New Oral Blood Thinners and New Dilemmas: What Do We Need To Know?

Transcription

1 New Oral Blood Thinners and New Dilemmas: What Do We Need To Know? Richard Mullvain RPH BCPS (AQC) Essentia Health Heart & Vascular Conference May 18 th, 2012 Objectives: Review and understand the pharmacodynamics of the new oral anticoagulants and antiplatelet agents. Learn and consider new practice changes and challenges created when utilizing the new oral blood thinners while reviewing the new CHEST Guidelines. Review and learn from a case study highlighting new opportunities and challenges with the new oral blood thinners Pathway to Clot Formation 1

2 Pathways to Platelet Aggregation Blood Thinners. What Are They? Just like WD-40 for the bloodstream? WD-40 Manufacturing Company CORPORATION CALIFORNIA 1061 Cudahy Place San Diego CALIFORNIA

3 4 Main Blood-Thinners Anti-Platelet Anti-Coagulant Anti-Thrombin Anti-Fibrin New Oral Blood Thinners FDA Approved New Oral Anticoagulants Dabigatran (Pradaxa) Rivaroxaban (Xaralto) Not FDA Approved Apixaban (Eliquis) (FDA Ruling due June 28 th, 2012) Edoxaban (Lixiana) FDA Approved New Antiplatelet Prasugrel (Effient) Ticagrelor (Brilinta) 3

4 New Anticoagulants ORAL PARENTERAL TTP889 X TF/VIIa IX TFPI (tifacogin) Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a Dabigatran XIMELAGATRAN Fibrinogen IIa Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007 Direct Factor Xa inhibition XIIa XIa IXa Xa Factor II (prothrombin) VIIa Rivaroxaban Apixaban YM150 DU-176b LY Betrixaban TAK 442 Tissue factor Fibrinogen Fibrin clot 4

5 Direct Thrombin inhibition XIIa XIa VIIa Tissue factor IXa Xa II XIMELAGATRAN Factor IIa (thrombin) Dabigatran Bye Bye Rat Poison? New Oral Anticoagulants Benefits Rapid Onset Fixed Dose Little Drug or Food Interaction Short Half Life Routine Testing Not Required Drawbacks Less Familiar Renal Variation No Antidote Cost Unknown Post-Marketing Surveillance Complications 5

6 Kinetics Pradaxa (Dabigatran) Cleared by the kidneys Half life hours Onset 30 minutes Therapeutic within 2 hours (No more waiting a few days for INR to become (No more waiting a few days for INR to become therapeutic!) 6

7 Hold Pradaxa Before Surgery/Invasive Procedures Hold 1-2 days if CrCl > 50 ml/min Hold 3 to 5 days if CrCl < 50 ml/min Pradaxa (Dabigatran) Monitoring? At recommended therapeutic doses, dabigatran etexilate prolongs the aptt and ecarin clotting time (ECT) With an oral dose of 150 mg twice daily the aptt is approximately 2x baseline Twelve hours after the last dose the median aptt is 1.5x baseline. 7

8 How Much Anticoagulation is Happening? Pradaxa's half life in normal renal function is between hours. If we assume a 12 hour minimum Pradaxa half life, My guess is as follows: 12 hours after last dose - aptt 1.5x baseline 24 hours after last dose - aptt 1.25x baseline 36 hours after last dose - aptt 1.13x baseline 48 hours after last dose - aptt 1.06x baseline 60 hours after last dose - aptt 1.03x baseline Dose Diversity Dabigatran (Pradaxa): Not enough doses? Rivaroxaban (Xarelto): Too many doses? 8

9 Kinetics: Rivaroxaban (Xarelto ) Absorption Tmax, Oral: 2 to 4 hours Bioavailability, il Oral: 80% to 100% Effects of food: no effect Distribution Vd: 50 L Protein binding, Albumin: 92% to 95% Metabolism Liver: major site Excretion Fecal: 28%, 7% unchanged Renal: 66%, 36% unchanged Dialyzable: No (hemodialysis) Total body clearance: 10 L/hr Elimination Half Life 5 to 9 hours (Age years old) 11 to 19 hours (Elderly) EINSTEIN PE (Compared to LMWH Enoxaparin and then Warfarin) 15 mg TWICE daily x 3 weeks, then 20 mg ONCE daily for 3, 6, or 12 months NOTE: NOT FDA Approved for PE Yet!!! The EINSTEIN-PE investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; DOI: /NEJMoa Available at: 9

10 Bleeding: Pradaxa try FEIBA? Xarelto try PCC? Dabigatran (Pradaxa) Moderate to Severe Bleeding symptomatic treatment mechanical compression surgical intervention fluid replacement and hemodynamic support blood product transfusion oral charcoal (if dabigatran administered < 2 hrs prior) hemodialysis (60% removal) Life Threatening Bleeding measures above charcoal filtration last resort: rviia or PCC (not anticipated to be effective) Rivaroxaban (Xaralto) Moderate to Severe Bleeding symptomatic treatment mechanical compression surgical intervention fluid replacement and hemodynamic support blood product transfusion oral charcoal (if rivaroxaban administered < 2 hrs prior) NOTE: not dialyzable Life Threatening Bleeding measures above charcoal filtration last resort: rviia or PCC Consider FEIBA? (per package insert) & Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: rfviia (NovoSeven) A recombinant form of human factor VIIa It is often used unlicensed in severe uncontrollable bleeding, although there has been safety concerns 10

11 FEIBA Factor eight inhibitor bypass activity (FEIBA NF) NF = Nanofiltered FEIBA NF is manufactured from large plasma pools of human plasma FEIBA NF contains Factors II, IX, and X, mainly nonactivated, and Factor VII, mainly in the activated form. The product contains approximately equal unitages of Factor VIII inhibitor bypassing activity and Prothrombin Complex Factors onatedplasmaproducts/ucm pdf PCC Prothrombin Complex Concentrates A group of blood products derived from pooled human plasma. Contains clotting Factors II, IX, and X, as well as varying amounts of Factor VII. May also contain proteins C, protein S, antithrombin, or heparin. 11

12 PCC Can be classified into three different types of products: (3-F PCC) Three Factor Prothrombin Complex Concentrates Contain Factors II, IX, and X, but only low concentrations of Factor VII (4-F PCC) Four Factor Prothrombin Complex Concentrates Contain Factors II, IX, VII and X (apcc) Activated Prothrombin Complex Concentrates Contain at least one factor in predominately the activated form PCC Currently, there are two 3-F PCC products (Profilnine SD and Bebulin), no 4-F FPCC products, and one apcc (FEIBA NF) available in the United States According to ClinicalTrials.gov, two 4-F PCC products (Octaplex and Beriplex) are currently being studied for the reversal of vitamin K antagonists in the United States 12

13 PCC COST COMPARISON: Product Cost per Unit Dose Cost for 75 kg patient Profilnine $ units/kg $1, $2, Bebulin $ units/kg $1, $3, FEIBA $ units $ $1, Courtesy Andrew Swartz, Pharm D, EH Formulary Class Review: Prothrombin Complex y,, y p Concentrates 13

14 What Else Do I Need To Know About New Oral Anticoagulants? History can teach us what to expect: Ethical & Legal Dilemma's Off Label Use Hospital Discharge Pressure Insurance Coverage and Cost and Value Issues Compliance BLEEDING! Renal Dose Adjustment Monitoring Issues Drug Interactions ti Herbal & Supplement Interactions Adverse Events Special Populations Higher Risk Patients Counterfeiting Usually published every 3 years in June 9 th Edition about 8 months late Shelf-Life of these Guidelines likely to be short, due to multiple advances in new oral antithrombotic therapies 14

15 2012 CHEST Guidelines Disclaimer: These slides are NOT inclusive of all topics and chapters in the 9 th Edition of the CHEST Guidelines Only select recommendations have been highlighted and reduced to a Power Point slide form to educate on key recommendations that have been changed, or are newly added Do NOT use these slides to guide your practice, but rather use them as a tool to steer you back to the published Guidelines to clarify the detailed recommendations for your practice 2012 CHEST Guidelines Evidence-Based Management of Anticoagulant Therapy 2.1 Loading Dose for Initiation of Vitamin K Antagonist (VKA) Therapy 2.1. For patients sufficiently healthy to be treated as outpatients, we suggest initiating VKA therapy with warfarin 10 mg daily for the first 2 days followed by dosing based on international normalized ratio (INR) measurements rather than starting with the estimated maintenance dose (Grade 2C). Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Chest 2012;141;7S-47S 15

16 2012 CHEST Guidelines 2.2 Initial Dose Selection and Pharmacogenetic Testing Evidence-Based Management of Anticoagulant Therapy 2.2. For patients initiating VKA therapy, we recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B). Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 3.1 Monitoring Frequency for VKAs Evidence-Based Management of Anticoagulant Therapy 3.1. For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (Grade 2B). 3.2 Management of the Single Out-of-Range INR 3.2. For patients taking VKAs with previously stable therapeutic INRs who present with a single out-of-range INR of 0.5 below or above therapeutic, we suggest continuing the current dose and testing the INR within 1 to 2 weeks (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 16

17 2012 CHEST Guidelines 3.3 Bridging for Low INRs Evidence-Based Management of Anticoagulant Therapy 3.3. For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 3.4 Vitamin K Supplementation Evidence-Based Management of Anticoagulant Therapy 3.4. For patients taking VKAs, we suggest against routine use of vitamin K supplementation (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 17

18 2012 CHEST Guidelines Evidence-Based Management of Anticoagulant Therapy 3.6 Patient Self-Testing and Self-Management 3.6. For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest patient self management rather than usual outpatient INR monitoring (Grade 2B). For all other patients, we suggest monitoring that includes the safeguards in our best practice statement 3.5. of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 6.1 Unfractionated Heparin (UFH) Dose Adjustment by Weight Evidence-Based Management of Anticoagulant Therapy 6.1. For patients starting IV UFH, we suggest that the initial bolus and the initial rate of the continuous infusion be weight adjusted (bolus 80 units/kg followed by 18 units/kg per h for VTE; bolus 70 units/kg followed by 15 units/kg per h for cardiac or stroke patients) or use of a fixed dose (bolus 5,000 units followed by 1,000 units/h) rather than alternative regimens (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 18

19 2012 CHEST Guidelines 6.2 Dose Management of Subcutaneous (SC) UFH Evidence-Based Management of Anticoagulant Therapy 6.2. For outpatients with VTE treated with SC UFH, we suggest weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weight adjusted dosing with monitoring (Grade 2C). They do Not clarify if it should be q12h or q8h??? of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 9.1 Vitamin K for Patients Taking VKAs With High INRs Without Bleeding Evidence-Based Management of Anticoagulant Therapy 9.1. (a) For patients taking VKAs with INRs between 4.5 and 10 and with no evidence of bleeding, we suggest against the routine use of vitamin K (Grade 2B). (b) For patients taking VKAs with INRs > 10.0 and with no evidence of bleeding, we suggest that oral vitamin K be administered (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 19

20 2012 CHEST Guidelines Evidence-Based Management of Anticoagulant Therapy 9.3 Treatment of Anticoagulant-Related Bleeding 9.3. For patients with VKA-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor prothrombin complex concentrate rather than with plasma. (Grade 2C). We suggest the additional use of vitamin K 5 to 10 mg administered by slow IV injection rather than reversal with coagulation factors alone (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 6.0 Persons Traveling Long-Distance Prevention of VTE in Nonsurgical Patients For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder), we suggest frequent ambulation, calf muscle exercise, or sitting in an aisle seat if feasible (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 20

21 2012 CHEST Guidelines Prevention of VTE in Nonsurgical Patients 6.0 Persons Traveling Long-Distance For long-distance travelers at increased risk of VTE, we suggest use of properly fitted, below- knee GCS (Graduated Compression Stockings) providing 15 to 30 mm Hg of pressure at the ankle during travel (Grade 2C). For all other long-distance travelers, we suggest against the use of GCS (Grade 2C) For long-distance travelers, we suggest against the use of aspirin or anticoagulants to prevent VTE (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 2.5 Perioperative Management of VKA-Treated Patients Who Require Minor Procedures Perioperative Management of Antithrombotic Therapy 2.5. In patients who require a minor dental procedure, we suggest continuing VKAs with coadministration of an oral prohemostatic agent or stopping VKAs 2 to 3 days before the procedure instead of alternative strategies (Grade 2C). In patients who require minor dermatologic procedures and are receiving VKA therapy, we suggest continuing VKAs around the time of the procedure and optimizing local hemostasis instead of other strategies t (Grade 2C). In patients who require cataract surgery and are receiving VKA therapy, we suggest continuing VKAs around the time of the surgery instead of other strategies (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 21

22 2012 CHEST Guidelines Perioperative Management of Antithrombotic Therapy 3.4 Patients Undergoing a Minor Dental, Dermatologic, or Ophthalmologic Procedure 3.4. In patients who are receiving acetylsalicylic acid (ASA) for the secondary prevention of cardiovascular disease and are having minor dental or dermatologic procedures or cataract surgery, we suggest continuing ASA around the time of the procedure instead of stopping ASA 7 to 10 days before the procedure (Grade 2C) In patients at moderate to high risk for cardiovascular events who are receiving ASA therapy and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C). In patients at low risk for cardiovascular events who are receiving ASA therapy, we suggest stopping ASA 7 to 10 days before surgery instead of continuation of ASA (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 3.7 Surgical Patients With Coronary Stents Perioperative Management of Antithrombotic Therapy 3.7. In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C). In patients who require surgery within 6 weeks of placement of a baremetal stent or within 6 months of placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7 to 10 days before surgery (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 22

23 2012 CHEST Guidelines Perioperative Management of Antithrombotic Therapy 4.3 Preoperative Interruption of Therapeutic-Dose Bridging LMWH 4.3. In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH, we suggest administering the last preoperative dose of LMWH approximately 24 h before surgery instead of 12 h before surgery (Grade 2C). 4.4 Postoperative Resumption of Therapeutic-Dose Bridging g LMWH 4.4. In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH and are undergoing high-bleedingrisk surgery, we suggest resuming therapeutic-dose LMWH 48 to 72 h after surgery instead of resuming LMWH within 24 h after surgery (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 2.1 Patients With Nonrheumatic Atrial Fibrillation (AF) Antithrombotic Therapy for Atrial Fibrillation For patients with AF, including those with paroxysmal AF, who are at low risk of stroke (eg, CHADS 2 [congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score = 0), we suggest no therapy rather than antithrombotic therapy (Grade 2B). For patients who do choose antithrombotic therapy, we suggest aspirin (75 mg to 325 mg once daily) rather than oral anticoagulation (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 23

24 2012 CHEST Guidelines 2.1 Patients With Nonrheumatic Atrial Fibrillation (AF) Antithrombotic Therapy for Atrial Fibrillation For patients with AF, including those with paroxysmal AF, who are at intermediate risk of stroke (eg, CHADS 2 score = 1), we recommend oral anticoagulation rather than no therapy (Grade 1B). We suggest oral anticoagulation rather than aspirin (75 mg to 325 mg once daily) (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). For patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns about major bleeding), we suggest combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Antithrombotic Therapy for Atrial Fibrillation 2.1 Patients With Nonrheumatic Atrial Fibrillation (AF) For patients with AF, including those with paroxysmal AF, who are at high risk of stroke (eg, CHADS 2 score = 2), we recommend oral anticoagulation rather than no therapy (Grade 1A), aspirin (75 mg to 325 mg once daily) (Grade 1B), or combination therapy with aspirin and clopidogrel (Grade 1B). For patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) (Grade 1B). of Chest Physicians Chest 2012;141;7S-47S 24

25 2012 CHEST Guidelines 2.1 Patients With Nonrheumatic Atrial Fibrillation (AF) Antithrombotic Therapy for Atrial Fibrillation For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation (including 2.1.9, , and excluding 2.2, 3.1, 3.2, 3.3), we suggest dabigatran 150 mg twice daily Rather than adjusted-dose VKA therapy (target INR range, ) (Grade 2B). Remarks : Dabigatran is excreted primarily by the kidney. It has not been studied and is contraindicated in patients with severe renal impairment (estimated creatinine clearance of 30 ml/min or less). Clinicians should be aware that there is no antidote for dabigatran. of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 2.2 Patients With AF and Mitral Stenosis Antithrombotic Therapy for Atrial Fibrillation 2.2. For patients with AF and mitral stenosis, we recommend adjusted-dose VKA therapy (target INR range, ) rather than no therapy, aspirin (75 mg to 325 mg once daily), or combination therapy with aspirin and clopidogrel (all Grade 1B). For patients with AF and mitral stenosis who are unsuitable for or choose not to take adjusted-dose VKA therapy (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) alone (Grade 1B). of Chest Physicians Chest 2012;141;7S-47S 25

26 2012 CHEST Guidelines 3.1 Patients With AF and Stable Coronary Artery Disease Antithrombotic Therapy for Atrial Fibrillation 3.1. For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation, we suggest adjusted-dose VKA therapy alone (target international normalized ratio [INR] range, ) rather than the combination of adjusted-dose VKA therapy and aspirin (Grade 2C). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines 3.2 Patients With AF and Placement of an Intracoronary Stent Antithrombotic Therapy for Atrial Fibrillation 3.2. For patients with AF at high risk of stroke (eg, CHADS 2 score of 2 or greater) during the first month after placement of a bare-metal stent or the first 3 to 6 months after placement of a drug-eluting stent, we suggest triple therapy (eg, VKA therapy, aspirin, and clopidogrel) rather than dual antiplatelet therapy (eg, aspirin and clopidogrel) (Grade 2C). After this initial period of triple therapy, we suggest a VKA (INR ) plus a single antiplatelet drug rather than VKA alone (Grade 2C). At 12 months after intracoronary stent placement, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). of Chest Physicians Chest 2012;141;7S-47S 26

27 2012 CHEST Guidelines 3.2 Patients With AF and Placement of an Intracoronary Stent Antithrombotic Therapy for Atrial Fibrillation For patients with AF at low to intermediate risk of stroke (eg, CHADS 2 score of 0 or 1) during the first 12 months after placement of an intracoronary stent (bare metal or drug eluting), we suggest dual antiplatelet therapy rather than triple therapy (Grade 2C). At 12 months after intracoronary stent placement, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Antithrombotic Therapy for Atrial Fibrillation 3.3 Patients With AF and ACS Who Do Not Undergo Intracoronary Stent Placement 3.3. For patients with AF at intermediate to high risk of stroke (eg, CHADS 2 score of 1 or greater) who experience an acute coronary syndrome and do not undergo intracoronary stent placement, we suggest for the first 12 months, adjusted-dose VKA therapy (INR ) plus single antiplatelet therapy rather than dual antiplatelet therapy (eg, aspirin and clopidogrel) or triple therapy (eg, warfarin, aspirin, and clopidogrel) (Grade 2C). After the first 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). of Chest Physicians Chest 2012;141;7S-47S 27

28 2012 CHEST Guidelines 3.3 Patients With AF and ACS Who Do Not Undergo Intracoronary Stent Placement Antithrombotic Therapy for Atrial Fibrillation For patients with AF at low risk of stroke (eg, CHADS 2 score of 0), we suggest dual antiplatelet therapy (eg, aspirin and clopidogrel) rather than adjusted-dose VKA therapy (INR ) plus single antiplatelet therapy or triple therapy (eg, warfarin, aspirin, and clopidogrel) (Grade 2C). After the first 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Antithrombotic Therapy for Atrial Fibrillation 3.5 Patients With Atrial Flutter 3.5. For patients with atrial flutter, we suggest that antithrombotic therapy decisions follow the same risk-based recommendations. as for AF of Chest Physicians Chest 2012;141;7S-47S 28

29 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 2.0 Primary Prevention of Cardiovascular Disease 2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 3.1 Choice of Long-term Antithrombotic Therapy in Patients With Established Coronary Artery Disease (CAD) For patients with established coronary artery disease (CAD), defined as patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, (including patients after the first year post-acs and/or with prior coronary artery bypass graft [CABG] surgery): We recommend long-term single antiplatelet therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no antiplatelet therapy (Grade 1A). We suggest single over dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 29

30 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 3.2 Choice of Antithrombotic Therapy Following ACS For patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI): We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily or clopidogrel 75 mg daily plus low-dose aspirin mg daily) over single antiplatelet therapy (Grade 1B). We suggest ticagrelor 90 mg daily (TYPO?? Twice daily?) plus low dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 3.2 Choice of Antithrombotic Therapy Following ACS For patients in the first year after an ACS who have undergone PCI with stent placement: We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin mg daily, clopidogrel 75 mg daily plus lowdose aspirin, or prasugrel 10 mg daily plus low-dose aspirin over single antiplatelet therapy) (Grade 1B). Remarks: Evidence suggests that prasugrel results in no benefit net harm in patients with a body weight of < 60 kg, age > 75 years, or with a previous stroke/transient ischemic attack. We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B). of Chest Physicians Chest 2012;141;7S-47S 30

31 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 4.0 Antithrombotic Therapy Following Elective PCI For patients who have undergone elective PCI with placement of BMS (Bare Metal Stent): For the first month, we recommend dual anti platelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A). For the subsequent 11 months, we suggest dual antiplatelet therapy with combination of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C). After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). of Chest Physicians Chest 2012;141;7S-47S 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 4.0 Antithrombotic Therapy Following Elective PCI For patients who have undergone elective PCI with ihplacement of fdes(d (Drug Eluting Stent): For the first 3 to 6 months, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A). After 3 to 6 months, we suggest continuation of dual antiplatelet therapy with low dose aspirin 75 to 100 mg and clopidogrel (75 mg daily) until 12 months over single antiplatelet therapy (Grade 2C). After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). Single antiplatelet therapy thereafter is recommended as per the established CAD recommendations (see recommendations ). of Chest Physicians Chest 2012;141;7S-47S 31

32 2012 CHEST Guidelines Primary and Secondary Prevention of Cardiovascular Disease 4.0 Antithrombotic Therapy Following Elective PCI For patients who have undergone elective BMS or DES stent placement: We suggest cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet regimen in patients with an allergy or intolerance of either drug class (Grade 2C). Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Chest 2012;141;7S-47S ADP Blockers and CABG (Clopidogrel, Prasugrel, & Ticagrelor) What do the new 2011 CABG Guidelines Say??? Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 32

33 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations Class I 1. Aspirin (100 mg to 325 mg daily) should be administered to CABG patients preoperatively (Level l of Evidence: B) 2. In patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 5 days before surgery (Level of Evidence: B) and prasugrel for at least 7 days (Level of Evidence: C) to limit blood transfusions. 3. In patients referred for urgent CABG, clopidogrel and ticagrelor should be discontinued for at least 24 hours to reduce major bleeding complications. 521, (Level of Evidence: B) Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4.1. Preoperative Antiplatelet Therapy: Recommendations Class IIb 1. In patients t referred for urgent CABG, it may be reasonable to perform surgery less than 5 days after clopidogrel or ticagrelor has been discontinued and less than 7 days after prasugrel has been discontinued. (Level of Evidence: C) Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 33

34 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations Although the use of thienopyridines (clopidogrel l or prasugrel) is associated with improved outcomes in subjects with UA or NSTEMI,305,306 their use is associated with an increase in post-cabg bleeding and need for transfusions. 520,522, Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations The risk of major bleeding complications (ie, pericardial tamponade or reoperation) is increased when CABG is performed 24 hours after clopidogrel s discontinuation. 524,525 Conversely, no increase in bleeding or transfusions is noted when CABG is performed 5 days after clopidogrel has been stopped. 529,532 Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 34

35 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations The magnitude of bleeding risk when CABG is performed 1 to 4 days after the discontinuation of clopidogrel is less certain. Although the incidence of life-threatening bleeding does not appear to be significantly increased during this time, an increase in blood transfusions is likely. 523,524,529,531 Accordingly, from the perspective of blood conservation, it is reasonable to delay elective CABG for 5 days after discontinuing clopidogrel. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations For patients requiring more urgent CABG, it can be performed 24 hours after clopidogrel has been stopped with little or no increased risk of major bleeding. Approximately two thirds of clopidogrel treated patients undergo CABG 5 days after clopidogrel discontinuation, 529, driven largely by concerns for patient stability, resource utilization, patient preference, and the confidence of the surgical team in managing hemostasis. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 35

36 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations Little experience with CABG in patients treated with prasugrel has been reported. In the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction) trial, the incidence of CABG-related major bleeding was higher in prasugrel-treated patients than in those on clopidogrel (13.4% versus 3.2%; P0.001). 533 When possible, therefore, CABG should be delayed for 7 days after prasugrel is discontinued. 533 Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations Ticagrelor, an oral agent that binds reversibly to the platelet P2Y12 receptor, provides faster, more effective, and more consistent t inhibition of platelet l t aggregation and more rapid recovery of platelet function after discontinuation than clopidogrel. 534 In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 632 patients in the ticagrelor group and 629 in the clopidogrel group underwent CABG within 7 days of the last dose of study drug. 521 Although the study protocol recommended waiting 5 days after stopping clopidogrel and 24 to 72 hours after ticagrelor, many patients underwent surgery before the recommended waiting times. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 36

37 4. Perioperative Management 4.1. Preoperative Antiplatelet Therapy: Recommendations The rates of major bleeding (59.3% with ticagrelor, 57.6% with clopidogrel) and transfusion requirements (55.7% with ticagrelor, 56.5% with clopidogrel) were similar. Furthermore, no difference in bleeding was noted between ticagrelor and clopidogrel with respect to time from last dose of study drug, even when CABG was performed 1, 2, or 3 days after discontinuation. On the basis of these data, it does not appear that the more rapid recovery of platelet function seen in ticagrelor pharmacokinetic studies translates to a lower risk of bleeding or less need for transfusion compared with clopidogrel when CABG is performed early (ie, 5 days) after drug discontinuation. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4.2. Postoperative Antiplatelet Therapy: Recommendations Class I 1. If aspirin i (100 mg to 325 mg daily) was not initiated preoperatively, it should be initiated within 6 hours postoperatively and then continued indefinitely to reduce the occurrence of SVG closure and adverse cardiovascular events. 519,535,536 (Level of Evidence: A) Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 37

38 4.2. Postoperative Antiplatelet Therapy: Recommendations Class IIa 1. For patients t undergoing CABG, clopidogrel l 75 mg daily is a reasonable alternative in patients who are intolerant of or allergic to aspirin. (Level of Evidence: C) See Online Data Supplement 23* for additional data on postoperative antiplatelet therapy Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e *Online Data Supplement 23 (Richard s quick analysis) 10 trials all focused on pre-cabg use of ADP blockers None mention post op use 38

39 4.2. Postoperative Antiplatelet Therapy: Recommendations A subset analysis of CABG patients from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) trial suggested that clopidogrel reduced the occurrence of cardiovascular death, MI, and stroke (14.5%) compared with placebo (16.2%). This benefit occurred primarily before surgery, however, and after CABG a difference in primary endpoints between groups was not demonstrable. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 4.2. Postoperative Antiplatelet Therapy: Recommendations (In CURE) Clopidogrel was stopped a median of 10 days before surgery and was restarted postoperatively in 75.3% of patients assigned to receive it. All patients received aspirin, 75 mg to 325 mg daily, but the details of aspirin administration in the study groups were not described.530 Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 39

40 Perioperative Bleeding/ Transfusion: Recommendations Class I 3. In patients taking thienopyridines (clopidogrel or prasugrel) or ticagrelor in whom elective CABG is planned, clopidogrel and ticagrelor should be withheld for at least 5 days 520,521,523,524,531, (Level of Evidence: B) and prasugrel for at least 7 days before surgery 533 (Level of Evidence: C). Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e Perioperative Bleeding/ Transfusion: Recommendations In subjects taking DAPT because of previous placement of a DES, clopidogrel can be stopped 1 year after the most recent DES placement. If CABG cannot be postponed, some operators have suggested that the patient be hospitalized for conversion of thienopyridine therapy to short- acting glycoprotein IIb/IIIa inhibitors for several days before surgery 497,1063,1108,1109; however, no data are available demonstrating the efficacy of such a management strategy. Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice Guidelines Circulation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e 40

41 What Does STS ask? ADP inhibitor within 5 days of Surgery? When discontinued? d? (How many days before surgery?) Was ADP inhibitor prescribed at discharge? What does STS consider an eligible case to be prescribed ADP blocker on discharge post CABG? How to define eligible case? (Patient Intolerant of Aspirin?) So, they are implying here... Don t need to prescribe Plavix after CABG unless patient cannot take Aspirin or If patient also had Drug Eluting Stent within the last year, then they still need to be on Dual Antiplatelet Therapy (Aspirin + Plavix) 41

42 Case Study: H.S. age 40 in yo male lbs. Technician at a nuclear power plant HTN, Hyperlipidemia, angina Sedentary lifestyle (loves beer) Refuses to take medications Dr. gives pep talk about therapeutic lifestyle changes H.S. age 45 in 1995 M.I. PCI w/bms ASA 325 mg Plavix 75 mg x 30 days Diagnose HTN, Hyperlidemia, CAD 42

43 H.S. age 50 in nd MI PCI w/bms ASA 325 mg qd Plavix 75 mg qd x 30 d H.S. age 55 in rd MI PCI w/des ASA 325 mg qd Plavix 75 mg x 1 year (Quit meds after 6 months due to stomach ulcer) 43

44 H.S. age 59 in 2009 Non-Compliant with Medications Restenois of old stent in RCA Angiogram with another DES Prasugrel (Effient) x 1 year + ASA 325 mg Bert Simpson by Twentieth Century Fox Film Corporation, Los Angeles, CA H.S. age 60 in 2010 A-Fib (Diabetic, EF=30%) Started on Warfarin ASA 325 mg Stopped Prasugrel (Effient) 44

45 H.S. age 61 in 2011 Still in A-Fib Stop Warfarin for colonoscopy Start Dabigatran (Pradaxa) H.S. age 62 in 2012 Stop Dabigatran (Pradaxa) 2 days before for dental surgery (too soon!) Significant bleeding post-op Consider Vitamin K, Protamine, and Fresh Frozen Plasma, PRBC s, 2 units blood (all inappropriately!) Called pharmacist, recommended FEIBA Resume Pradaxa 1 week later 45

46 H.S. age 62 in months later need a knee replacement Quit Pradaxa 4 days prior Start Rivaroxaban (Xarelto) post op H.S. age 63 in months later, has another MI 1 vessel stented with DES Need for urgent CABG Xarelto, ASA, Plavix, Heparin on board 46

47 H.S. age 63 in 2013 CABG performed within 2 days Significant bleeding FEIBA used in past, call pharmacist? Pharmacist notices this is Rivaroxaban (Xarelto) Recommends 4F-PCC (Activated) Prothrombin Complex Concentrates Recovers, sent home on Ticagrelor (Brilinta), Xarelto, Aspirin 81 mg H.S. age 64 in 2014 Lose job & insurance Stop Xarelto & Brilinta 30 day free sample of Apixaban Stop when it ran out 47

48 H.S. age 65 in 2015 Sign up for Medicare Attempt Lifestyle Changes Hit Doughnut Hole Resume Warfarin and ASA 81 mg Questions? 48

49 Blood Thinner Clinical Pearls The new oral anticoagulants recently approved by the FDA are Dabigatran (Pradaxa ) and Rivaroxaban (Xaralto ) The new oral anticoagulants are not yet indicated for many of the current indications for Warfarin Expect new indications to be awarded to the oral anticoagulants in a staggered fashion as the FDA reviews new clinical i l trial data New oral anticoagulants likely to be approved in the future are Apixaban (Eliquis) (FDA Ruling due June 28th, 2012), and Edoxaban (Lixiana) The new oral anticoagulants appear at least as effective as warfarin, and perhaps as effective as injectable Low Molecular Weight Heparins (LMWH) Advantages of the new oral anticoagulants include: Rapid Onset, Fixed Dose, Little Drug or Food Interaction, Short Half Life, and Routine Testing Not Required Disadvantages of the new oral anticoagulants include: Less Familiarity, Renal Variation, No Clear Antidotes for Bleeding, Cost, Unknown Post-Marketing Surveillance Complications, Lack of Good Measurement of Level of Anticoagulation The New CHEST Guidelines 2012 contain many changes, some of which may still be considered controversial, including a recommendation for persons aged 50 years or older without symptomatic cardiovascular disease, suggesting low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) Discomfort with utilizing the new oral anticoagulants will continue until we have better ways to measure their effects, and new antidotes/reversal agents are developed to deal with bleeding. References Report of the American College of Cardiology Foundation/American Heart 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery : A Association Task Force on Practice GuidelinesCirculation 2011, 124:e652-e735: originally published online November 7, 2011doi: /CIR.0b013e31823c074e Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Chest 2012;141;7S-47S Pharm D, EH Formulary Class Review: Prothrombin Complex Concentrates. Courtesy Andrew Swartz, 5/10/12 ducts/licensedproductsblas/fractionatedplasmaproducts/ucm pdf & Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: The EINSTEIN-PE investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; DOI: /NEJMoa Available at: b h i ingelheim.com/biwebaccess/viewservlet.ser?docbase=renetnt&folderpath=/prescribing% 20Information/PIs/Pradaxa/Pradaxa.pdf Adapted from Weitz & Bates, J Thromb Haemost 2007 Stangier U et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-lable, parallel-group, single-center study. Clin Pharmakokinetcs 2010:49: Kubitza D et al. Effects of renal impairment on the harmacokinets, pharmacodynamics and satefy of rivaroxaban, an oral direct Factor Xa inhibior. B J Clin Pharmacol 2010: 70: Critical Care Medicine, Vol. 39, No. 12 (Suppl). 49