Cardiovascular Update: Antiplatelet therapy in acute coronary syndromes PHILLIP WEEKS, PHARM.D., BCPS-AQ CARDIOLOGY Learning Objectives Interpret guidelines as they relate to constructing an antiplatelet therapy plan for a patient who has suffered an acute coronary syndrome (ACS) Review recently published primary literature of antiplatelet therapy in ACS Discern patient-specific factors necessary to consider in the selection of antiplatelet therapies in ACS Epidemiology of Acute Coronary Syndrome Cardiovascular disease accounts for approximately 1 in 3 deaths in the United States Coronary heart disease is the leading cause of this (45.1%) Every 40 seconds an American will suffer a heart attack (ACS) From 2004 to 2014 annual deaths attributable to coronary disease has declined but remains very high ACS and coronary heart disease represent 2 of the 10 most expensive hospital discharge diagnoses Circulation. 2017; 135:e1-458 1
J Am Coll Cardiol. 2014;64:e139-228 Patient Case JS is 74 YO M PMH HTN HLD TIA in 2014 PSH 40 pack-year history smoking Presents with significant chest pain, diaphoretic Receives aspirin 325mg chewable and nitroglycerin 0.4mg SL in ED, started on UFH infusion Chest pain is relieved TnI 4.1ng/mL; CK-MB 9.5ng/mL EKG ST depressions in V2-V4 with T-wave inversions; no ST elevations noted Patient Case What is the patient likely suffering from? A. Indigestion B. Unstable angina C. Non-STEMI ACS D. STEMI ACS 2
Pharmacotherapy in Acute Coronary Syndrome Aspirin Beta-blockers (non-shock) P2Y12 Receptor Antagonist ACS Nitroglycerin GP IIb/IIIa Inhibitors (select patients) Heparin or LMWH 3
Guidelines 2013 ACCF/AHA Guideline for the Management of STEMI Aspirin 162-325mg prior to primary PCI (Class I; LOE B) Should be continued indefinitely 81-325mg (Class I; LOE A) 81 mg preferred maintenance dose (Class IIa; LOE B) Loading dose of P2Y12 receptor inhibitor as early as possible or at time of primary PCI Clopidogrel 600mg (Class I; LOE B) Prasugrel 60mg (Class I; LOE B) Ticagrelor 180mg (Class I; LOE B) P2Y12 inhibitor continued for 1 year with DES or BMS (Class I; LOE B) Continue beyond 1 year if DES (Class IIb; LOE C) No prasugrel in patient with history of stroke/tia (Class III; LOE B) J Am Coll Cardiol. 2013;61:e78-140 2013 ACCF/AHA Guideline for the Management of STEMI IV GP IIb/IIIa receptor antagonists in conjunction with UFH or bivalirudin Abciximab (Class IIa; LOE A) Tirofiban (Class IIa; LOE B) Eptifibatide (Class IIa; LOE B) Pre-catheterization laboratory administration (Class IIb; LOE B) Intracoronary abciximab (Class IIb; LOE B) J Am Coll Cardiol. 2013;61:e78-140 4
2014 AHA/ACC Guideline for the Management of Patients with NSTEMI ACS Aspirin (non-enteric coated) 162-325mg as soon as possible and maintenance 81-325mg daily indefinitely (Class I; LOE A) P2Y12 inhibitor should be administered up to 12 months to all patients with NSTE-ACS treated with early invasive or ischemia-guided strategy Clopidogrel 300-600mg loading then 75mg daily (Class I; LOE B) Ticagrelor 180mg loading then 90mg twice daily (Class I; LOE B) Ticagrelor preferred over clopidogrel (Class IIa; LOE B) Prasugrel may be option to continue in post-pci patients treated with coronary stents (Class I; LOE B) GP IIb/IIIa inhibitor (eptifibatide and tirofiban) in patients treated with early invasive strategy with intermediate/high risk features (Class IIb; LOE B) Not recommended in all NSTEMI ACS At time of PCI in patient not pre-treated with P2Y12inhibitor (Class I; LOE A) J Am Coll Cardiol. 2014;64:e139-228 2016 ACC/AHA Guideline Focused Update on Duration of DAPT in CAD In patients with any ACS treated with stent implantation or NSTE-ACS treated medically, it is reasonable to use ticagrelor over clopidogrel (Class IIa, LOE B) In patients with any ACS treated with stent implantation without high risk of bleeding and no history of stroke/tia, it is reasonable to use prasugrel over clopidogrel (Class IIa, LOE B) Prasugrel should not be administered to patients with prior history of stroke or TIA (Class III, LOE B) J Am Coll Cardiol. 2016;68:1082-115 2016 ACC/AHA Guideline Focused Update on Duration of DAPT in CAD In patients treated with DAPT, a daily dose of 81mg (75-100mg) daily is recommended (Class I, LOE B) In ACS patients treated with DAPT after stent implantation, a P2Y12 inhibitor should be given at least 12 months (Class I, LOE B) With high risk of bleeding (treatment with oral anticoagulant) or at high risk of severe bleeding 6mo may be reasonable (Class IIb, LOE C) In patients without high risk of bleeding or taking oral anticoagulants >12mo may be reasonable (Class IIb, LOE A) DAPT Score may help define who could benefit J Am Coll Cardiol. 2016;68:1082-115 5
J Am Coll Cardiol. 2016;68:1082-115 What s changed? Maintenance aspirin dose always 81mg Ticagrelor or prasugrel may be recommended over clopidogrel following ACS GP IIb/IIIa lower recommendation Strongest indication remains NSTEMI patient undergoing PCI not pretreated with oral P2Y12 inhibitor Duration of DAPT may be variable based on multiple factors 12mo still seems optimal in ACS patients Oral P2Y12 inhibitor therapy 6
Selection of Oral P2Y12 inhibitor Clopidogrel Prasugrel Ticagrelor Cyclopentyltiazolopyrimidine Thienopyridine Thienopyridine Chemical class 300-600mg LD 60mg LD 180mg LD Dose 75mg daily 10mg daily 90mg twice daily On strong CYP 2C19 On strong CYP 3A4- Contraindications History of stroke/tia inhibiting drugs inducing drugs Binding Irreversible Irreversible Reversible Onset of activity 2-6hrs 30min 30min Duration of effect 3-10 days 7-10 days 3-5 days Recommended withdrawal 5 days 7 days 5 days before surgery Yes, with variable Yes; with predictable No; active drug with Pro-drug metabolism metabolism active metabolite Generic available Yes No No Patient on DAPT plus ACS patient with or Favored situation ACS patient with PCI anticoagulation without PCI Eur Heart J. 2016;37:267-315 Prasugrel in ACS patients receiving PCI TRITON-TIMI 38 trial Prasugrel vs clopidogrel in ACS patients undergoing PCI Loading dose of clopidogrel group 300mg GP IIb/IIIa inhibitor use ~54% Primary endpoint CV death, nonfatal MI, stroke Within 3 days of PCI - 5.6 vs 4.7% (p=0.01) 3 days and beyond 6.9 vs 5.6% (p=0.003) History of stroke or TIA no benefit and greater risk of safety events Composite death, nonfatal MI, stroke,timi major bleeding 16 vs 23% (p=0.04) N Engl J Med. 2007;357:2001-15 Ticagrelor in ACS PLATO trial Ticagrelor vs clopidogrel in patients with ACS STEMI comprised 37.7% PCI during index hospitalization 61% GP IIb/IIIa inhibitor use 26.6% Primary outcome Death from vascular causes, MI, or stroke HR 0.84 (0.77-0.92) Safety endpoints No difference in study-defined or TIMI major bleeding More fatal intracranial bleed N Engl J Med. 2009;361:1045-57 7
Ticagrelor >12mo PEGASUS-TIMI 54 Ticagrelor 90mg vs ticagrelor 60mg vs placebo Enrolled patients with MI 1-3 years prior continuing DAPT Primary efficacy Outcome Death, MI, Stroke Similar between ticagrelor groups Both better than placebo Safety All bleeding outcomes increased on both ticagrelor groups N Engl J Med. 2015;372:1791-800 DAPT Score Evaluation in patients who receive stent implantation Randomized to receive placebo or thienopyridine at 12mo s/p PCI Clopidogrel or prasugrel Aimed to determine optimal duration of DAPT based on risk factors Predictors of bleeding and MI/Stent thrombosis JAMA. 2016;315:1735-49 Score <2 Score 2 JAMA. 2016;315:1735-49 8
Patient Case JS undergoes successful PCI of left anterior descending coronary artery and circumflex coronary artery with placement of two everolimus-eluting stents. Patient has received aspirin 325mg orally x 1 dose Patient Case What would be the most appropriate plan for dual antiplatelet therapy for JS? A. Ticagrelor 180mg loading dose then 90mg BID plus aspirin 81mg daily for at least 12months. B. Prasugrel 60mg loading dose then 10mg daily plus aspirin 81mg daily for 1 month C. Clopidogrel 300mg loading dose then 75mg daily plus aspirin 81mg daily for 6 months. D. Ticagrelor 180mg loading dose then 90mg BID plus aspirin 325mg daily for 12 months. Cangrelor 9
Cangrelor Intravenous P2Y12 receptor antagonist Approved as adjunctive therapy for PCI to reduce the risk of periprocedural MI, repeat revascularization and stent thrombosis in patients who have not been treated with a P2Y12 inhibitor previously and are not being given a GP IIb/IIIa inhibitor. 30mcg/kg IV bolus followed by 4mcg/kg/min infusion for at least 2 hours or the duration of PCI (whichever is longer) Oral P2Y12 inhibitor should be administered as loading dose immediately after discontinuation of cangrelor infusion Short half-life Offset of platelet inhibition ~ 1hour Kengreal (Cangrelor). Package insert. The Medicine s Company. 2015 Pharmacokinetics/Pharmacodynamics Kengreal (Cangrelor). Package insert. The Medicine s Company. 2015 Clinical Studies Patient GPIIb/IIIa Inhibitor Cangrelor Dosing Population Use SIHD (15%), 30mcg/kg bolus UA/NSTEMI followed by Procedural permitted CHAMPION (74%), and 4mcg/kg/min; per treating physician PCI STEMI (11%) Procedure (26.5%) requiring PCI duration ( 2h) 30mcg/kg bolus SIHD (5%), followed by CHAMPION Used sparingly UA/NSTEMI 4mcg/kg/min PLATFORM (9.2%) (95%) during procedure (2-4 hours) 30mcg/kg bolus SIHD (58%), followed by CHAMPION - UA/NSTEMI Permitted as rescue 4mcg/kg/min ; PHOENIX (26%), STEMI therapy during PCI Procedure (16%) duration ( 2h) Oral P2Y12 Inhibitor Clopidogrel 600mg before PCI Clopidogrel 600mg after PCI or end of cangrelor Clopidogrel 300 or 600mg before or after PCI Primary Ischemic Outcome OR 1.05 (0.88-1.24; p=0.59) OR 0.86 (0.7-1.05; p=0.15) OR 0.78 (0.66-0.93; p=0.005) N Engl J Med. 2009;361:2318-29 N Engl J Med. 2009;361:2330-41 N Engl J Med. 2013;368:1303-13 TIMI Major or Minor Bleeding Major OR 1.36 (0.68-2.71, p=0.39) Minor OR 1.39 (0.84-2.3, p=0.21) Major OR 0.44 (0.14-1.44, p=0.17) Minor OR 1.37 (0.72-2.62, p=0.34) Major OR 1.0 (0.29-3.45, p>0.999) Minor OR 3.0 (0.81-11.10, p=0.08) 10
Cangrelor in Bridging Antiplatelet Therapy ACS patients s/p PCI on DAPT needing non-emergent CABG surgery Patients had received either loading or been on maintenance dose thienopyridine Randomized to either cangrelor or placebo Dosing of cangrelor titrated according to VerifyNow PRU results Goal antiplatelet effect <240PRU Dose range 0.5-2mcg/kg/min 0.75mcg/kg/min considered optimal Comparison No differences in bleeding outcomes JAMA. 2012;307:265-74 Cangrelor Not currently included in ACS guidelines issued by ACC/AHA European Society of Cardiology non-stemi Guidelines Cangrelor may be considered in P2Y12 inhibitor-naïve patients undergoing PCI (Class IIb, LOE A) May be useful in bridging P2Y12 inhibitor therapy prior to urgent/emergent surgery in patients who have recently undergone implantation of coronary stents (off-label) Eur Heart J. 2016;37:267-315 Who should get this? Patients undergoing PCI not pre-treated with oral p2y12inhibitor and not receiving GP IIb/IIIa inhibitor Patients unable to take oral medications undergoing PCI Patients with complicated interventions who may require subsequent coronary artery bypass graft surgery (off-label) Patients requiring surgical procedures for whom prolonged discontinuation of DAPT may be dangerous (off-label) Cardiac or urgent non-cardiac surgery 11
Vorapaxar Vorapaxar PAR-1 receptor antagonist inhibits thrombin-induced platelet aggregation PAR-1 and PAR-4 receptor mediate thrombin activation of platelet PAR-1 activated by lower concentration of thrombin, mediates more rapid platelet-activation response Clinical Studies Patient Population Vorapaxar dosing Background antiplatelet therapy Primary Ischemic Outcome TIMI Major or Minor Bleeding TRACER ACS (without STelevation) 40mg LD then 2.5mg daily Aspirin (>99%) Clopidogrel (91.8%) GP IIb/IIIa (20.9%) HR 0.92 (CI 0.85-1.01; p=0.07) HR 1.53 (CI 1.24-1.9; p<0.001) TRA 2P-TIMI 50 History of atherosclerosis; MI or ischemic stroke within 2 weeks to 12months or PAD 2.5mg daily Aspirin (80-98%) Thienopyridine (20-78%) HR 0.87 (CI 0.8-0.94) HR 1.46 (CI 1.36-1.57) N Engl J Med. 2011;366:20-33 N Engl J Med. 2012;366:1404-13 12
Vorapaxar Not included in ACC/AHA ACS guidelines ESC Guidelines indicate Benefit of vorapaxar is modest and must be carefully weighed against the increase bleeding events including intracranial hemorrhage Contraindicated in patients with cerebrovascular disease Eur Heart J. 2015; ACS guideline web addenda Patient Case JS attends his follow-up appointment with his cardiologist at 1 year following his NSTEMI and PCI. Patient has no complaints and appears to be doing well. Echocardiogram reveals his LVEF ~25-30% DAPT score calculated to be 3pts MI at presentation 1pt s/p PCI with stent placement 1pt Cigarette smoking 1pt HF or LVEF <30% 2pt Age now 75 YO -2pt Patient Case What would be the optimal treatment option with JS antiplatelet regimen? A. Continue aspirin only, discontinue ticagrelor B. Continue aspirin, switch ticagrelor to prasugrel 10mg daily C. Continue aspirin, switch ticagrelor 90mg BID to 60mg BID D. Discontinue all antiplatelet agents, patient has reached 1 year 13
Conclusions Aspirin dosing should be 325mg once initially followed by 81mg daily maintenance dose Choice of DAPT based on patient factors Ticagrelor or prasugrel may be moderately superior in ACS patients No prasugrel in patients with stroke/tia Duration should remain 12mo following ACS DAPT score may define Cangrelor represents a new IV P2Y12 receptor antagonist Lower risk of stent thrombosis + possibly higher risk of bleeding Routine place in therapy remains questionable Vorapaxar role in current therapy unclear Cardiovascular Update: Antiplatelet therapy in acute coronary syndromes PHILLIP WEEKS, PHARM.D., BCPS-AQ CARDIOLOGY 14