Pharmacologic management of UA/NSTEMI

1. Pharmacologic management of UA/NSTEMI Nogury, M.S., Pharm.D. Internal Medicine In-service

2. UA/NSTEMI • A clinical syndrome usually caused by atherosclerotic CAD • Associated with an increased risk of cardiac death and MI • UA vs. NSTEMI • Ischemia in NSTEMI is severe enough to have detectable cardiac markers

3. Pathogenesis of UA/NSTEMI • Non-occlusive thrombus on pre-existing plaque • Dynamic obstruction (coronary spasm or vasoconstriction) • Progressive mechanical obstruction • Inflammation and/or infection • Secondary UA

4. Presentation of UA/NSTEMI • Rest angina: usually > 20 min • New onset angina: ≥CCS class III • Increasing angina: more frequent, longer in duration, or lower in threshold • Should determine short-term risk of death or nonfatal MI based on history, character of pain, clinical findings, ECG changes, and presence of cardiac markers

5. Pharmacologic treatment • Goals • Immediate relief of ischemia and the prevention of serious adverse outcomes • Options • Anti-ischemic drugs • nitrates, morphine, beta-blockers • Anti-platelet drugs & anticoagulants • aspirin, clopidogrel, heparin, LMWH, GPIIb/IIIa antagonists • Risk-modifying drugs • lipid lowering agents (statins)

6. Nitrates • MOA: ↓ preload & afterload → ↓ MVO2 • Indicated when chest pain despite SL NTG x 3 • Administered by either IV, topical, or oral route • IV NTG: initiated with 10 μg/min with increment of 10 μg/min q3-5min up to 200 μg/min

7. Nitrates-continued • Once pt stabilized, may convert to nitropaste and subsequently po isosorbide • Does not decrease mortality in AMI • ADRs: Hypotension, headache, reflex tachycardia • Tolerance can develop • Monitoring parameters: SBP - ≥110 mmHg in normotensive pts - ≤ 25% decrease in MAP in hypertensive pts

8. Morphine sulfate • Has analgesic, anxiolytic and favorable hemodynamic effects • Indicated • when pain despite SL NTG x 3 • recurrent symptoms despite adequate anti-ischemic therapy • 1-5 mg IV q5-30 min

9. Morphine sulfate-cont’d • ADRs • Hypotension, nausea/vomiting, respiratory depression • Naloxone (0.4-2.0 mg IV) for morphine overdose • Meperidine for morphine allergy pt

10. Beta-blockers • Has anti-arrhythmic, anti-ischemic, and antihypertensive properties • 13% reduction in MI among pts with UA • Unless contraindication exists, all pts should receive intravenous followed by oral beta-blockers • CIs: marked 1st degree AV block, 2nd and 3rd degree AV block, severe LV dysfn with CHF

11. Beta-blockers cont’d • Goal: resting HR < 60 bpm • Do not use β-blockers with ISA • Should be held when SBP < 90 mmHg or HR < 50 bpm, decompensated CHF • ADRs: bradycardia, hypotension, bronchospasm • Dosing • Metoprolol: 5 mg IV q 5 min x 3; followed by 50 mg po q6h for 48 hrs

12. Beta-blockers cont’d • Chronic oral therapy

13. Calcium antagonists • ↓ afterload (& ↓ conduction velocity) • Verapamil or diltiazem is indicated when beta-blockers are contraindicated • Dihydropyridine do not have consistent beneficial effect on mortality or MI recurrence • Do not use immediate-release, short-acting nifedipine b/c of ↑ in mortality

14. Aspirin • Irreversibly inhibits COX-dependent platelet activation at low dose (>75 mg/d) • ↓ mortality and rate of MI, stroke and vascular death • All pts should receive aspirin unless contraindication exists • At first sign of CP, chew and swallow 325 mg x 1, then continue 81-325 mg qd for life

15. Aspirin-cont’d • Contraindications • Intolerance, allergy, active bleeding, hemophilia, active retinal bleeding, severe untreated hypertension, active peptic ulcer, GI or GU bleeding

16. Clopidogrel • Irreversible ADP antagonist • Takes several days to show complete effect • At least as effective as ASA • Dosing • 300 mg loading followed by 75 mg po QD

17. Clopidogrel-cont’d • Indications • when ASA is contraindicated • Should be added to ASA ASAP on admission and given for at least 1 mo and for up to 9 mo in pts with no early intervention plan • Should be started and continued for at least 1 mo and for up to 9 mo in pts with PCI planned • Should be held for at least 5 days, preferably 7 days, in pts when CABG is planned

18. Unfractionated heparin • Complexes with antithrombin III to inhibit thrombin, factors Xa, XIa, XIIa and IXa • Early admin. ↓ the incidence of AMI • Should be added to ASA + clopidogrel • Dosing • 60~70 U/kg bolus (max: 5,000 U) followed by 12~15 U/kg/h (max: 1,000 U/kg/h) • Duration: undefined for asymptomatic pts or continued until an invasive intervention in symptomatic pts

19. Unfractionated heparin-cont’d • Monitoring parameters • aPTT at 1.5-2.5 times control values • aPTT q6h after initiating therapy and after subsequent dosage adjustment • Once 2 consecutive aPPTs within the target, aPTT q24h • PLT, Hct/Hgb • ADRs • Thrombocytopenia: not-dose and not-duration dependent

20. Low Molecular Weight Heparin • More selective for factor Xa compared to thrombin • Advantages: • More predictable and sustained anticoagulation b/c of dose-independent clearance with longer t1/2 • Do not usually require lab monitoring activity • Enoxaparin may be superior to UFH in the treatment of UA

21. Low Molecular Weight Heparin-cont’d • Enoxaparin dosing: 1 mg/kg SC q12h • Should Not be used • CrCl <30 ml/min • Very obese: >120 kg • May monitor antifactor Xa 4hr after the admin. • UFH is preferred in pts likely to undergo CABG within 24h, b/c of the reversibility of anticoagulating effect • LMWH should be held at least 8 hr before the intervention

22. GPIIb/IIIa antagonists • Inhibits platelet aggregation by blocking GPIIb/IIIa receptor to which fibrinogen binds • Abciximab, eptifibatide, tirofiban • Indications • Should be given, in addition to ASA, clopidogrel and UFH, to pts when catheterization and PCI are planned • Should be given, in addition to ASA and UFH or LMWH, to pts with continuing ischemia or an elevated troponin

23. GPIIb/IIIa antagonists Monitor plt 2-4 hr after bolus and then daily (Reopro), 6 hr after bolus and then daily (Integrelin & Aggrastat)

24. ACE I • ↓ LV dysfn and slow progression to HF by preventing LV remodelling • ↓ mortality in pts • with AMI • who recently had an MI, and have LV dysfn • in diabetic pts with LV dysfn • in a broad spectrum of pts with high-risk chronic CAD, including pts with normal LV fn • Initiated after ASA + clopidogrel and beta-blockers when pt is hemodynamically stable

25. ACE I-cont’d • Contraindications • Hypotension • Bilateral renal artery stenosis • Acute renal failure • Angioedema • Pregnancy • Hyperkalemia • ADRs • Hyperkalemia, angioedema, dry cough, hypotension

26. ACE I-cont’d

27. Lipid lowering agents (Statins) • Inhibits HMG-CoA reductase, a rate limiting enzyme of cholesterol biosynthesis • ↓ rate of AMI • Goal • LDL < 100 mg/dL • HDL > 40 mg/dL • Should be initiated 24-96 hr after admission • May provide benefit independent of lipid lowering effect

28. Other modifiable risks • Hypertension • Smoking • Diabetes

29. Typical discharge regimen • SL NTG • Clopidogrel + ASA • Beta-blocker • ACE I • Statin

30. References • Braunwald et al, ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. 2002 www.acc.org/clinical/guidlines/unstable/unstable.pdf

31. Abbreviations • UA: unstable angina • NSTEMI: non ST segment elevation myocardial infarction • CAD: coronary artery diseases • MI: myocardial infarction • CCS: Canadian Cardiovascular Society • ECG: electrocardiogram • LMWH: low molecular weight heparin • GPIIb/IIIa: glycoprotein IIb/IIIa • MOA: mechanism of action • MVO2: myocardial wall tension • SL NTG: subligual nitroglycerin • AMI: acute myocardial infarction • ADRs: adverse drug reactions • SBP: systolic blood pressure • MAP: mean arterial blood pressure

32. Abbreviations • Pt(s): patient(s) • CIs: contraindications • AV: atrioventricular • LV: left ventricular • Dysfn: dysfunction • CHF: congestive heart failure • HR: heart rate • ISA: intrinsic sympathomimetic activity • bpm: beat per minute • b/c: because • COX: cyclooxygenase • CP: chest pain • GI: gastrointestinal • GU: genitourinary • ADP: adenosine diphosphate • ASA: aspirin • ASAP: as soon as possible

33. Abbreviations • PCI: percutaneous coronary intervention • CABG: coronary artery bypass graft • aPTT: activated partial thrombin time • PLT: platelet • Hct: hematocrit • Hgb: hemoglobin • UFH: unfractionated heparin • CrCl: creatinine clearance • HF: heart failure • HMG: hydroxymethylglutaryl • LDL: low density lipoprotein • HDL: high density lipoprotein