What Goes Together: Peanut Butter & Jam, Cookies & Milk - PowerPoint PPT Presentation

What Goes Together: Peanut Butter & Jam, Cookies & Milk Antiplatelets & Anticoagulants??? Lily Lin and Kevin Kwok LMPS Pharmacy Residents December 10, 2019 Preceptor: Elaine Lum 1

Learning Objectives ● Review the mechanism of action of antiplatelets and anticoagulants ● List the indications and review the guidelines and/or evidence for combination therapy of anticoagulants and antiplatelets ● Describe an approach in applying guideline recommendations and evidence to a patient who may require combination therapy

Cardiovascular Disease (CVD) Treatment ● Antiplatelet therapy indicated for secondary prophylaxis of atherosclerotic disease ● Anticoagulant therapy has specific indications such as atrial fibrillation or venous thromboembolic disease

Antithrombotic Drugs Antiplatelets: prevent platelets from clumping Anticoagulants: reduces fibrin formation and prevents clots from growing

Antiplatelet Therapy ● Primary therapy used to prevent arterial thrombosis in patients with atherosclerotic disease ● Dual antiplatelet therapy (aspirin + P2Y12 receptor inhibitor): treatment for ACS with stenting, elective PCI with stenting, stroke

Antiplatelets: Mechanism of Action Aspirin irreversibly inhibits cyclooxygenase-1 and prevents platelet dependent thromboxane formation P2Y12 Receptor Inhibitors prevent platelet activation by inhibiting binding to adenosine diphosphate (ADP) - Clopidogrel and prasugrel: irreversible inhibition - Ticagrelor: reversible inhibition

Anticoagulant Therapy ● Commonly indicated for treatment/prevention of venous thromboembolism and stroke prophylaxis in atrial fibrillation ● Includes variety of agents that inhibit different parts of coagulation cascade ○ Vitamin K antagonism ○ Direct thrombin inhibition ○ Direct factor Xa inhibition

Oral Anticoagulants ● Vitamin K antagonists (warfarin) ○ Inhibit vitamin K epoxide reductase → block hepatic synthesis of active vitamin K ● Direct thrombin inhibitors (dabigatran) ○ Prevent thrombin from cleaving fibrinogen → fibrin ● Direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) ● Prevent factor Xa from cleaving prothrombin to thrombin

Dual Antiplatelet Therapy (DAPT) in PCI ● Used in patients who undergo percutaneous coronary intervention with stenting for acute coronary syndrome (ACS) and non-ACS indications (“elective”) ● DAPT significantly lowers the risk of stent thrombosis

What do the guidelines recommend for DAPT in PCI?

CCS Guidelines for Elective PCI (2018) 1

CCS Guidelines for STEMI/NSTEMI (2018) 1

Why do DAPT and not single antiplatelet therapy?

Stent Thrombosis post-PCI 17

DAPT: P2Y12I + ASA CURE (2001) 2 Clopidogrel 300mg po loading dose then 75mg po + ASA reduce mortality, non- fatal MI, stroke vs. ASA alone post ACS (NSTEMI/UA) Conclusion: DAPT > SAPT post ACS (NSTEMI/UA) PCI-CURE (2001) 3 In patients with NSTEMI undergoing PCI , clopidogrel 75mg + ASA x 3-12 months reduce CV death, MI, revascularization vs. ASA. Based on this trial, guidelines suggest 12 month DAPT after ACS and PCI. TRITON-TIMI 38 In patients with ACS (STEMI/NSTEMI) and scheduled PCI, prasugrel 60mg po (2007) 4 loading dose then 10mg po + ASA reduce CV mortality and morbidity but increase bleeding vs. clopidogrel 75mg po + ASA PLATO (2009) 5 In patients with ACS (STEMI/NSTEMI), ticagrelor 180mg po loading dose then 90mg BID po + ASA reduce CV death, MI, stroke without increasing bleeding vs. clopidogrel 75mg po + ASA N Engl J Med 2001; 345:494-502 Lancet 2001; 358: 527–33 N Engl J Med 2007; 357:2001-2015 N Engl J Med 2009; 361:1045-1057

Should therapy be extended beyond 1 year post-PCI?

DAPT (2014) 6 P (N=9961) Undergoing PCI with stent or had PCI with stent in prior 3 days 62yo, 31% prior PCI, 12% prior CABG Indication for PCI: 11% STEMI, 16% NSTEMI, 17% UA, 38% stable angina P2Y12: 65% clopidogre l, 35% prasugrel I DAPT: ASA 75-162mg daily plus clopidogrel 75mg daily or prasugrel 10mg daily for another 18 months after 12 months of DAPT C SAPT: ASA 75-162mg daily + placebo after 12 months of DAPT O Primary outcomes: ● Stent thrombosis: 0.4% vs 1.4% ARR 1% NNT 100 ● All-cause mortality, MI or stroke: 4.3% vs 4.9% ARR 0.6% NNT 62 ● Moderate or severe bleeding (GUSTO criteria): 2.5% vs 1.6% ARR 0.9% NNH 111 Bottom Line: Extended DAPT (ASA and clopidogrel OR prasugrel) decreases stent thrombosis but increases bleeding risk (moderate-severe) and all cause mortality. Weigh risk vs. benefit before extending DAPT duration.

What about ticagrelor? Does extended duration provide any benefit? What dose should be used if extending therapy beyond 1 year post ACS?

PEGASUS-TIMI (2015) 7 ≥ 50 y/o, MI 1-3 years prior, ≥ 1 of: ≥ 65, diabetes requiring medical therapy, second prior MI, P multivessel CAD, CKD with CrCl < 60mL/min Baseline: age 65, 59% multivessel CAD, 16% > 1 previous MI, 83% PCI history Medications: 99.8% ASA , 93% statin, 82% beta-blocker, ACE/ARB 81% I Ticagrelor 90mg BID OR Ticagrelor 60mg BID C Placebo All patients received ASA 75 to 150mg daily O Primary - CV mortality, MI or stroke at three years Ticagrelor 90mg BID vs. placebo: 7.85% vs. 9.04% (HR 0.85, CI 0.75-0.96, p=0.008) Ticagrelor 60mg BID vs. placebo: 7.77% vs. 9.04% (HR 0.84, CI 0.74-0.95, p=0.004) Secondary - TIMI major bleeding Ticagrelor 90mg BID vs. placebo: 2.6 vs. 1.06% (HR 2.59, NNH 65) Ticagrelor 60mg BID vs. placebo: 2.3% vs. 1.06% (HR 2.32, NNT 81)

Primary Outcome (CV mortality, MI, stroke) ** Kaplan Meier Rates through 3 years. Study drugs were administered twice daily.

PEGASUS-TIMI: Conclusion - Adding ticagrelor to ASA in stable CAD patients reduced the risk of CV death, MI or stroke - Both doses of ticagrelor had similar efficacy and increased bleeding Bottom line: weigh risk and benefits before extending DAPT. Use lower dose (60mg BID) if extending DAPT. Note: 60mg NOT covered by PharmaCare

CCS Guidelines (2018) 1

Do we use DAPT post coronary artery bypass graft (CABG)?

DAPT Post-CABG Overall, more literature to support effect of clopidogrel + ASA (vs. ASA monotherapy) in maintaining post- operative vein graft patency after OFF-pump CABG 8 Note: Use of ticagrelor and prasugrel explored in post-hoc analyses of PLATO and TRITON-TIMI 38 trials, respectively, but no prospective randomized data available.

What are the guideline recommendations for DAPT post-CABG? How long do we treat for?

Antithrombotics Post CABG (AHA Guidelines) 8 Bottom Line: ASA should be continued for life in all CABG patients. Depending on if patient is: 1) off-pump CABG: ASA 81mg daily + Clopidogrel 75mg daily x 1yr (strong recommendation) 2) on-pump CABG: consider ASA 81mg daily + Clopidogrel 75mg daily x1yr (weaker recommendation) Circulation. 2015;131:927-964

What do we do in patients requiring an oral anticoagulant (e.g. atrial fibrillation, mechanical valve) and have undergone PCI? Is triple therapy (OAC + DAPT) safe? How does dual therapy (OAC + single antiplatelet) compare?

WOEST (2013) 9 Adults, indication for OAC for ≥ 1 year after study, severe coronary lesion with indication for P (n=563) PCI Baseline: age 70 years, Indication for OAC: 69% atrial fibrillation/atrial flutter, 10% mechanical valve, 20% other (eg, apical aneurysm or PE) I Clopidogrel 75mg + warfarin (titrated to INR 2) C Clopidogrel 75mg + ASA 80-100mg + warfarin (titrated to INR 2) O Primary: - Any bleeding by year 1: 19.4% vs. 44.4% (HR 0.39, CI 0.26-0.50, NNT 4) Secondary: - Stent thrombosis NSS (1.4% vs. 3.2%. HR 0.44, CI 0.14-1.44) - Death: 2.5% vs. 6.3% (HR 0.39, CI 0.16-0.93, p=0.027, NNT 26) Lancet. 2013 Mar 30;381(9872):1107-15

Primary Outcome (Any Bleeding by Year 1)

WOEST: Limitations ● Unclear why bleeding rates so high in study ● Low rate of proton pump inhibitors in this population ● Underpowered to detect differences in stent thrombosis ● Broad indication for oral anticoagulants

WOEST: Conclusion/Bottom Line Strategy of oral anticoagulant and single antiplatelet therapy (P2Y12I) appears to reduce bleeding risk vs. triple therapy. Bottom Line: In patients with an indication for OAC and have undergone PCI, addition of single antiplatelet (clopidogrel) is safer than DAPT (ASA + clopidogrel). More trials required to determine efficacy (stent thrombosis, stroke, myocardial infarction)

Atrial Fibrillation and PCI ● Increased risk of bleeding when anticoagulation is added to antiplatelet therapy ● Stent thrombosis and ischemic stroke must be balanced with risk of bleeding 2 General Approaches to managing AF and PCI: ● Dual therapy: OAC + P2Y12 inhibitor ● Triple therapy (TT): OAC + DAPT

AF and PCI: Trials to Date 1. PIONEER AF-PCI (2016) 2. RE-DUAL PCI (2017) 3. ENTRUST-AF PCI (2019) 4. AUGUSTUS (2019) *included medically managed patients*