Pharmacotherapy Update for STEMI: What Is New? Michael J. Lipinski, MD, PhD MedStar Washington Hospital Center

Michael J. Lipinski, MD, PhD   Medicure Inc: Research grant and consulting

STEMI: The Epidemiological Impact Half of individuals present with unheralded AMI or SCD as their first manifestation of CAD Approximately 500,000 STEMI per year in the US Adverse outcomes remain high (4.7% In-hospital mortality and 9.0% at 1 year) Montalescot, EHJ 2007 While we have reduced mortality, many of these patients develop heart failure

The Pefect STEMI A patient with no medical problems calls 911 immediately after onset of chest pain and decides to chew aspirin 325 mg at that time. EMS arrives, rapidly transports the patient to the PCI-capable hospital down the street and performs an ECG en route. In the ED, patient has an IV placed, takes an rapid-onset oral P2Y12 inhibitor, and heads to the cath lab The interventionalist explains the risks/benefits of PCI as the patient is draped and the procedure begins. You make the perfect stick, anticoagulation is started, you rapidly perform angiography, wire a thrombotic 90% stenosis, and perform direct stenting. Door to stent time was 30 minutes, but your oral P2Y12 inhibitor won’t kick in for over an hour!!!

Example STEMI 64 y/o female with HTN and HLD presents to the ED for chest pain and ECG shows inferior STEMI. IV Heparin bolus, morphine 2mg IV, ASA 324 mg, and Ticagrelor 180 mg given in the ED but vomited going to the lab.

The Problem with MONA Aspirin is really the only good thing. When 324 mg vs 81 mg? Oxygen was recently shown not to help unless hypoxic. Nitro is bad for RV involvement. Morphine slows uptake of oral P2Y12 inhibitor.

Kubica, Eur Heart J, 2015

Pharmacotherapy for PCI The Ideal: Immediate anticoagulation and platelet inhibition to minimize ischemic events. No increase in bleeding risk. Anti-platelet coverage to enable time for oral P2Y12 inhibitor to take effect. Can glycoprotein IIb/IIIa inhibitors (GPI) or cangrelor fill this roll? Rapid Platelet Inhibition with GPI Onset of Oral P2Y12 Inhibition

GP IIb/IIIa Inhibitors Only to be used on the way to the cath lab or in the cath lab Good for large thrombus burden, complex PCI, inadequate antiplatelet therapy. Is there a contraindication? Recent surgery Prior major GI bleed or ICH Prior stroke Thrombocytopenia Great caution with use after thrombolytic therapy Abciximab: monoclonal antibody blocking fibinogen and GP receptor Prolonged platelet inhibition Tirofiban and Eptifibatide: small molecule GPIs Cleared relatively quickly (3 hour half-life) Requires renal dosing Meta-analysis shows greater bleeding risk but less MACE

What About Cangrelor?? Rapid-onset, intravenous, rapidly-reversible P2Y12 inhibitor Half-life is 3 to 5 minutes Ticagrelor can be given concomitantly Must wait to load with clopidogrel or prasugrel until after PCI Big problem if patient is already loaded Ideal if concern for surgical disease (rapid off-set) Major drawback is the cost

Anticoagulation prior to the Lab Fondaparinux is an option, though not often used (Messy in the lab) Bivalirudin or Argatroban for patients with HIT (Unsure there is benefit) If going directly to the cath lab, either UFH or nothing at all Lovenox has been shown to be superior to UFH in NSTEMI for ACS

Heparin in the Lab UFH bolus (70 units/kg) but most don’t give too much above 5000 units IV. Data with larger boluses (100 units/kg) just associated with greater bleeding. Ideal ACT between 250-300 for heparin without GP IIb/IIIa inhibitor. When using GP IIb/IIIa inhibitor, ACT should be between 200-250 to prevent increased bleeding. UFH redosing often based on estimates (ACT from initial bolus and drop during case) Many operators are very particular regarding sheath pulls/closure based on pharmacology

Bivalirudin (Angiomax) Set it and forget it!!?? Specific and reversible direct thrombin inhibitor Cleared by kidneys and proteolytic cleavage so renal dosed in bad CKD/ARF No risk for HITT Half-life is 25 minutes Dosing: Bolus 0.75 mg/kg, Infusion 1.75 mg/kg/h Check ACT after initial bolus. If ACT<300, I give a 1/3 dose re-bolus GP IIb/IIIa inhibitors should be used provisionally (aka bailout)

Bivalirudin vs UFH Cost is a real issue. Bivalirudin is much more expensive. Bivalirudin significantly decreases bleeding risk by 40% (both access and non-access site bleeding) Bivalirudin associated with 60% increase in early stent thrombosis Initial heparin bolus in the ER and prolonged PCI-dosed infusion of Angiomax shown to mitigate risk of acute ST Consider access (radial vs femoral). MATRIX trial and EuroMAX are important reads Also, assess thrombus burden!! If you are going to use a GPI, I would pick heparin.

Oral P2Y12 Inhibitors: Clopidogrel Member of thienopyridine family which is an irreversible ADP receptor inhibitor Requires 2 steps to be activated in the liver 600 mg Loading dose faster than 300 mg and shown to be better for MACE If no loading dose, therapeutic in 4 to 6 days!! Compliance and cost are a big driver for choosing this med

Oral P2Y12 Inhibitors: Prasugrel Member of thienopyridine family which is an irreversible ADP receptor inhibitor Requires a single step for activation in the liver Rapid onset of action and achieves much greater platelet inhibition than clopidogrel TRITON-TIMI trial showed superior to clopidogrel Old small people with stroke Contraindications: prior stroke/TIA, age >75, <60 kg Surgery is a big problem (7 days) and greater bleeding

Oral P2Y12 Inhibitors: Ticagrelor Reversible direct oral P2Y12 inhibitor Major efficacy trial in ACS was PLATO Comparison in STEMI and NSTEMI Superior to Clopidogrel Rapid Onset No difference in CABG-related bleeding Greater minor bleeding Adenosine-mediated effects (SOB, HF, Asthma, Bradycardia)

STEMI: Current Optimal Medical Therapy Aspirin 325 mg immediately Immediate loading with oral P2Y12 inhibitor (preference for ticagrelor or prasugrel) Emergent Revascularization with heparin or bivalirudin for anticoagulation Consider IV platelet inhibition with GP IIb/IIIa inhibitor or cangrelor Early initiation of beta-blocker Addition of renin-angiotensin-aldosterone system blockade Early initiation of statin therapy

Conclusions There are a variety of potential new therapies to treat pts with STEMI Studies are needed to better clarify the utility of IV anti-platelet medications in the cath lab Heparin reduces thrombotic events while bivalirudin reduces bleeding Loading with oral antiplatelet agents should occur before leaving the lab