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Pharmacologic management of UA/NSTEMI Nogury, M.S., Pharm.D. Internal Medicine In-service 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 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 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 Pharmacologic treatment • Goals – Immediate relief of ischemia and the prevention of serious adverse outcomes • Options 1) Anti-ischemic drugs nitrates, morphine, beta-blockers 2) Anti-platelet drugs & anticoagulants aspirin, clopidogrel, heparin, LMWH, GPIIb/IIIa antagonists 3) Risk-modifying drugs lipid lowering agents (statins) 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 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 Morphine sulfate • Has analgesic, anxiolytic and favorable hemodynamic effects • Indicated – when pain despite SL NTG x 3 – recurrent symptoms despite adequate antiischemic therapy • 1-5 mg IV q5-30 min 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 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 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 Beta-blockers cont’d • Chronic oral therapy β-blockers β 1-selective Elimination Target dose Metoprolol tartarate (Lopressor) Yes Hepatic 100 mg BID Metoprolol succinate (Toprol XL) Yes Hepatic 200 mg QD Atenolol (Tenormin) Yes Renal 50-100 mg QD Carvediol (Coreg) No Hepatic 25 mg BID 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, shortacting nifedipine b/c of ↑ in mortality 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 Aspirin-cont’d • Contraindications – Intolerance, allergy, active bleeding, hemophilia, active retinal bleeding, severe untreated hypertension, active peptic ulcer, GI or GU bleeding 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 Clopidogrel-cont’d • Indications 1) when ASA is contraindicated 2) 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 3) 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 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 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 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 Low Molecular Weight Heparin -cont’d • • Enoxaparin dosing: 1 mg/kg SC q12h Should Not be used 1) CrCl <30 ml/min 2) 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 GPIIb/IIIa antagonists • • • Inhibits platelet aggregation by blocking GPIIb/IIIa receptor to which fibrinogen binds Abciximab, eptifibatide, tirofiban Indications 1) Should be given, in addition to ASA, clopidogrel and UFH, to pts when catheterization and PCI are planned 2) Should be given, in addition to ASA and UFH or LMWH, to pts with continuing ischemia or an elevated troponin GPIIb/IIIa antagonists Abciximab (Reopro) Eptifibatide (Integrelin) Tirofiban (Aggrastat) Renal Dosing Elimination T1/2 ADRs IIb/IIIa selectivity Proteolytic breakdown Short but high affinity Bleeding Thrombocytopenia No No Renal 2.5 h Bleeding Thrombocytopenia Yes Yes Renal 1.5-3 hr Bleeding Thrombocytopenia Yes Yes Monitor plt 2-4 hr after bolus and then daily (Reopro), 6 hr after bolus and then daily (Integrelin & Aggrastat) ACE I • • ↓ LV dysfn and slow progression to HF by preventing LV remodelling ↓ mortality in pts 1) 2) 3) 4) • 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 betablockers when pt is hemodynamically stable ACE I-cont’d • Contraindications – – – – – – • Hypotension Bilateral renal artery stenosis Acute renal failure Angioedema Pregnancy Hyperkalemia ADRs – Hyperkalemia, angioedema, dry cough, hypotension ACE I-cont’d Initial dose (mg, po) Target dose (mg, po) Captopril 6.25-12.5, TID 50, TID Enalapril 2.5-5, QD 10, BID Lisinopril 2.5-5, QD 20, QD Ramipril 1.25-2.5, QD 5, BID Trandolapril 1, QD 4, QD Lipid lowering agents (Statins) • • • Inhibits HMG-CoA reductase, a rate limiting enzyme of cholesterol biosynthesis ↓ rate of AMI Goal 1) 2) • • LDL < 100 mg/dL HDL > 40 mg/dL Should be initiated 24-96 hr after admission May provide benefit independent of lipid lowering effect Other modifiable risks • Hypertension • Smoking • Diabetes Typical discharge regimen • • • • • SL NTG Clopidogrel + ASA Beta-blocker ACE I Statin References 1. Braunwald et al, ACC/AHA guideline update for the management of patients with unstable angina and non-STsegment elevation myocardial infarction. 2002 www.acc.org/clinical/guidlines/unstable/unstable.pdf 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 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 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