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4/9/2013 Objectives Lindsey Clark, PharmD, BCPS UC Health: University of Cincinnati Medical Center Cardiology-Medicine Clinical Pharmacy Specialist May 3, 2013 Patient Case: KS 41 F admitted for biopsy of renal mass Home Medications PMH: CAD with multiple stents to RCA, L circumflex, and LAD ○ Most recent DES placed to LAD 23 days ago Rabdomyosarcoma of right eye s/p head and neck radiation Left renal mass (shown to be enlarging on CT abdomen after stent placed) HTN, HLD, GERD, Depression Review pharmacology of antiplatelet therapy Identify recommended indications for dual antiplatelet therapy (DAPT) Assess cardiac and bleeding risk of patients on DAPT who must undergo surgery Develop an appropriate bridging strategy for patients on DAPT undergoing surgery Match the Following Aspirin 325 mg daily Clopidogrel 75 mg daily Isosorbide mononitrate 30 mg QHS Metoprolol XL 50 mg daily Rosuvastatin 20 mg QHS Furosemide 20 mg Q48H Fentanyl 75 mcg TD Q48H Fluoxetine 10 mg daily Pantoprazole 40 mg daily Senna 1 tab BID Zolpidem 5 mg QHS Nitroglycerin SL PRN Tizanidine PRN Vicodin PRN Promethazine PRN Match the Following According to package inserts, how long should each agent be held prior to surgery? Aspirin Ticlopidine 3. Clopidogrel 4. Prasugrel 5. Ticagrelor Continue 5 days C. 7 days D. 10-14 days E. None of the above 1. A. 2. B. Platelets According to package inserts, how long should each agent be held prior to surgery? Aspirin Ticlopidine 3. Clopidogrel 4. Prasugrel 5. Ticagrelor Continue 5 days C. 7 days D. 10-14 days E. None of the above 1. A. 2. B. Gurbel PA and Udaya ST. Circulation 2010;121:569-583. Patrono C et al. Chest 2008;133:199-233. 1 4/9/2013 Adenosine Diphosphate (ADP) Clopidogrel Prasugrel Ticagrelor Abciximab Eptifibatide Tirofiban P2Y12 GP IIb/IIIa PI3K Thrombin PAR-1 Rap1b/Akt Phospholipid Release Intracellular Signaling Arachadonic Acid Aspirin COX-1 Thromboxane A2 (TxA2) TxA2 Gurbel PA and Udaya ST. Circulation 2010;121:569-583. Indications for DAPT Indication Recommended Duration Study Coronary Artery Disease Primary Prevention N Secondary Prevention N NSTEMI/UA without PCI Y CHARISMA CHARISMA 1 year (min 1 month) CURE STEMI without PCI Y Minimum14 days COMMIT, CLARITYTIMI 28 PCI Y BMS: Min 1 month DES: Min 1 year PCI-CURE, CREDO BASKET-LATE Drug Eluting Stent (DES) vs. Bare Metal Stent (BMS) Timing Stroke Atherosclerotic ischemic (1°and 2°prevention) N (Y) MATCH SAMMPRIS Cardioembolic (AF) N (Y) CLAAF, ACTIVE-A, ACTIVE-W N CAMPER, CASPAR Peripheral Arterial Disease AF = Atrial fibrillation; min = minimum; NSTEMI = Non-ST elevation myocardial infarction; PCI = Percutaneous coronary intervention; STEMI = ST elevation myocardial infarction; UA = Unstable angina Reaume KT, et al. Ann Pharmacother. 2008;42:550-7. Antman EM, et al. Circulation. 2008;117:296-329. Anderson JL, et al. Circulation. 2011;123:e426-e579. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 Supplements. Delayed Arterial Healing in Drug-Eluting Stents Early Stent Thrombosis • Acute • Subacute DES BMS < 24 hours 24 hours to 1 month Late Stent Thrombosis 1 month to 1 year Very Late Stent Thrombosis > 1 year Restenosis Shuchman M. N Engl J Med. 2006; 355:1949-1952. Incidence of Surgery within One Year after Stenting Bare metal stent Mean % endothelialization 100 Neointima 90 80 Strut 70 60 15-mo. following stent placement in the LAD 50 40 Drug-eluting stent 30 Bare metal stent 20 Drug-eluting stent 10 0 1 2 4 5 6 9 19 20 24 50 Months after implantation Joner M, et al. J Am Coll Cardiol. 2006;48:193-202. Savonitto S, et al. J Thromb Haemost 2011; 9: 2133–42. 2 4/9/2013 Cardiac Risk Scoring Systems NSQIP Risk Model Revised Cardiac Risk Index (RCRI) Cardiac and non-cardiac surgery Non-emergent, non-cardiac surgery Predicts Myocardial Infarction Cardiac arrest Myocardial infarction Primary cardiac arrest Ventricular fibrillation Pulmonary edema Complete heart block Includes Age Serum creatinine > 1.5 mg/dL ASA Physical Status Class Preoperative functional status Type of surgery High-risk type of surgery History of ischemic heart disease History of heart failure Historiy of cerebrovascular disease Diabetes requiring insulin Serum creatinine > 2 mg/dL surgicalriskcalculator.com/miorcardiacarrest 0 points: 0.4% 1 point: 0.9% 2 points: 6.6% 3 or more: 11% Use Scoring C-statistic 2007 = 0.884 2008 = 0.874 C-statistic = 0.747 NSQIP = National Surgical Quality Improvement; ASA = American Society of Anesthesiologists MICA = intraoperative or postoperative myocardial infarction or cardiac arrest Gupta PK, et al. Circulation. 2011 Jul 26;124(4):381-7. Lee TH, et al. Circulation. 1999; 100:1043-1049. Cardiac Risk for Surgery Gupta PK, et al. Circulation. 2011 Jul 26;124(4):381-7. Major Events vs. Days from Stent Placement P = 0.003 Barash P, Akhtar S. Br. J. Anaesth. 2010;105:i3-i15 Surgical Related Bleeding Risk Risk of Bleeding Type of Surgery (non-cardiac) Low Endoscopy; biopsies Eye anterior chamber (cataract surgery) Dental extraction and dental surgery Otolaryngology surgery Minor orthopaedic surgery Cutaneous surgery; plastic surgery Intermediate Visceral surgery Major orthopaedic surgery Urologic surgery High Intracranial neurosurgery Spinal canal surgery Eye posterior chamber surgery Transurethral prostatectomy Motovska Z. Drugs 2011;71(14):1797-1806 Major Events vs. Surgical Risk P = 0.136 Motovska Z. Drugs 2011;71(14):1797-1806 P = 0.046 P < 0.001 P <0.001 Motovska Z. Drugs 2011;71(14):1797-1806 3 4/9/2013 Major Events vs. Need for Emergent Surgery Now with a better understanding of risks of bleeding and stent thrombosis what would you like to do with KS’s DAPT prior to biopsy? A. Continue both aspirin and clopidogrel B. Continue aspirin alone and stop clopidogrel 5 days before biopsy C. Stop both aspirin 7 days before and clopidogrel 5 days before biopsy, D. Continue aspirin, stop clopidogrel 5 days before biopsy, and start eptifibatide E. Postpone the biopsy P = 0.003 P = 0.006 P = 0.016 Motovska Z. Drugs 2011;71(14):1797-1806 Patient Case: KS Clopidogrel discontinued 23 days after DES placed and aspirin discontinued 26 days after DES placed Eptifibatide 180 mcg/kg bolus then 2 mcg/kg/min Preoperative Management Surgical vs. Cardiac Risk Level KS undergoes biopsy 5 days after clopidogrel discontinued Cardiac Risk More than 3 months after PCI, BMS, or CABG More than 6 months after ACS or MI More than 12 months after regular DES Peripheral and wall surgery Minor ENT and orthopedics Endoscopy without biopsy or resection Eye anterior chamber or dentistry Intermediate Six to 12 weeks after PCI, BMS, or CABG Six to 24 weeks after ACS or MI More than 12 months after high-risk DES Visceral and vascular surgery Major ENT and orthopedics Urology Endoscopy with biopsy or resection High < 6 weeks after PCI, BMS, CABG, ACS, or MI < 12 months after DES Cardiac surgery Surgery with massive bleeding Surgery in closed space (intracranial, intramedullary canal, posterior eye chamber) Aspirin 325 mg daily reinitiated day of biopsy Eptifibatide continued until pathology results reported Proliferation of malignant spindle cells Surgical Risk Low Heme/onc and urology determine that surgery will be necessary for removal of the left renal mass Chassot PG, et al. Br J Anaesth. 2007;99(3):322. Preoperative Management Surgical vs. Cardiac Risk Level Chassot PG, et al. Br J Anaesth. 2007;99(3):322. Preoperative Management Surgical vs. Cardiac Risk Level Chassot PG, et al. Br J Anaesth. 2007;99(3):322. 4 4/9/2013 Recommendations What if surgery is unavoidable? If surgical need known prior to PCI, recommend placement of BMS or balloon angioplasty Stress the importance of minimum duration of DAPT Tirofiban BMS: 1 month Eptifibatide Postpone surgery until minimum duration met If surgery cannot be postponed, Cangrelor Consider continuing aspirin during the peri-operative period Restart P2Y12 inhibitor as soon as possible post-operatively P2Y12 Inhibitors Ticagrelor DES: 12 months Platelet function assessment GP IIB/IIIA Inhibitors High risk surgeries should be performed at hospitals with 24 hour cath lab facilities Reversal of antiplatelet medications Continue DAPT Grines CL, et al. Circulation. 2007;115:813-818. Assessment of Platelet Function Type Test Advantages Platelet-Platelet Aggregation Platelet aggregometry • Turbidometric Gold standard • Impedance Whole blood assay Sample preparation Reproducibility Expensive Large sample needed Time consuming Activation Dependent VerifyNow Simple, rapid POC Small sample volume No instrument adjustment Plateletworks Little sample preparation Not well studied Flow Cytometry Low sample volume Sample preparation Expensive Requires flow cytometer Experienced staff Clot Shear Resistance Shear Induced Platelet Adhesion Thromboelastogram POC; Platelet clot formation and clot lysis data Limited studies Impact Cone and Plate(let) Analyzer Simple, rapid POC Small sample volume High shear Not widely available Patni R, et al. Heart Lung Circ. 2012 Aug;21(8):455-62. Braunwald E, et al. Clin. Cardiol. (Suppl. 1) 31, 3, I-10–I-16 (2008) DES placed within 6 months of surgery Admit 2 – 3 days prior to surgery for tirofiban infusion Abciximab Tirofiban Eptifibatide Antibody Fab fragment Nonpeptide Cyclic heptapeptide Molecular Weight 48 kDa < 1 kDa < 1 kDa Onset Rapid Rapid Rapid Drug half-life 10-30 min 2h 2.5 h Excretion Unknown 40-70% renal 50% renal 24-48 hours 50% to normal within 4 hours 4-6 hours Structure Return of platelet function Eikelboom JW, et al. Chest 2012;141;e89S-e119S. Bridge with Tirofiban Bridge with Tirofiban Discontinue Clopidogrel +/Aspirin 5 days prior to surgery GP IIB/IIIA Inhibitors Disadvantage Discontinue tirofiban 4 hours prior to surgery Resume DAPT as soon as possible Retrospective, observational study of 36 patients 15 CABG No MACE noted 6 bleeding episodes noted 21 non-cardiac interventions ○ 9 Minor ○ 12 Major Outcomes followed for 30 days post bridge Major adverse cardiac events (MACE) ○ Death, repeat MI, target vessel or target lesion revascularization, or stent thrombosis Bleeding ○ Hematuria, GI bleed, transfusion w/o bleeding, decrease Hgb, post-op bleeding requiring intervention TUR = Transurethral resection; CABG = Coronary artery bypass grafting Exclusion: thrombocytopenia, anemia, decreased renal function, serious liver disease, and recent CVA or any operation < 6 weeks Marcos EG, et al. Neth Heart J. 2011;19:412–417. Marcos EG, et al. Neth Heart J. 2011;19:412–417. 5 4/9/2013 Bridge with Eptifibatide Study Patients Morrison, et al 19 patients with median DES placement 102 days prior to surgery • 6 non-cardiac • 13 cardiac Start eptifibatide median 2 days after last dose of clopidogrel 100 consecutive patients with stent needing surgery • 22 non-cardiac • 71 cardiac • 7 did not undergo surgery • 89% of patients had a DES • Median time from stent placement was 156 days Start eptifibatide bridge to surgery (median duration of infusion 5 days) Retrospective chart review Rassi, et al Retrospective chart review Bridge with Eptifibatide Intervention Outcomes Stopped eptifibatide median 10 hours prior to surgery Propensity matched control comparison of 68 of 71 cardiovascular surgery patients 7 (53.9%) major bleeds in cardiac surgery 2 minor bleeds – 1 CTS & 1 non-cardiac surg Blood transfusions: 65% bridged vs. 66% control Mean # of units transfused: 4.84 ± 6.93 bridged 3.65 ±7.46 control Return to the OR for bleeding or tamponade (p 0.085): 10% bridged vs. 2.9% control Morrison TB, et al. Cath and Card Intervent 2012;79:575–582. Rassi AN, et al. Am J Cardiol 2012 Aug 15;110(4):485-90. Rassi AN, et al. Am J Cardiol 2012 Aug 15;110(4):485-90. P2Y12 Inhibitors Pharmacokinetic Variability The ONSET/OFFSET Study Clopidogrel Prasugrel Ticagrelor Cangrelor Thienopyridine Thienopyridine ATP analog ATP analog Oral daily Oral daily Oral BID Continuous Intravenous Infusion No No Yes Yes Peak Platelet Inhibition 4-6 hours 2 hours 2 hours 30 minutes CYP450 Metabolism CYP2C19 CYP3A4 CYP2B6 CYP3A4 CYP3A5 None Half Life 6-8 hours 2-15 hours 6-12 hours 3 minutes 5 days 7 days 5 days TBD Structure Dosing Reversible Hold prior to surgery ATP = Adenosine triphosphate; TBD = To be determined Packard KA, et al. Pharmacotherapy 2012;32(3):244–273. The ONSET/OFFSET Study Gurbel PA, et al. Circulation. 2009;120:2577-2585. The ONSET/OFFSET Study: Subgroup Analysis (n = 14) (n = 46) Gurbel PA, et al. Circulation. 2009;120:2577-2585. Storey RF, et al. J Thromb Haemost 2011; 9:1730–7. 6 4/9/2013 Bridge Trial: Cangrelor vs. Placebo 210 patients randomized Administered for at least 48 hours prior to surgery Stopped 1-6 hours before CABG Primary Endpoint Platelet reactivity assessed using VerifyNow® ○ Measured in P2Y12 reaction units (PRUs) ○ Goal PRU < 240 106 cangrelor 104 placebo Secondary Endpoints 400 300 200 100 0 Baseline 1 Efficacy: 90 Safety: 101 Efficacy: 93 Safety: 106 Cangrelor Platelet Reactivity (PRU) Continuous infusion of cangrelor 0.75 mcg/kg/min Placebo Patients undergoing non-emergent cardiac surgery Platelet Reactivity (PRU) Bridge Trial: Efficacy 2 3 4 5 6 7 400 300 200 100 Last sample on infusion Day Excessive CABG surgery-related bleeding 0 Pre-CABG sample Placebo 86 76 73 57 34 24 14 2 Placebo 84 75 Cangrelor 85 80 70 55 33 7 6 1 Cangrelor 84 78 Composite: death, MI, stroke, or urgent revascularization Angiolillo DJ, et al. JAMA. 2012;307(3):265-274 Angiolillo DJ, et al. JAMA. 2012;307(3):265-274 Reversal of Antiplatelet Therapy: Platelet Protocol Bridge Trial: Safety Cangrelor (n = 102) Placebo (n = 96) p-value Protocol defined bleeding 12 (11.8) 10 (10.4) 0.76 BARC Bleeding 10 (9.8) 10 (10.4) 0.89 Ischemic 3 (2.8) 4 (4) NR Endpoint BARC = Bleeding Academic Research Consortium Protocol defined Surgical reexploration 2-4 hour chest tube output of > 1.5 L PRBC transfusion > 4 units BARC Bleeding Reoperation following closure of sternotomy Chest tube output of > 2 L in 24 hours PRBC or whole blood transfusion of > 5 units Fatal bleeding Perioperative intracranial bleeding Angiolillo DJ, et al. JAMA. 2012;307(3):265-274 Thiele T, et al. J Thromb Haemost 2012; 10: 968–71. Reversal of Antiplatelet Therapy: Platelet Protocol 14 patients enrolled Indications for dual antiplatelet therapy: Surgical interventions Reversal of Antiplatelet Therapy: Platelet Protocol Spine surgery (n = 5) Orbita bottom surgery (n = 1) months (n = 9) BMS < 4 weeks, ACS < 12 months, severe coronary artery stenosis, insertion of a renal artery BMS< 9 days, transaortic valve implantation < 3 months (n = 1 each). Orthopedic hip/knee joint Results Clopidogrel reinitiation median 48 hours Intracranial surgery (n = 2) Insertion of a DES < 12 Thiele T, et al. J Thromb Haemost 2012; 10: 968–71. PCs = Platelet Concentrates; ASA = Aspirin Nephrectomy patient developed prolonged bleeding but no PRBCs transfused 1 ACS reported after hemicolectomy ○ No stent thrombosis seen on catheterization replacement surgery (n = 4) Nephrectomy (n = 1) Hemicolectomy (n = 1) Limitations: May not be applicable for other P2Y12 inhibitors Platelet transfusion reactions or adverse effects Thiele T, et al. J Thromb Haemost 2012; 10: 968–71. 7 4/9/2013 Non-cardiac Surgeries on DAPT Non-cardiac Surgeries on DAPT PAVR = Percutaneous aortic valve replacement CEA = Carotid endarterectomy; EVAR = Endovascular abdominal aortic aneurysm repair; oAAA = Open abdominal aortic aneurysm repair Stone DH, et all. J Vasc Surg 2011;54:779-84. Quante M, et al. Arch Surg. November 2011;146(11):1334-1335. Patient Case: KS Cost and Other Considerations Discussion between attending surgeon and interventional cardiologist (and pharmacists) Aspirin 81 mg daily Eptifibatide continued until 4-6 hours prior to surgery Resection of retroperitoneal mass 40 days after DES placed Eptifibatide reinitiated when immediate surgical bleeding risk stable Agent Cost per unit Ticagrelor $3.48 Eptifibatide $328.32 Platelets Approx $500 Cangrelor TBD Approximately 6 hours after surgery Clopidogrel 300 mg once day after surgery then 75 mg daily Admission to the hospital? Days off work for patient? Waiting for OR scheduling? Duration of therapy? Platelet function testing? Cost of a bleeding episode? Cost of a cath lab visit? Conclusions Recommended Actions Indication for dual antiplatelet therapy? Data regarding bridging strategies for patients requiring DAPT is limited Small study sizes Case reports or retrospective Urgency for surgery? Variability in definitions and practices with transfusions Cardiac vs. surgical bleeding risk? A multidisciplinary care team should have open communication and come to a consensus for, and with, each patient Future directions? Cangrelor FDA approval Discussion among providers Shorter duration of DAPT after DES placement? ○ RESET Trial (J Am Coll Cardiol 2012;60:1340–8) ○ MATRIX Registry (Catheter Cardiovasc Interv. 2012 Sep 1;80(3):408-16.) ○ CREDO-Kyoto PCI/CABG Registry Cohort-2 (Circ Cardiovasc Interv. 2012 Jun;5(3):381-91.) Plan development 8 4/9/2013 Lindsey Clark, PharmD, BCPS UC Health: University of Cincinnati Medical Center Cardiology-Medicine Clinical Pharmacy Specialist May 3, 2013 9