Becoming apt at DAPT: incorporating new dual antiplatelet therapy guidelines into clinical practice _________________ Caitlin M. Gibson, PharmD, BCPS Assistant Professor, Department of Pharmacotherapy University of North Texas System College of Pharmacy

Learning objectives Pharmacists Given a patient case, calculate a DAPT score and formulate a treatment recommendation for a patient receiving DAPT Technicians Identify standard treatment durations for patients receiving DAPT

Abbreviations ACS = acute coronary syndromes NNH = number needed to harm ARR = absolute risk reduction NNT = number needed to treat ASA = aspirin NSTE = non-ST elevation BMS = bare metal stent PCI = percutaneous coronary intervention CABG = coronary artery bypass grafting SIHD = stable ischemic heart disease DAPT = dual antiplatelet therapy STEMI = ST-elevation MI DES = drug-eluting stent TIA = transient ischemic attack MACE = major adverse cardiovascular events TIMI = thrombolysis in myocardial infarction MI = myocardial infarction USA = unstable angina

Drug and dose selection Outline Background Duration of DAPT Drug and dose selection Special populations

What is Dual Antiplatelet Therapy? (DAPT) P2Y12 Receptor Antagonist Clopidogrel Aspirin Prasugrel Ticagrelor

CURE trial Design Double-blind, placebo-controlled RCT Patients 12,562 NSTE-ACS patients Interventions ASA 325 mg daily + clopidogrel 75 mg daily or ASA 325 mg daily + PBO Primary outcomes Composite of death from CV causes, nonfatal MI, or stroke Composite of above or refractory ischemia DAPT Aspirin p value NNT 9.3% 11.4% <0.001 47 DAPT Aspirin p value NNT 16.5% 18.8% <0.001 43 NEJM 2001;345:494-502.

Review of P2Y12 Antagonists   Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) Loading dose 300 or 600mg PO 60mg PO 180mg PO Maintenance dose 75mg PO daily 10mg PO daily 60 or 90mg PO BID Dose adjustments -- Weight <60kg, consider 5mg daily Degree of platelet inhibition + ++ Adverse events + Bleeding ++ Bleeding Time to peak effect ~6 hours ~30 minutes ~90 minutes Metabolism Prodrug (CYP 2C19) Prodrug Active drug Drug interactions Inhibitors of CYP 2C19 may prevent activation of drug (omeprazole, esomeprazole, fluoxetine)

Review of P2Y12 Antagonists   Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) Contraindications Active bleeding History of CVA or TIA (stroke or mini-stroke) Pearls 25-30% of patients have genetic polymorphism reducing efficacy of clopidogrel  genetic or platelet reactivity testing  Not for medical management Aspirin must be dosed <100 mg daily Can cause dyspnea Generic available? Yes No

Where do these guidelines fit? Updates to recommendations in various American Heart Association collaborative guidelines: SIHD NSTE-ACS STEMI PCI CABG Non-cardiac surgery

Drug and dose selection Outline Background Duration of DAPT Drug and dose selection Special populations

Ischemic Events Bleeding Balancing risks Prolonged DAPT Shortened DAPT Anticoagulants Clopidogrel Prior MI Ticagrelor Prasugrel Ischemic Events Bleeding

Duration of DAPT Medical Management PCI with BMS PCI with DES CABG   Medical Management PCI with BMS PCI with DES CABG Fibrinolysis SIHD N/A > 1 month > 6 months 12 months ACS > 12 months Total of 12 months* 14 days – 12 months *If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months Class I recommendation Class IIa recommendation JACC 2016;68(10):1082-115

CABG recommendations Mixed results in studies; most do not show benefit for DAPT Largest meta-analysis showed DAPT vs. ASA alone resulted in: Reduced early saphenous vein graft occlusion RR=0.59, 95% CI 0.43-0.82, p=0.002 Reduced incidence of 30-day/in-hospital mortality Incidence 0.8% vs. 1.9%, p<0.001 Trend toward increase bleeding risk RR=1.17, 95% CI 1.00-1.37, p=0.05 J Card Surg. 2013;28:109-16.

Duration of DAPT: Longer may be reasonable   Medical Management PCI with BMS PCI with DES+ CABG Fibrinolysis SIHD N/A > 1 month > 6 months 12 months ACS > 12 months Total of 12 months* 14 days – 12 months *If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months +Second-generation drug-eluting stents JACC 2016;68(10):1082-115

Duration of DAPT: Longer may be reasonable Trial Patients Intervention Drugs Endpoints Results: long vs. standard NNT/NNH DAPT NEJM 2014; 371(23): 2155-66. N = 9961 Any IHD with stent placed 30 vs. 12 mo DAPT after DES ASA 75-162mg Clopidogrel Prasugrel Stent thrombosis 0.4% vs. 1.4% (p<0.001) 100 Major adverse cardiovascular and cerebrovascular events 4.3% vs. 5.9% (p<0.001) 63 Moderate-severe bleeding 2.5% vs 1.6% (p=0.001) 111

Duration of DAPT: Shorter may be reasonable   Medical Management PCI with BMS PCI with DES CABG Fibrinolysis SIHD N/A > 1 month > 6 months 12 months ACS > 12 months Total of 12 months* 14 days – 12 months *If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months JACC 2016;68(10):1082-115

Results*: short vs. standard Trial Patients Intervention Drugs Primary endpoint Results*: short vs. standard SECURITY JACC 2014;64(20): 2086-97. N = 1399 SIHD, USA 6 vs. 12 mo DAPT after DES ASA - ? Dose Clopidogrel Ischemic event or bleeding 4.5% vs 3.7% (p<0.05) EXCELLENT Circulation 2012;125:505-13. N = 1443 Any IHD ASA 100-200 mg Target vessel failure 4.8% vs. 4.3% (p=0.001) RESET JACC 2012;60(15): 1340-48. N = 2117 3 vs. 12 mo DAPT after DES ASA 100 mg Ischemic event, revascularization, or bleeding 4.7% vs. 4.7% (p<0.001) OPTIMIZE JAMA 2013:310(33): 2510-22. N = 3211 SIHD or low-risk ACS 6.0% vs. 5.8% (p=0.002) *All p-values are for non-inferiority

Risk vs. benefit of DAPT duration Generally, extending duration of DAPT >12 months results in a 1-2% decrease in late stent thrombosis & ischemic complications, but a 1% increase in risk of bleeding For every 1000 patients, prolonged DAPT after DES implantation results in 6 fewer MIs and 3 fewer stent thomboses, but also 5 major bleeds Prolonged DAPT is most likely to benefit patients with a history of MI JACC 2016;68(10):1082-115

DAPT Score Variable Points Age >75 years -2 Age 65 – 74 -1 Current smoker 1 Diabetes mellitus MI at presentation Prior PCI or MI Stent diameter <3mm Paclitaxel-eluting stent CHF or LVEF <30% 2 Saphenous vein graft PCI A score of >2 is associated with a favorable benefit/risk ratio for prolonged DAPT; <2 is associated with an unfavorable ratio JACC 2016;68(10):1082-115

Drug and dose selection Outline Background Duration of DAPT Drug and dose selection Special populations

Aspirin dosing in DAPT I A daily aspirin dose of 81 mg (range: 75-100 mg) is recommended Daily ASA doses as low as 30-50 mg inactivate COX-1 and inhibit thromboxane production Studies comparing low-dose to standard dose aspirin have consistently found comparable rates of ischemic events but higher bleeding rates with high dose aspirin: TRANSLATE-ACS: NNT for 1 major bleed = 67 PCI-CURE: NNT for 1 major bleed = 50 Serenbrauny, et al: NNT for any bleed = 16 JACC 2016;68(10):1082-115. Circulation. 2015: 132(3):174-81. Eur Heart J. 2009; 30(8):900-7. Am J Cardiol. 2005; 95(10):1218-22.

P2Y12 selection Medical Management PCI with BMS PCI with DES CABG   Medical Management PCI with BMS PCI with DES CABG Fibrinolysis SIHD Clopidogrel NSTEMI/USA or STEMI Ticagrelor > clopidogrel Ticagrelor or prasugrel > clopidogrel Clopidogrel, prasugrel, ticagrelor JACC 2016;68(10):1082-115

Prasugrel – TRITON-TIMI 38 Randomized, double-blind, multinational trial Patients: ACS undergoing PCI (n=13,608) Median age = 61 years; 74% male; 92% white race 74% NSTE-ACS; 26% STEMI 99% PCI (94% stented); 1% CABG Prasugrel 60mg  10mg PO daily Clopidogrel 300mg  75mg PO daily vs. New Eng J Med 2007;357(20): 2001-15.

Prasugrel – TRITON-TIMI 38 Endpoint Outcome in prasugrel group ARR NNT Primary endpoint Reduction CV death, MI, or stroke 2.2% 45 Secondary endpoints Nonfatal MIs Stent thrombosis 1.3% 77 Cardiovascular mortality NS Safety Incidence of TIMI major bleeding 0.6% 167 New Eng J Med 2007;357(20): 2001-15.

Prasugrel – TRITON-TIMI 38 Net benefit - Patients with diabetes (HR 0.70, 95% CI 0.58-0.85) No net benefit / net harm - History of stroke or transient ischemic attack (HR 1.54, 95% CI 1.02-2.32) - > 75 years - <60 kg

Ticagrelor - PLATO Randomized, double-blind, multinational trial Patients: ACS patients (n=18,624) Median age = 62 years; 72% male; 92% white race 59% NSTE-ACS; 38% STEMI 64% PCI (61% stented); 10% CABG Ticagrelor 180mg  90mg PO BID Clopidogrel 300-600mg  75mg PO daily vs. Lancet 2010;375: 283-93.

Ticagrelor - PLATO Endpoint Outcome in Ticagrelor Group ARR NNT Primary endpoint Reduction CV death, MI, or stroke 1.9% 53 Secondary endpoints Nonfatal MIs 1.1% 91 Stent thrombosis 0.7% 143 Cardiovascular mortality 1.4% 71 Safety Incidence of TIMI major bleeding NS Lancet 2010;375: 283-93.

Prasugrel – TRITON-TIMI 38 Net benefit No net benefit - Not taking lipid-lowering drugs - Less than median weight for sex - Enrolled in North America (ASA dosing?)

Ticagrelor – PEGASUS-TIMI 54 Randomized, double-blind, 33-months Does long-term therapy with ticagrelor added to low-dose aspirin reduce the risk of major adverse cardiovascular events among stable patients with a history of myocardial infarction? Patients: History of MI in prior 1-3 years (n=21,162) Median age = 65 years; 76% male; 87% white race 41% NSTE-ACS; 53% STEMI 83% PCI (61% stented); 10% CABG Ticagrelor 90mg PO BID + ASA Ticagrelor 60mg PO BID + ASA Placebo + ASA vs. vs. N Eng J Med 2015;372(19):1791-1800.

Ticagrelor – PEGASUS-TIMI 54 Endpoint Outcome in ticagrelor group 90mg v. PBO ARR 60mg v. PBO ARR Primary endpoint Reduction CV death, MI, or stroke 1.2% 1.3% Secondary endpoints Incidence of MIs 0.9% 0.7% Cardiovascular mortality NS Safety Incidence of TIMI major bleeding 1.5% N Eng J Med 2015;372(19):1791-1800.

Ticagrelor – PEGASUS-TIMI 54 Patients had already received a year of DAPT No head-to-head data against other P2Y12 antagonists in this setting FDA approved to reduce the rate of CV death, MI, and stroke in patients with a history of MI Package insert: Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily

Drug and dose selection Outline Background Duration of DAPT Drug and dose selection Special populations

Triple therapy Results in 2-3x increased bleeding risk Recommendations: Assess ischemic and bleeding risks Keep duration as short as possible With warfarin, target INR of 2.0-2.5 Clopidogrel is preferred P2Y12 inhibitor JACC 2016;68(10):1082-115

Proton pump inhibitors Controversial drug interaction Place in DAPT therapy: I History of prior gastrointestinal bleeding IIa Increased risk of gastrointestinal bleeding: Advanced age Concomitant warfarin, steroids, or nonsteroidal anti-inflammatory drugs III Routine use in low-risk patients JACC 2016;68(10):1082-115

DAPT and elective non-cardiac surgery Delay surgery 30 days after BMS implantation Delay surgery optimally 6 months after DES implantation IIb Surgery may be considered after 3 months of DAPT III Surgery should not be performed within 30 days after BMS or 3 months of DES implantation JACC 2016;68(10):1082-115

Take home points Customizing duration of a DAPT regimen is reasonable Weigh risk vs. benefit Consider limitations of trials Drug selection Aspirin should be dosed at <100mg in DAPT Ticagrelor and prasugrel may be a reasonable preference over clopidogrel Special populations Use triple therapy sparingly Reserve PPI use for high-risk patients

Becoming apt at DAPT: incorporating new dual antiplatelet therapy guidelines into clinical practice _________________ Caitlin M. Gibson, PharmD, BCPS Assistant Professor, Department of Pharmacotherapy University of North Texas System College of Pharmacy