, ACT, or heparin anti-factor Xa assay (the anticoagulation monitoring test you use depends on the clinical indication) You can also administer high doses of heparin subcutaneously and give twice a day to achieve a therapeutic anticoagulation effect. The dose is calculated using the patient's weight. VTE = Venous thromboembolism 25 Unfractionated Heparin: Dosing (cont.) Heparin requirements are increased during pulmonary embolic disease Heparin requirements are reduced and elimination t1/2 is prolonged in hypothermia The doses of UFH recommended for ACS are LOWER than those used for VTE treatment Thus, hospitals should use 2 different dosing nomograms for heparin depending on the indication ACS = Acute Coronary Syndrome VTE = Venous thromboembolism 26 Unfractionated Heparin: Adverse Effects Bleeding/Hemorrhage Is the most common serious adverse effect Risk of bleeding INCREASES with heparin dose Most common site usually is the GI System Thrombocytopenia Osteoporosis (due to aldosterone suppression) Complication of long-term heparin therapy Injection site reactions such as erythema, hematoma Hyperkalemia Anaphylactoid and hypersensitivity reactions Fever, chills, urticaria, tachycardia, hypertension, dyspnea, cardiopulmonary arrest Warkentin TE et al. Chest 2008;133(6 suppl): 340-380S 27 Unfractionated Heparin: Drug-Drug Interactions Can displace alkaline drugs from protein binding sites May have interaction with drugs such as diazepam and propranolol which are highly protein bound drugs Nitroglycerin has been reported to decrease heparin’s anticoagulant effects which may increase the required dose of heparin 28 Thrombocytopenia Thrombocytopenia resulting from the use of heparin products can be classified into two distinct categories/syndromes Heparin-associated thrombocytopenia (HAT) Heparin-induced thrombocytopenia (HIT) Heparin-associated thrombocytopenia (HAT) Early, mild, transient fall in platelet count Defined as a platelet count of 100 – 130 × 103/mm3 Occurs 1 – 4 days after the start of heparin therapy Occurs in up to 25% of patients who receive heparin and this is the more common syndrome Patients with heparin-associated thrombocytopenia usually do not experience thrombotic complications Treatment is not necessary because platelet counts recover soon after heparin is discontinued Dager WE, White RH. Ann Pharmcother. 2002;36:489–503. 29 Heparin Induced Thrombocytopenia (HIT): Pathophysiology The 2nd, more severe thrombocytopenia, is called heparin-induced thrombocytopenia Is an antibody, immune-mediated syndrome caused by heparin therapy PF4 is found on the surface of platelets and endothelial cells Heparin binds to PF4 forming a heparin-PF4 complex. IgG antibodies in circulation bind to this complex & activate platelets & cause the release of prothrombotic microparticles, platelet consumption, thrombocytopenia & thrombosis Cruz-Gonzalez et al. Rev Esp Cardiol. 2007;60(10): 1071-82 PF4 = Platelet Factor 4 30 Heparin Induced Thrombocytopenia (HIT): Clinical Presentation HIT occurs in up to 5% of patient’s receiving UFH Diagnosis of HIT is based on both clinical and serological findings: Platelet count drop < 150,000 mm3 OR 50% drop in baseline platelet count (even if the platelet count is > 150,000 mm3) Onset within 5-14 days after starting ANY UFH product Thrombosis associated with thrombocytopenia Other causes of thrombocytopenia ruled out PLUS Presence of Anti-PF4-Antibodies Warkentin TE et al. Chest 2008;133: 340-380S 31 Heparin Induced Thrombocytopenia (HIT): Complications Thrombosis is the fundamental clinical complication from HIT development and can occur in arteries or veins manifesting as a DVT, PE, MI, or thrombotic stroke Cruz-Gonzalez et al. Rev Esp Cardiol. 2007;60(10): 1071-82 Warkentin TE et al. Chest 2008;133: 340-380S 32 Heparin Induced Thrombocytopenia (HIT): Treatment Discontinue ALL heparin products IMMEDIATELY, regardless of the source Injectable direct thrombin inhibitors are the first line anticoagulants of choice in the treatment of HIT (these are nonheparin anticoagulants) Warkentin TE et al. Chest 2008;133: 340-380S 33 Unfractionated Heparin: Reversal Agent Protamine sulfate is the antidote to the anticoagulation effect from unfractionated heparin therapy Protamine is a positively charged strong base polypeptide that interacts with negatively charged acidic heparin molecules via a neutralization reaction (acid-base interaction) to form a stable salt complex that has no anticoagulant properties. These heparinprotamine complexes are then removed by the reticuloendothelial system Heparin neutralization occurs within 5 minutes after intravenous administration of an appropriate dose of protamine sulfate Clearance of protamine by the reticuloendothelial system (within 20 minutes) is more rapid than heparin clearance and this may explain, in part, the phenomenon of heparin rebound Protamine administered IV in the absence of heparin or given in excess has anticoagulant activity Warkentin TE et al. Chest 2008;133: 340-380S 34 Unfractionated Heparin: Reversal Agent (cont.) Protamine Reversal Dosing Dose is approximately 1 mg of protamine to inactivate 100 USP units of heparin predicted to still be in circulation Another calculation used is administration of 1.3 mg/kg of protamine for each 100 USP units of heparin present as calculated from the ACT Protamine sulfate’s t1/2 = 7 minutes (short) Warkentin TE et al. Chest 2008;133: 340-380S Stoelting, RK. Pharmacology and Physiology in Anesthetic Practice. 4th edition 35 Unfractionated Heparin: Reversal Agent (cont.) Protamine adverse reactions Hypotension Bradycardia Flushing, feeling of warmth, dyspnea Pulmonary vasoconstriction, acute pulmonary hypertension Noncardiogenic pulmonary edema Bronchoconstriction Cardiovascular collapse (right ventricular failure) Anaphylactic or anaphylactoid reactions Nausea and vomiting Warkentin TE et al. Chest 2008;133: 340-380S 36 Unfractionated Heparin: Reversal Agent (cont.) Protamine adverse reactions (cont.) Rapid IV injection of protamine may be associated with histamine release causing severe hypotension, bradycardia, facial flushing, dyspnea. Rapid IV administration can also increase the risk of anaphylactoid reactions Minimized by extending the infusion time (administer protamine no faster than 5 mg/min) Pre-treat with H1 & H2 antagonists if needed Warkentin TE et al. Chest 2008;133: 340-380S Stoelting, RK. Pharmacology and Physiology in Anesthetic Practice. 4th edition 37 Unfractionated Heparin: Reversal Agent (cont.) Hypersensitivity reactions Allergic reactions to protamine have been described most often in diabetics receiving insulin preparations containing protamine Patients that are allergic to fish may have a higher incidence of allergic reactions to protamine since protamine sulfate is derived from fish sperm Patients can be pre-treated with antihistamines and corticosteroids if there is a concern for protamine allergy Warkentin TE et al. Chest 2008;133: 340-380S 38 Unfractionated Heparin: Neuraxial Anesthesia Implications The recommendations differ depending on whether you are going to administer heparin intravenously or subcutaneously For Intravenous heparin Discontinue heparin infusion 4 to 6 hours AND verify normal coagulation status prior to neuraxial blockade Delay heparin administration for 1 hour after needle placement Please refer to regional anesthesia and pain medicine guidelines for further recommendations For Subcutaneous prophylaxis (< 5000 units) low dose heparin Neuraxial block occur 4 to 6 hours after heparin administration The administration of 5000 units BID or TID is acceptable while neuraxial catheter is in place as this is not contraindicated. Catheter removal should occur 4 to 6 hours after heparin administration and subsequent heparin administration may occur 1 hour after catheter removal LP=Lumbar Puncture; BID=Twice daily; TID=Three times daily 39 Low Molecular Weight Heparins (LMWH’s) These agents are all derived from UFH by chemical OR enzymatic depolymerization to yield fragments that are ~1/3rd the size of UFH Are heterogenous in size with a mean molecular weight of 4000 - 5000 Dalton (smaller than UFH) These agents differ in their pharmacokinetic properties and anticoagulant profiles due to their different preparation methods LMWHs are NEVER clinically interchangeable with one another on a unit-for-unit basis! § May be given IV or SQ Ÿ Never give via IM Injection Warkentin TE et al. Chest 2008;133: 340-380S 40 Low Molecular Weight Heparins: On the Market Lovenox® (Enoxaparin) Fragmin® (Dalteparin) Innohep® (Tinzaparin) Intrinsic Pathway: Surface contact/Vessel Injury Extrinsic Pathway: Tissue Damage/Cell Damage THE COAGULATION CASCADE XII XIIa XI Tissue Factor XIa IX VIIa VII IXa VIII X VIIIa XIII Xa Va V Ca2+ 2+ Ca Thrombin (IIa) II Low Molecular Weight Heparins + AT XIIIa Ca2+ Common Pathway Fibrinogen (I) Soluble Fibrin (Ia) Stabilized 41Fibrin 42 Low Molecular Weight Heparins: Mechanism of Action LMWH’s first bind to antithrombin by a unique pentasaccharide sequence that is found on the LMWH which causes a conformational change in antithrombin and this LMWH/AT complex then inactivates factor Xa and inactivates to a lesser degree thrombin (factor IIa), BUT both factors are inactivated LMWH’s have less effect on inhibiting thrombin since they are generally too short in length to bridge thrombin and antithrombin simultaneously (see picture) Enoxaparin is the most select LMWH for factor Xa and is said to have a anti-Xa to anti-IIa ratio of 4:1 Warkentin TE et al. Chest 2008;133: 340-380S 43 Low Molecular Weight Heparins: Mechanism of Action (cont.) LMWH 44 Low Molecular Weight Heparins: Pharmacokinetics Bioavailability is 90% via SQ injection – good SQ absorption Produces a more PREDICTABLE & longer duration of anticoagulant response compared to UFH since LMWH’s have less binding to circulating and cellular proteins compared to UFH Peak Anti-Xa activity is reached in 3-5 hours after dosing t1/2 = 3-6 hours (longer than UFH) t1/2 is dose-INDEPENDENT and prolonged in renal dysfunction Excretion Cleared primarily via the kidneys Require dose adjustments in patient’s with renal dysfunction Warkentin TE et al. Chest 2008;133: 340-380S 45 Low Molecular Weight Heparins: Monitoring Routine anticoagulant laboratory monitoring IS NOT necessary due to their predictable anticoagulant response and pharmacokinetic profile Antifactor-Xa level for LMWH is the recommended test if anticoagulant monitoring is required Antifactor-Xa goal level varies based on which LMWH is being used and the clinical indication aPTT, ACT and PT/INR are not effected by LMWH’s Monitor for signs & symptoms of bleeding Labs to monitor are CBC, Hgb/Hct, Platelet count, Scr 46 Low Molecular Weight Heparins: Clinical Uses Prophylaxis of VTE In medical patients, patients undergoing hip-replacement surgery, during and following hospitalization, patients undergoing kneereplacement surgery, patients undergoing abdominal surgery Treatment of VTE Treatment of acute coronary syndrome (STEMI, NSTEMI, UA) Extended treatment of symptomatic VTE to reduce the recurrence of VTE in patient’s with cancer (Fragmin® ONLY) VTE = Venous thromboembolism STEMI = ST segment elevation myocardial infarction NSTEMI = Non-ST segment elevation myocardial infarction UA = Unstable angina 47 Low Molecular Weight Heparins: Adverse Effects Bleeding Bleeding risk is increased in renal dysfunction and elderly There is NO true reversal agent for LMWH’s Protamine Sulfate (1% solution) can be given at a dose of 1mg protamine for every 100 anti-Xa IU of LMWH but the degree of neutralization varies with a maximum neutralization of up to 60% Injection site reactions – hematoma, pain at injection site Thrombocytopenia Risk of HIT is < 1% Allergic reactions (pruritus, rash, fever, bulleous eruption) 48 Comparison of UFH to LMWH’s Compared with UFH, LMWH’s have: Reduced ability to catalyze the inactivation of thrombin (factor IIa) Reduced nonspecific binding to plasma proteins, with a corresponding improvement in the predictability of their dose-response relationship Reduced binding to macrophages and endothelial cells explains the increase in plasma half-life Reduced binding to platelets and PF4 explains the lower incidence of HIT Reduced binding to osteoclasts and less bone loss 49 Low Molecular Weight Heparins: Neuraxial Anesthesia Implications Spinal anesthesia/epidural anesthesia/LP Prior to procedure (i.e.: preoperative setting) Wait at least 12 hours after the last dose of a prophylaxis LMWH dose BEFORE catheter placement Wait at least 24 hours after the last dose of a treatment LMWH dose BEFORE catheter placement Administer the first dose of LMWH a MINIMUM of 4 hours AFTER the catheter has been removed LP = Lumbar Puncture 50 Arixtra® (fondaparinux) Is a synthetic pentasaccharide class agent Is a synthetic analog of the AT-binding pentasaccharide sequence found in UFH and LMWHs Is a Non-Heparin Product! Is a selective, in-direct inhibitor of Factor Xa only! Fondaparinux reversibly binds to AT causing a conformational change in AT and then the fondaparinux-AT complex inhibits factor Xa only Because fondaparinux is too short to bridge AT to thrombin, fondaparinux DOES NOT increase the rate of thrombin inhibition by antithrombin AT = Antithrombin Intrinsic Pathway: Surface contact/Vessel Injury Extrinsic Pathway: Tissue Damage/Cell Damage THE COAGULATION CASCADE XII XIIa XI Tissue Factor XIa IX VIIa VII IXa VIII Thrombin (IIa) X VIIIa Fondaparinux + AT XIII Xa Va V Ca2+ 2+ Thrombin (IIa) II Ca XIIIa Ca2+ Common Pathway Fibrinogen (I) Soluble Fibrin (Ia) Stabilized 51Fibrin 52 Arixtra® (fondaparinux): Mechanism of Action Fondaparinux indirectly inhibits ONLY factor Xa by reversibly binding to antithrombin Factor Xa Fondaparinux Antithrombin Antithrombin Antithrombin Factor Xa 53 Arixtra® (fondaparinux): Pharmacokinetics Rapidly and completely absorbed after SQ administration 100% bioavailable after SQ injection t1/2 = 17 – 21 hours (longer than UFH and LMWHs) t1/2 is prolonged in renal dysfunction Excretion Occurs via the kidneys as unchanged drug Contraindicated patient’s with severe renal dysfunction (CrCl < 30 mL/min) DOES NOT bind to plasma proteins or other molecules (i.e.: endothelial cells, etc.) compared to UFH 54 Arixtra® (fondaparinux): Monitoring Routine lab monitoring is NOT required to monitor the anticoagulant effects due to its predictable anticoagulant response and pharmacokinetic profile Fondaparinux-specific anti-Xa assay If the anticoagulant activity of fondaparinux must be monitored then use of a fondaparinux-specific anti-Xa assay is recommended DOES NOT alter the aPTT, ACT or PT/INR Monitor patient for signs & symptoms of bleeding, CBC, Hgb/Hct, Platelet Count, & Scr There is NO reversal agent for fondaparinux Protamine DOES NOT work Treatment doses (5 mg – 10 mg/day) are CONTRAINDICATED for use while neuraxial catheter in place 55 Arixtra® (fondaparinux): Adverse Effects Bleeding Most common serious complication Thrombocytopenia Injection site reactions Injection site bleeding, rash, pruritis Arixtra® Package Insert 56 Arixtra® (fondaparinux): Clinical Uses Prophylaxis of VTE in patients undergoing hip replacement, knee replacement, pt’s with hip fractures, abdominal surgery, and in medical patients Treatment of acute DVT/PE when administered in conjunction with warfarin Treatment of acute coronary syndromes (STEMI, NSTEMI, UA) Used as an anticoagulant in bridging with warfarin for thromboprophylaxis in non-valvular atrial fibrillation patients 57 3-6 hours Nutescu, EA, Dager, WE. Heparin, low molecular weight heparin, and fondaparinux. In Gulseth MP ed. Managing Anticoagulation Patients in the Hospital. Bethesda: ASHP; 2007: 177-202. 58 Direct Thrombin Inhibitors Mechanism of action Direct thrombin inhibitors bind DIRECTLY to thrombin (factor IIa) and inhibit thrombin’s functions/actions Inhibits BOTH free and clot-bound thrombin (factor IIa) Biophysical properties DO NOT cause HIT Are not bound to plasma proteins such as platelet factor-4 DTI’s have a more predictable anticoagulant response compared to UFH Are AT-Independent (These agents do not require antithrombin as a cofactor for their anticoagulant response) Direct thrombin inhibitors differ in their potency, pharmacokinetic profiles, binding affinity to thrombin, monitoring requirements and routes of administration AT = Antithrombin HIT = Heparin Induced Thrombocytopenia 59 Direct Thrombin Inhibitors There is currently no antidote available for any PARENTERAL direct thrombin inhibitor agent! Direct thrombin inhibitors increase/prolong all of the following anticoagulation laboratory tests: aPTT, ACT, thrombin time, PT/INR, chromogenic anti-IIa assays, and the ecarin clotting time In patients receiving parenteral direct thrombin inhibitors, neuraxial techniques are not recommended 60 Direct Thrombin Inhibitors: On the Market Parenteral formulations available on the market Angiomax® (Bivalirudin) Argatroban Iprivask® (Desirudin) Subcutaneous use only Refludan® (Lepirudin) Manufacturer has discontinued manufacturing product and no further product will be distributed after May 31, 2012 Intrinsic Pathway: Surface contact/Vessel Injury Extrinsic Pathway: Tissue Damage/Cell Damage THE COAGULATION CASCADE XII XIIa XI Tissue Factor XIa IX VIIa VII IXa VIII X VIIIa Direct Thrombin Inhibitors XIII Xa Va V Ca2+ 2+ Thrombin (IIa) II Ca XIIIa Ca2+ Common Pathway Fibrinogen (I) Soluble Fibrin (Ia) Stabilized 61Fibrin 62 Direct Thrombin Inhibitors: Iprivask® (Desirudin) Is a recombinant form of hirudin, that is a single polypeptide chain of 65 amino acids Natural hirudin comes from salivary glands of leeches (Hirudo medicinalis) Mechanism of action Binds irreversibly, selectively & directly to inhibit both clot-bound and free thrombin (Factor IIa) Is the only DTI approved for use as a subcutaneous injection and is only administered SQ and used for prophylaxis of DVT/PE in patients undergoing hip replacement Excreted primarily via the kidneys 63 Direct Thrombin Inhibitors: Refludan® (Lepirudin) Lepirudin is also a recombinant derivative of hirudin, similar to desirudin, that forms a 1:1 stoichiometric complex with thrombin and causes irreversible inhibition of thrombin Although there are minor differences in the composition of lepirudin and desirudin, their mechanism of action and pharmacokinetic properties are identical Lepirudin is given via continuous IV infusion at a dose to maintain the aPTT at 1.5–2.5x control Used in the management of HIT patients Bayer Healthcare Corporation has made a decision to discontinue Refludan® (lepirudin (rDNA)) for injection. No further product will be distributed from Bayer after May 31, 2012 64 Direct Thrombin Inhibitors: Angiomax® (Bivalirudin) A 20-amino acid synthetic polypeptide that is an analog of hirudin Mechanism of action Reversibly binds directly to clot-bound and free thrombin and inhibits thrombin and thus inhibits fibrin formation Reversibility means thrombin itself can cleave bivalirudin from the active site after bivalirudin has bound to it and thrombin can resume its hemostatic function t1/2= 25 minutes (short) Elimination Kidneys (20%) & Enzymatic metabolism (80%) t1/2 is prolonged in renal dysfunction Dosing adjustments are required in patient’s with renal dysfunction 65 Direct Thrombin Inhibitors: Angiomax® (Bivalirudin) Laboratory monitoring of anticoagulant effects (depends on indication) HIT use aPTT: Goal 1.5–2.5x control PCI or CABG use ACT: Goal 300–450 seconds Adverse Effects Bleeding – most common Hypotension Stop time prior to surgery is ~4-6 hours 66 Direct Thrombin Inhibitors: Angiomax® (Bivalirudin) Clinical uses Used as an alternative to heparin in patients undergoing cardiopulmonary bypass surgery As an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) As an anticoagulant in acute coronary syndrome patients undergoing PCI with provisional use of GPIIb/IIIa inhibitor For treatment of patients with, or at risk of, HIT with or without thrombosis undergoing PCI 67 Direct Thrombin Inhibitors: Argatroban Is a small molecule synthetic, univalent direct thrombin inhibitor derived from L-arginine Mechanism of action Competitive inhibitor of thrombin that binds reversibly to the active site of both clot-bound and free thrombin and inhibits thrombins function and thus inhibits fibrin formation Reversibility means thrombin can cleave argatroban from the active site after argatroban has bound to it and thrombin can resume its hemostatic function Clinical uses Is an alternative to heparin for anticoagulation in patients requiring CABG, especially in the presence of HIT For the treatment and prophylaxis of thrombosis in HIT As an anticoagulant in patient’s with HIT or at risk of HIT, undergoing PCI when heparin is contraindicated 68 Direct Thrombin Inhibitors: Argatroban Administered as a continuous IV infusion Metabolism occurs in the liver Dose adjustments required in patients with liver impairment t1/2= 39-51 minutes Prolonged with hepatic dysfunction Excretion Primarily in the feces, through biliary secretion Argatroban can be used safely in patients with varying degrees of renal dysfunction as no dosage adjustments are required in patients with renal impairment 69 Direct Thrombin Inhibitors: Argatroban Laboratory monitoring of anticoagulant effect HIT use aPTT: Goal of 1.5–3 x control (not to exceed 100 seconds) PCI or CABG use ACT: 300–450 seconds Obtain baseline value prior to administration Check 5 to 10 min after bolus given Check q 20 to 30 minutes during a long procedure Adverse effects Bleeding – most common Dyspnea (8.1%) Hypotension (7.2%) Oral Direct Thrombin Inhibitor 70 71 Pradaxa® (Dabigatran etexilate) Is a synthetic, selective, reversible, competitive direct thrombin inhibitor that is only given ORALLY Pradaxa® is a prodrug and requires metabolic conversion into its pharmacologically active form DOES NOT require the cofactor antithrombin for its anticoagulant effect Metabolism After oral administration, dabigatran etexilate is metabolized by esterase enzymes into the active metabolite form dabigatran Dabigatran (the active form) is then further metabolized in the liver by non-CYP 450 pathways forming several glucuronide active metabolites that have similar pharmacological activity to dabigatran 72 Pradaxa® (Dabigatran etexilate): Mechanism of Action Dabigatran and the other active metabolites selectively bind to the active site of both free and clotbound thrombin and inhibits thrombin’s function Because thrombin enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus (clot) and prevents thrombin-induced platelet aggregation (this is true of ALL direct thrombin inhibitors) Has a rapid onset of action, anticoagulant effect occurs within 1-3 hours Di Nisio M et al. N Eng J Med. 2005; 353:1028-1040 http://vte.pradaxa.com/what-is-pradaxa/mechanism-of-action.html 73 Pradaxa® (Dabigatran etexilate): Pharmacokinetics Protein binding: Low (35%) t1/2 = 12-17 hours Increases with worsening renal function Excretion Dabigatran and its metabolites are primarily excreted via the kidneys Dosage adjustments are required in patients with renal dysfunction 74 Pradaxa® (Dabigatran etexilate): Laboratory Monitoring No routine coagulation monitoring is required to assess the anticoagulant effect since dabigatran exhibits a predictable pharmacokinetic and pharmacodynamic profile At recommended doses, dabigatran prolongs the aPTT, thrombin time (TT) and ecarin clotting time The aPTT is NEVER used for routine monitoring since the effects of Pradaxa® on the aPTT are not consistent Thrombin time (TT) or ecarin clotting time (ECT) are the preferred/most sensitive tests over the aPTT to perform if Pradaxa® anticoagulant effect is to be assessed/determined A dabigatran lab assay is also available Monitor for signs/sx of bleeding, CBC with diff, Hgb/Hct, renal function (Scr) and liver function tests 75 Pradaxa® (Dabigatran etexilate): Adverse Effects Dyspepsia Bleeding Risk of bleeding increases with age, renal dysfunction and when used concomitantly with other medications that increase the risk of bleeding (i.e.: ASA, NSAIDS, etc.) Hemodialysis can be used to remove in an overdose situation Pradaxa® Prescribing Information 76 Pradaxa® (Dabigatran etexilate): Neuraxial Anesthesia Implications Spinal anesthesia/epidural anesthesia/LP Pradaxa® is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters in place The most recent regional anesthesia and pain medicine guidelines has published updated recommendations on how to manage spinal/epidural anesthesia or punctures in patients receiving Pradaxa ® and it is best to refer to those guidelines in clinical practice LP = Lumbar Puncture 77 Pradaxa® (Dabigatran etexilate): Reversal Agent Praxbind® (Idarucizumab) Is a humanized monoclonal antibody fragment (Fab) indicated when the reversal of the anticoagulant effects of dabigatran is needed: For emergency/urgent procedures In life-threatening bleeding Mechanism of action Idarucizumab binds directly to dabigatran and its metabolites with higher affinity than the binding of dabigatran to thrombin and neutralizes their anticoagulant effect immediately after administration Adverse effects Hypokalemia, delirum, pyrexia IV administration only Oral Direct Factor Xa Inhibitors 78 79 Oral Direct Factor Xa Inhibitors: On the market Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Betrixaban (Bevyxxa®) 80 Rivaroxaban, Apixaban, Edoxaban, Betrixaban: Direct Factor Xa Inhibitors Rivaroxaban, apixaban, edoxaban and betrixaban are oral only, selective, competitive, direct factor Xa inhibitors These agents DO NOT require the cofactor antithrombin for their anticoagulant effect Class mechanism of action All of these agents bind DIRECTLY to factor Xa and inhibit free factor Xa, clot-bound factor Xa, and factor Xa within the prothrombinase complex. By directly inhibiting Factor Xa, they all decrease thrombin (factor IIa) generation These agents have a rapid onset of action providing anticoagulant effects usually within 1-3 hours depending on the agent 81 Rivaroxaban, Apixaban, Edoxaban, Betrixaban: Pharmacology Comparison Rivaroxaban Apixaban Edoxaban Betrixaban Direct Factor Xa inhibitor Direct Factor Xa inhibitor Direct Factor Xa inhibitor Direct Factor Xa inhibitor Protein Binding High High ~55% ~60% Half-life (hours) 5-9 12 10-14 19-27 Metabolism Liver – CYP 450 Liver – CYP 450 Liver – NonCYP 450 Liver – NonCYP 450 Excretion Kidney & feces Kidney & feces Kidney & feces Feces & Kidney Mechanism of action All 4 of these agents can accumulate in both hepatic and renal dysfunction, thus, their half-lives are prolonged with either hepatic or renal dysfunction 82 Rivaroxaban, Apixaban, Edoxaban, Betrixaban: Laboratory Monitoring No routine coagulation monitoring is required to assess their anticoagulant effect since both exhibit a predictable pharmacokinetic and pharmacodynamic profile A chromogenic anti-Xa assay is the most useful test to check the anticoagulant effect of these agents Most hospitals do not have this test available Edoxaban does not have an assay at this time The prothrombin time/INR (PT/INR) is less reliable but can be used if a chromogenic anti-Xa assay is not available Monitor for signs/sx of bleeding, CBC with diff, Hgb/Hct, renal function (Scr), liver function tests 83 Rivaroxaban, Apixaban, Edoxaban, Betrixaban: Adverse Effects & Reversal Agent Adverse effects Bleeding – most common side effect Reveral Agent There is NOW an FDA approved reversal agent ONLY for rivaroxaban and apixaban, called ANDEXXA® ANDEXXA®, coagulation factor Xa (recombinant), inactivated-zhzo ANDEXXA®, which is officially called “coagulation factor Xa (recombinant), inactivated-zhzo” is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding Mechanism of action Exerts its procoagulant effect by binding to and sequestering the factor Xa inhibitors Also inhibits the tissue factor pathway inhibitor (TFPI) activity For IV use only Has a rapid onset of action and starts to decrease anti-factor Xa levels in 2-5 minutes ANDEXXA®, coagulation factor Xa (recombinant) Adverse reactions Most Common: urinary tract infections, pneumonia and infusion- related reactions Rare: Arterial and venous thromboembolic events and ischemic events 86 Rivaroxaban, Apixaban, Edoxaban, Betrixaban: Neuraxial Anesthesia Implications CONTRAINDICATED to use FULL anticoagulant doses of these agents while spinal catheter is in place Concomitant use of antiplatelet agents (ASA, clopidogrel, etc.), NSAIDs or any other medication that also causes bleeding further increases the patients risk of bleeding Each direct factor Xa inhibitor has specific recommendations on how to manage spinal/epidural anesthesia or punctures and it is best to refer to the agent specific FDA package insert for these recommendations as these recommendations vary from agent to agent. You can also refer to the most recent regional anesthesia and pain medicine guidelines as well, which has similar recommendations Intrinsic Pathway: Surface contact/Vessel Injury Extrinsic Pathway: Tissue Damage/Cell Damage THE COAGULATION CASCADE XII XIIa XI Tissue Factor XIa IX VIIa VII IXa VIII Thrombin (IIa) X VIIIa Vitamin K Antagonists XIII Xa V Va Ca2+ Thrombin (IIa) II Protein C + Thrombomodulin XIIIa Ca2+ Activated Protein C Protein S 2+ Ca Common Pathway Fibrinogen (I) Soluble Fibrin (Ia) Stabilized 87Fibrin 88 Coumadin® (Warfarin): Mechanism of Action Warfarin is the only vitamin K antagonist agent available for clinical use Warfarin acts by inhibiting the enzyme vitamin K epoxide reductase (VKOR). Inhibiting this enzyme prevents the conversion of oxidized vitamin K epoxide into its reduced form and this prevents the SYNTHESIS of the vitamin K-dependent clotting factors II (prothrombin), VII, IX, X and prevents the SYNTHESIS of protein C & protein S Since warfarin prevents the synthesis of Protein C and S, it has the potential to be a pro-coagulant initially Warfarin DOES NOT bind to and inactivate circulating clotting factors like other anticoagulant medications Warfarin is available as a racemic mixture of R and S isomers Warfarin interferes with the extrinsic pathway 89 Copyright © American College of Chest Physicians. All rights reserved. From: Oral Anticoagulant TherapyOral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest. 2012;141(2_suppl):e44S-e88S. doi:10.1378/chest.11-2292 Figure Legend: [Section 1.1] Vitamin K1 is reduced to vitamin KH2. The major warfarin-sensitive enzyme in this reaction is the vitamin K oxide reductase mainly inhibited by the S-enantiomer of warfarin. S-warfarin is metabolized by the p450 cytochrome enzyme, CYP2C9. Reprinted with permission from Ansell et al.8 90 Coumadin® (Warfarin): Pharmacokinetics Absorption: Rapid and completely absorbed Protein binding: 97% protein bound to albumin Metabolism: Metabolized in the liver via multiple CYP 450 enzymes into inactive metabolites, which are excreted in both the bile and urine Enhanced anticoagulant effect in the presence of liver disease The elimination of warfarin is almost entirely by metabolism t1/2 ranges between 20 – 60 hours 91 Coumadin® (Warfarin): Pharmacodynamics The time to onset and offset of the anticoagulant effect of warfarin is delayed by 2 main factors: 1. 2. The long elimination half-life of warfarin (20 – 60 hours) The elimination half-life of the already made 4 vitamin Kdependent clotting factors Onset of effect: usually within 24 hours, which is due to Factor VII depletion Full/Peak effect: can take up to 5-7 days, which is due to Factor II depletion Stoelting text states that the peak effects of warfarin do not occur for 36-72 hours, but this is an incorrect statement! 92 Coumadin® (Warfarin): Reversal Agents Anticoagulant effects are reversed by administering: 1. Vitamin K1 2. Fresh frozen plasma (FFP) 3. Prothrombin complex concentrates (PCCs) – these will be reviewed next semester 4. Activated prothrombin complex concentrates (aPCCs) 5. Recombinant factor VIIa – this is an agent of last resort, this will be reviewed next semester Vitamin K1 (Phytonadione) Vitamin K is an essential cofactor that is necessary for the production of factors II, VII, IX, and X in the liver Phytonadione administration promotes hepatic production of vitamin K-dependent clotting factors II, VII, IX, and X, which are depleted by warfarin Vitamin K1 is recommended to be given via oral or IV route depending on the clinical situation. It is no longer recommended to given via IM or SQ IM – causes hematoma SQ – has slower onset of action, unpredictable absorption and action Vitamin K1 (Phytonadione) Vitamin K1 IV administration Onset is usually within 2 hours and reaches peak therapeutic effect in 12-24 hours Reserved typically only for more urgent reversal situations (severe/life-threatening bleeding or reversal prior to surgery) Is associated with anaphylactic reactions so to decrease this risk, Vitamin K should be mixed in at least 50 ml of a compatible fluid and administered over a minimum of 1 mg/min Vitamin K1 Oral administration Decreases the INR usually within 24 hours Is the preferred route when non-urgent reversal is needed 95 Prothrombin Complex Concentrate (Human), Kcentra® Is the first FDA-Approved 4-Factor Prothrombin Complex Concentrate (PCC) for warfarin reversal in the United States Is for IV use only Is a blood coagulation factor replacement product that is derived from human plasma Mechanism of action Kcentra® contains factors II (prothrombin), VII, IX and X, and antithrombotic proteins C and S This product rapidly increases plasma levels of the vitamin Kdependent coagulation factors II, VII, IX, and X as well as the antithrombotic proteins C and S (these are all factors that are reduced by warfarin) 96 Prothrombin Complex Concentrate (Human), Kcentra® Indication For the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding or need for an urgent surgery/invasive procedure 97 Coumadin® (Warfarin): Drug Interactions There are numerous drug-drug, drug-food, and drug-patient genetic interactions with warfarin, which is a major disadvantage of the drug Concurrent administration with other drugs such as antiplatelet agents (ASA, clopidogrel, etc.), NSAIDs, bactrim, high dose PCNs, 2nd and 3rd generation cephalosporins all increase the risk of bleeding Warfarin + CYP 450 inhibitors Increases warfarin plasma levels & increase risk of bleeding i.e.: Amiodarone, quinidine, cimetidine Warfarin + CYP 450 inducers Decreases warfarin plasma levels & decreases risk of bleeding & increases risk of possible thrombotic complications i.e.: Rifampin, phenytoin, barbiturates, carbamazepine 98 Coumadin® (Warfarin): Clinical Uses Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic complications associated with atrial fibrillation/flutter or cardiac prosthetic valve replacement Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI 99 Coumadin® (Warfarin): Anticoagulant Lab Monitoring Anticoagulant effects are monitored using the prothrombin time/international normalized ratio (INR) test Goal INR: 2-3 (for most indications) Goal INR: 2.5-3.5 (select indications such as mechanical mitral valve replacement) 100 Coumadin® (Warfarin): Adverse Effects Bleeding, Bleeding, Bleeding – main adverse effect The higher the INR, the greater the risk of bleeding Intracranial hemorrhage is of great concern Fatal or non-fatal hemorrhage from any tissue or organ can occur Other less common adverse effects Warfarin skin necrosis and limb gangrene – usually seen between days 3 – 8 of therapy Purple toe syndrome Urticaria, dermatitis including bullous eruptions Warfarin crosses the placenta and can produce fetal CNS damage, fetal bleeding, embryonic changes, and fetal death 101 Coumadin® (Warfarin): Surgical and Spinal Anesthesia Implications Spinal anesthesia/epidural anesthesia/LP Hold Time Prior to Initiation of Neuraxial Blockade: Hold warfarin between 4-5 days (ideally) prior to procedure & INR is normalized It is generally recommended that warfarin not be administered while an epidural catheter is in place, however, the newest regional anesthesia and pain medicine guidelines do make recommendations on how to manage specific and select cases when it is determined that warfarin will be given while an epidural catheter is in place. These are rare and complex situations and you can consult the recommendations on how to manage these select cases Urgent reversal of warfarin prior to surgery – administer Vitamin K IV via slow infusion or can give FFP or Kcentra® 102 Coumadin® (Warfarin): Surgical and Spinal Anesthesia Implications Determining when to stop a patient’s warfarin prior to surgery and re-start therapy is determined based on the patient’s thrombotic risks and the type of surgical procedure. Most clinician’s follow the recommendations from the American College of Chest of Physicians guidelines but there are several other recommendations that are used clinically In general, those at greatest thrombotic risks have warfarin stopped 5 days prior to a procedure and are bridged with a parenteral anticoagulant Always check the PT/INR preoperatively in a patient who is receiving warfarin 103 Antiplatelet Agents Aspirin Dipyridmole (Persantine®) Thienopyridine P2Y12 ADP-Receptor Antagonists Ticlopidine (Ticlid®) Clopidogrel (Plavix®) Prasugrel (Effient®) Non-Thienopyridine P2Y12 ADP-Receptor Antagonists Ticagrelor (Brilinta®) Cangrelor (Kengreal®) Glycoprotein IIb/IIIa Receptor Inhibitors/Antagonists Abciximab (Reopro®) Eptifibatide (Integrilin®) Tirofiban (Aggrastat®) 104 Antiplatelet Agents: Targets Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor dipyridamole phosphodiesterase ADP P2Y12 ADP GPIIb/IIIa Antagonists Gp IIb/IIIa (Fibrinogen Receptor) Activation COX-1 Collagen Thrombin TXA2 -1 R PA TXA2 aspirin ADP=Adenosine diphosphate, COX=Cyclooxygenase, PAR-1=Protease-activated receptor1, TXA2=Thromboxane A2, TRAP=Thrombin receptor agonist peptide Schafer AI. Am J Med 1996;101:199–209 Thrombin TRAP 105 Aspirin: Mechanism of action ASA inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase-1 (COX-1) enzyme, thereby preventing the formation of thromboxane A2, which is a potent platelet aggregate and potent vasoconstrictor Platelet cyclooxygenase-1 (COX-1) enzyme is the rate limiting enzyme step in the conversion of arachidonic acid to thromboxane A2 The effects of preventing platelet aggregation last for the lifetime of the platelet (7-10 days) since ASA produces irreversible inhibition of platelet cyclooxygenase-1 Low-dose aspirin selectively inhibits COX-1, and high-dose aspirin inhibits both COX-1 and COX-2 (COX-2 enzyme is primarily responsible for PGI2 synthesis, which inhibits platelet aggregation) 106 Aspirin: Pharmacokinetics Rapidly absorbed in stomach & upper intestine Non-enteric coated plasma levels peak 30 to 40 minutes Inhibition of platelet function occurs within 1 hour Enteric coated plasma levels peak 3 - 4 hours Rapidly cleared from the body (t1/2 = 20 min) but the effects of aspirin on platelets are irreversible and last for the life of the platelet (7-10 days) Chest February 2012 141:2 suppl e326S-e350S; doi:10.1378/chest.11-2298 107 Aspirin Used for a wide range of indications Stroke Prevention Reduce MI risk in patient’s with coronary artery disease Anti-inflammatory Analgesic ACS (UA/NTEMI/STEMI) Management Bleeding is the main adverse event Bleeding risk increases when used with other anti-platelet agents, NSAIDs, and anticoagulants If required, aspirin should be stopped 7-10 days prior to surgery but, in general, aspirin is continued up to surgery based on most evidence based guideline recommendations 108 Dipyridamole Is both a vasodilator and antiplatelet agent Mechanism of action Inhibits platelet function by increasing cAMP platelet concentrations via 2 different mechanisms 1. 2. Dipyridamole inhibits cyclic nucleotide phosphodiesterases, the enzyme that degrades cyclic adenosine monophosphate to 5′-AMP, resulting in the intraplatelet accumulation of cyclic AMP, which inhibits platelet aggregation Dipyridamole inhibits the uptake of adenosine into platelets and endothelial cells, which results in an increase in local adenosine concentrations that acts on platelet adenosine A2 receptors thereby stimulating platelet adenylyl cyclase which increases platelet cAMP levels & cAMP inhibits platelet aggregation 109 Dipyridamole Clinical uses Oral product Most often used in combination with warfarin to inhibit embolization from prosthetic valves Also used in combination with ASA for stroke prophylaxis Discontinue 24 hours prior to surgery Injection product Dipyridamole injection is indicated as an alternative to exercise in thallium myocardial perfusion imaging for the evaluation of coronary artery disease in patients who cannot exercise adequately Pletal® (Cilostazol) Cilostazol is a phosphodiesterase III inhibitor indicated for the reduction of symptoms of intermittent claudication Cilostazol and its active metabolites selectively inhibit phosphodiesterase III activity and suppress cAMP degradation with a resultant increase in cAMP concentrations in platelets and blood vessels, leading to reversible inhibition of platelet aggregation and vasodilation of various vascular beds Pletal® (Cilostazol) Is metabolized in the liver via CYP-450 with metabolites then excreted via the kidneys Has a half-life of 11-13 hours for both cilostazol and its active metabolites Do not administer neuraxial blockade while on this medication Neuraxial techniques should be avoided for 2 days AFTER discontinuing cilostazol (this is based on the elimination halflife) 112 Ticlopidine (Ticlid®) Thienopyridine Class Antiplatelet Agent Mechanism of action Is a prodrug that requires the liver for metabolic conversion to its active metabolite The active metabolite then binds irreversibly to P2Y12 receptors on the surface of platelets and inhibits ADP induced platelet aggregation and activation Inhibits platelet function for the life span of the platelet (7-10 days) Hold 10 days prior to surgery and hold 10 days prior to placement of neuraxial anesthesia Clinical use has all but been eliminated due to newer agents and due to ticlopidine’s risk of causing severe neutropenia (ANC < 500/μL) and thrombotic thrombocytopenia purpuria (TTP) 113 Clopidogrel (Plavix®) Thienopyridine Class Antiplatelet Agent Mechanism of action Is a prodrug that requires several liver CYP 450 enzymes for a 2step metabolic conversion into its active metabolite The active metabolite then binds irreversibly to P2Y12 receptors on the surface of platelets and inhibits ADP induced platelet aggregation and activation Inhibits platelet function for the life span of the platelet (7-10 days) Concomitant use of drugs that inhibit the CYP 450 enzymes used to metabolize clopidogrel to its active metabolite results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition 114 Clopidogrel (Plavix®) Onset of effect is not immediate but is delayed and can take hours to have an effect (generally >1 hour) Clopidogrel is a more potent antiplatelet agent than ticlopidine Indications ACS (UA/NTEMI/STEMI) Recent MI, Recent Stroke, or Established Peripheral Arterial Disease Caution when used with NSAIDS, warfarin, SSRIs, SNRIs, or any other medications that increase bleeding risk as the combined use will increase the risk of bleeding 115 Clopidogrel (Plavix®) Adverse effects Bleeding – major adverse effect Other Hypersensitivity including rash and angioedema Neutropenia, thrombotic thrombocytopenic purpura (TTP) These are very rare and occur much less frequently compared to ticlopidine Discontinue at least 7 days prior to major surgery or elective surgery 116 Prasugrel (Effient®) Thienopyridine Class Antiplatelet Agent Mechanism of action Is a prodrug that is converted into its active metabolite by a single step process in the liver by several CYP 450 enzymes The active metabolite then binds irreversibly to P2Y12 receptors on the surface of platelets and inhibits ADP induced platelet aggregation and activation Inhibits platelet function for life span of the platelet (7-10 days) Prasugrel can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes 117 Prasugrel (Effient®) Onset of platelet inhibition (dose-dependent) is more rapid (~30 minutes) compared with clopidogrel Is a more potent inhibitor of platelet aggregation than clopidogrel and achieves more consistent and complete inhibition of ADP-induced platelet aggregation. The trade off for this potent inhibition is a greater risk of bleeding from prasugrel compared to clopidogrel! 118 Prasugrel (Effient®) Indicated to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with ST-elevation myocardial infarction (STEMI), unstable angina (UA) or non–ST-elevation myocardial infarction (NSTEMI) 119 Prasugrel (Effient®) Adverse effects Bleeding – most common Angioedema & thrombotic thrombocytopenic purpura (TTP) have been reported but are rare Contraindications Active bleeding Any previous TIA or stroke 120 Prasugrel (Effient®) Caution when used with NSAIDS, warfarin, SSRIs, SNRIs, or any other medication that increases bleeding risk as the combined use will increase the risk of bleeding Discontinue at least 7 days prior to ANY surgery 121 Ticagrelor (Brilinta®) Non-thienopyridine class antiplatelet agent Cyclopentyl-triazolo-pyrimidine drug class (CPTP) Stoelting has incorrectly stated that ticagrelor is a thienopyridine agent Mechanism of action Ticagrelor and its active metabolite bind REVERSIBLY to P2Y12 receptors on the surface of platelets and inhibit ADP induced platelet aggregation and activation Ticagrelor and its active metabolite are approximately equipotent Ticagrelor is not a prodrug and DOES NOT require metabolic activation – Ticagrelor is a direct-acting agent Is considered a more potent inhibitor of platelet aggregation than clopidogrel but less than prasugrel 122 Ticagrelor (Brilinta®) Metabolism: Hepatic CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite Elimination The primary route of ticagrelor elimination is hepatic metabolism 123 Ticagrelor (Brilinta®) Indication Indicated to reduce the rate of thrombotic cardiovascular (CV) events, in combination with ASA, in pts with ACS & has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel It also reduces the rate of stent thrombosis in patients treated with percutaneous coronary intervention 124 Ticagrelor (Brilinta®) Adverse effects Bleeding & dyspnea – most common Others: Bradyarrhythmia’s (including ventricular pauses) Caution when used with NSAIDS, warfarin, SSRIs, SNRIs, or any other medication that increases bleeding risk as the combined use will increase the risk of bleeding Discontinue ticagrelor at least 5 days prior to ANY surgery 125 Kengreal® (Cangrelor) A nonthienopyridine ATP analogue that is as a direct-acting and reversible P2Y12 platelet receptor antagonist and is administered by IV administration only FDA approved for use as an adjunct to PCI in the management of ACS patients Used off-label as a bridging agent in CAD patients requiring DAPT undergoing cardiac or non-cardiac surgery Mechanism of action A direct P2Y12 platelet receptor inhibitor that blocks ADPinduced platelet activation and aggregation. Cangrelor binds selectively, competitively and reversibly to the P2Y12 receptor to prevent further signaling and platelet activation ACS = Acute Coronary Syndrome PCI = Percutaneous Coronary Intervention 126 Kengreal® (Cangrelor) Cangrelor has an immediate onset and rapid offset of action Immediate onset Onset of anti-platelet activity: within 2 minutes Rapid offset Return of complete platelet function occurs within one hour after drug discontinuation Metabolism Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside t1/2 = 3-6 minutes 127 Kengreal® (Cangrelor) Most common adverse reaction is bleeding Does not interfere with other drugs metabolized by hepatic enzymes and is not affected by sex, age, renal status or hepatic function There is no specific treatment to reverse the antiplatelet effect of cangrelor but the effect is gone within one hour after the drug is discontinued 128 Aspirin & P2Y12 Receptor Antagonists: Epidural Catheter Implications Hold Time Before Placement While Neuraxial Catheter is in place (Catheter is maintained) Hold Time After Removal Aspirin No specific concerns as to the timing of single-injection or catheter techniques in relationship to the dosing of aspirin, postoperative monitoring, or the timing of neuraxial catheter removal Ticlopidine 10 days Clopidogrel 5-7 days Prasugrel 7-10 days Contraindicated 0-6 hours1 Ticagrelor 5-7 days Contraindicated 0-6 hours1 Cangrelor 3 hours Contraindicated 8 hours Catheter can be maintained for 1- 0-6 hours1 2 days, assuming no loading dose 0-6 hours1 1Can be resumed immediately after catheter removal assuming no loading dose given. Wait 6 hours between catheter removal and administration if a loading dose is given. Horlocker TT, et al. Regional Anesthesia and Pain Medicine. 2018; 43:263-309. Gogarten W, et al. Eur J Anaesthesiol. 2010;27:999-1015. 129 Antiplatelet Agents: Glycoprotein IIb/IIIa Antagonists Available in United States Abciximab (Reopro®) Eptifibatide (Integrilin®) Tirofiban (Aggrastat®) 130 Glycoprotein IIb/IIIa Antagonists: Injectable Antiplatelet Agents Class mechanism of action The interaction of fibrinogen with the GP IIb/IIIa receptor is the final common pathway to platelet aggregation GP IIb/IIIa antagonists either bind via steric hindrance OR bind competitively (reversibly) to the GP IIb/IIIa receptor on platelets and prevent the binding of fibrinogen, von Willebrand factor, and/or other adhesive ligands to the GP IIb/IIIa receptor and thus inhibit platelet aggregation All agents cause a dose-dependent inhibition of platelet aggregation These agents are given in conjunction with heparin or LMWHs and antiplatelet agents such as aspirin and P2Y12 antagonists, all of which increases the risk of bleeding Concurrent administration with NSAIDs, thrombolytics, or oral anticoagulants also increases the risk of bleeding GP = Glycoprotein 131 Glycoprotein IIb/IIIa Antagonists: Injectable Antiplatelet Agents Clinical uses Management of STEMI, NSTEMI, unstable angina patients with or without PCI depending on the agent Administration All these agents are administered as a continuous IV infusion The administration of platelets is recommended if severe thrombocytopenia or bleeding develops 132 Glycoprotein IIb/IIIa Antagonists: Abciximab (Reopro®) Is a monoclonal antibody type agent that binds to and blocks the GP IIb/IIIa receptor via steric hindrance instead of reversible binding Terminal t1/2 = 12-24 hours Time to normal platelet function: ~12-24 hours but effects on platelets can be seen for up to 48 hours or longer after stopping infusion Adverse effects Bleeding – Most Common Hypotension Thrombocytopenia, intracranial hemorrhage, hemorrhagic stroke Immunogenicity reactions – because the agent is a monoclonal antibody GP = Glycoprotein 133 Glycoprotein IIb/IIIa Antagonists: Eptifibatide (Integrilin®) Is a small, synthetic cyclic heptapeptide agent that binds to and reversibly inhibits the GP IIb/IIIa platelet receptor Produces reversible inhibition of platelet aggregation Plasma t1/2= 2.5 hours Time to normal platelet function: usually ~ 4-6 hours Excretion: Renal (50%) Dose adjustments are necessary in renal dysfunction Adverse effects Most common – Bleeding and hypotension Others – Thrombocytopenia, intracranial hemorrhage, hemorrhagic stroke GP = Glycoprotein 134 Glycoprotein IIb/IIIa Antagonists: Tirofiban (Aggrastat®) Is a non-peptide, small molecule antagonist of the platelet GP IIb/IIIa receptor that has the same mechanism of action as eptifibatide Produces reversible inhibition of platelet aggregation Plasma t1/2= 2 hours Is eliminated primarily by the kidneys but also in the feces Adverse effects Bleeding – most common Thrombocytopenia Monitoring parameters and contraindications are similar to those for eptifibatide GP = Glycoprotein 135 Glycoprotein IIb/IIIa Antagonists: Surgical Implications Abciximab Typically discontinued 72 hours before surgery Eptifibitide and Tirofiban Typically discontinued 24 hours before surgery Horlocker TT, et al. Regional Anesthesia and Pain Medicine. 2010 Jan;35(1): 64-101. Gogarten W, et al. Eur J Anaesthesiol. 2010;27:999-1015. 136 Glycoprotein IIb/IIIa Antagonists: Epidural Catheter Implications Hold Time Before Placement Abciximab Hold Time Before Removal 48 hours EptifibatideΨ 4-8 hours TirofibanΨ 4-8 hours Ψ Hold Time After Placement Contraindicated while epidural catheter in place Medications are renally eliminated. May need to hold longer in renal impairment Horlocker TT, et al. Regional Anesthesia and Pain Medicine. 2018; 43:263-309. Gogarten W, et al. Eur J Anaesthesiol. 2010;27:999-1015. Hold Time After Removal Not recommended within 4-6 weeks of surgery 137 Fibrinolytic/Thrombolytic Agents These agents are called fibrinolytic or thrombolytic agents because they act as plasminogen activators since they convert endogenous proenzyme plasminogen into the fibrinolytic enzyme plasmin and plasmin then degrades fibrin into fibrin split products Fibrin is a major structural component of a thrombus The most common complication from these agents is bleeding Anticoagulants and drugs that inhibit platelet function increase the risk of bleeding when given with these agents 138 Fibrinolytic/Thrombolytic Agents These agents are classified as either fibrin-specific or non- fibrin-specific agents Fibrin-specific agents These agents act preferentially on plasminogen molecules that are located within a fibrin clot and produce limited conversion of plasminogen into plasmin in the absence of fibrin, thus causing a limited systemic effect This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen 139 Fibrinolytic/Thrombolytic Agents Non-Fibrin-Specific Agents (aka: First generation agents) Streptokinase (Streptase®) – No longer available in the U.S.A Urokinase (Abbokinase®) – No longer available in the U.S.A Fibrin-Specific Agents (aka: Second generation agents) Alteplase (Activase®, Cathflo®Activase®) Reteplase (Retavase®) Tenecteplase (TNKase®) These agents are ALL produced by recombinant DNA technology and are the only fibrinolytic agents commercially available in the United States at this time 140 Fibrinolytic/Thrombolytic Agents Absolute contraindications Any prior intracranial hemorrhage/hemorrhagic stroke Ischemic stroke within 3 months Known structural cerebral vascular lesion Arteriovenous malformation, Aneurysm Known intracranial neoplasm Suspected aortic dissection Active Internal bleeding or bleeding diathesis Considerable facial trauma or closed head trauma in past 3 months 141 Fibrinolytic/Thrombolytic Agents Relative contraindications Severe hypertension (SBP >180 and/or DBP >110) History of chronic poorly controlled hypertension INR 2-3 on warfarin Recent trauma, major surgery, prolonged CPR, minor head trauma, internal bleeding within past 2-4 weeks Active peptic ulcer disease Streptokinase exposure > 5 days earlier or prior allergic reaction to streptokinase Pregnancy Age > 75 years Known intracranial pathology (dementia) 142 Streptokinase (Streptase®) Streptokinase is a non-enzymatic fibrinolytic agent produced by beta-hemolytic streptococci Streptokinase by itself IS NOT a plasminogen activator and does not convert plasminogen directly into plasmin by proteolytic cleavage like other plasminogen activators because it is not an enzyme. Rather, streptokinase binds non-covalently to plasminogen (or binds to plasmin) to form a streptokinase:plasminogen activator complex, and THIS COMPLEX then acts on other plasminogen molecules to generate plasmin Is a non-fibrin specific agent so it acts on both free & fibrinbound plasminogen resulting in systemic fibrinolysis Plasma t1/2 = 20 minutes 143 Streptokinase (Streptase®) Is antigenic since it is produced from beta-hemolytic streptococci Circulating anti-streptokinase antibodies may be formed after administration Adverse effects Bleeding – most common Hypotension Allergic reactions such as fever, shivering, and rarely anaphylaxis due to presence of antibodies Arrhythmias (rare) 144 Pharmacologic Properties of Fibrin-Specific Thrombolytics Mechanism of action All available fibrin-specific thrombolytic agents have the same general mechanism of fibrinolysis When introduced into systemic circulation, alteplase, reteplase, and tenectaplase preferentially bind to fibrin within a thrombus and enzymatically convert the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. Plasmin then breaks down fibrin into fibrin-split products. Fibrinogen, a precursor to fibrin, is also degraded by plasmin These agents produce limited conversion of plasminogen into plasmin in the absence of fibrin All available thrombolytic agents differ in their fibrin specificity, thrombolytic potency, and resistance to inactivation by plasminogen activator inhibitor (PAI-1) 145 Alteplase (Activase®) Is a serine protease that acts as a tissue plasminogen activator and is manufactured by recombinant DNA technology Is a single-chain polypeptide that is a recombinant form of human tissue-type plasminogen activator Is also called rt-PA (recombinant tissue plasminogen activator) Plasma t1/2 = < 5 min (shorter than streptokinase) In contrast to streptokinase, alteplase has a much shorter half- life, is a fibrin-specific agent which results in less fibrinogen depletion, is non-antigenic, and is associated with far less hypotensive effects Liver metabolism is the major clearance mechanism 146 Alteplase (Activase®): FDA Indications Ischemic stroke Administer within 3 hours of stroke symptom onset It is also appropriate to use within 3 to 4.5 hour window (there are additional inclusion criteria than 3 hour criteria) Is the ONLY FDA approved thrombolytic drug for use in ischemic stroke Pulmonary embolism Acute MI (STEMI) UA= Unstable Angina, STEMI = ST Segment Elevation Myocardial Infarction NSTEMI= Non-ST Segment Elevation Myocardial Infarction 147 Alteplase (Activase®): Adverse Effects Bleeding – most common Minimal hypotensive effects Allergic reactions, cholesterol embolization and arrhythmias associated with reperfusion are extremely rare Never re-administer alteplase 148 Alteplase (Activase®): Epidural Catheter Implications Alteplase (rt-PA) Full Dose Cathflo®Activase® Hold Time Before Placement Hold Time After Placement Hold Time Hold Time Before Removal After Removal Not recommended if have received tPA therapy Contraindicated If unexpected thrombolytic therapy occurs, fibrinogen level monitoring is suggested to evaluate timing of epidural removal No specific restrictions Horlocker TT, et al. Regional Anesthesia and Pain Medicine. 2018; 43:263-309. Gogarten W, et al. Eur J Anaesthesiol. 2010;27:999-1015. 10 days 149 Reteplase (Retavase®) Is a non-glycosylated modified form of human tissue-type plasminogen activator that is produced by recombinant DNA technology Is also called r-PA (recombinant plasminogen activator) Mechanism of action is the same as alteplase and tenecteplase Plasma t1/2= 13-16 minutes (longer than alteplase) Longer t1/2 permits double bolus dosing of 10 units 30 minutes apart (10 units + 10 units double-bolus injection) Is non-antigenic and rarely causes allergic reactions Cleared primarily by the liver and kidney Major adverse effect – bleeding Indication – Acute MI (STEMI) only 150 Tenecteplase (TNKase®) Is a genetically engineered modified form of human tissue-type plasminogen activator that is produced by recombinant DNA technology It is different from human tissue plasminogen activator by having three amino acid substitutions resulting in the following pharmacologic differences when compared to rt-PA: 1. Has increased fibrin specificity – tenecteplase has the highest degree of fibrin specificity and binding 2. Has greater resistance to plasminogen activator inhibitor-1 (PAI-1) 3. Has a longer plasma t1/2 (t1/2 = 20-24 minutes), which allows it to be administered as a single IV bolus over 5-seconds 151 Tenecteplase (TNKase®) Mechanism of action is the same as alteplase and reteplase Non-antigenic and rarely causes allergic reactions Major adverse effect – bleeding Is associated with a significantly lower rate of non-cerebral bleeding complications and need for transfusions compared to alteplase Liver metabolism is the major clearance mechanism Indication – Acute MI (STEMI) only 152 The End! World Cup 2010: Germany Beats England 4-1