Acute Coronary Syndromes Robert Smith September 21, 2004

Outline Definitions Diagnosis –Chest Pain History –Evaluation of the ECG Pathophysiology Treatment Conclusions

Definitions Acute coronary syndrome is defined as myocardial ischemia due to myocardial infarction (NSTEMI or STEMI) or unstable angina Unstable angina is defined as angina at rest, new onset exertional angina (<2 months), recent acceleration of angina (<2 months), or post revascularization angina

Diagnosis Dx of acute coronary syndrome is based on history, physical exam, ECG, cardiac enzymes Patients can then be divided into several groups – Non-cardiac chest pain (i.e., Gastrointestinal, musculoskeletal, pulmonary embolus) – Stable angina – Unstable angina – Myocardial infarction (STEMI or NSTEMI) – Other cardiac causes of chest pain (i.e., aortic dissection, pericarditis)

Assessment of Chest Pain: History Time of onset Duration Relieving factors and time of relief Activity at time of onset Exertional Component Character of pain Radiation Associated symptoms

Assessment of Chest Pain: Risk Factors Age (>55yrs for males, >65 yrs for females) Gender DM HTN Hyperlipidemia Cigarette Smoking Family History PAD, CVD

“Typical” Chest Pain Pressure, Crushing, Squeezing Retrosternal/Substernal +/- Exertion Usually between 2 and 20 minutes for unstable angina, chronic stable angina Usually greater than 20 minutes for NSTEMI, STEMI Relieved by rest, NTG +/- radiation to arms (L>R), jaw, gums +/- associated SOB, diaphoresis, nausea, vomiting Consistent with previous angina

“Atypical” Chest Pain Sharp, Positional, Exacerbated by deep inspiration, Reproducible to palpation Non-Exertional, Improved With Activity Fleeting (seconds) Constant (hours without positive markers) Non-Radiating No Associated Symptoms or Unusual Associated Symptoms

ST Segment Depression (Ischemia)

ST Segment Elevation (Infarction)

Pre-test Probability In the absence of abnormal findings on physical exam, ECG, or enzymes, the pre-test probability of acute coronary syndrome must be determined by the clinician A good history is crucial (is the chest pain typical or atypical; what are the associated symptoms) Determination of risk factors is also crucial (male, age >55, smoking, DM, HTN, FamHx, hyperlipidemia, known CAD)

Pathophysiology of ACS Plaque rupture and subsequent formation of thrombus – this can be either occlusive or non- occlusive (STEMI, NSTEMI, USA) Vasospasm such as that seen in Prinzmetal’s angina, cocaine use (STEMI, NSTEMI, USA) Progression of obstructive coronary atherosclerotic disease (USA) In-stent thrombosis (early post PCI) In-stent restenosis (late post PCI Poor surgical technique (post CABG)

Pathophysiology of ACS Acute coronary syndromes can also be due to secondary causes –Thyrotoxicosis –Anemia –Tachycardia –Hypotension –Hypoxemia –Aterial inflammation (infection, arteritis)

Treatment of ACS; Aspirin Aspirin is an antiplatelet agent that initiates the irreversible inhibition of cyclooxygenase, thereby preventing platelet production of thromboxane A2 and decreasing platelet aggregation Administration of ASA in ACS reduces cardiac endpoints

Aspirin Trials VA Cooperative Study Canadian Multicenter Trial RISC Antithrombotic Trialists Collaberation PURSUIT

ACC/AHA Guidelines for Aspirin Therapy Aspirin should be given in a dose of mg/day to all patients with ACS unless there is a contraindication (in which case, clopidogrel should be given)

Treatment of ACS; Nitrates Nitroglycerin is considered a cornerstone of anti- anginal therapy, despite little objective evidence for its benefit Benefit is thought to occur via reduction in myocardial O2 demand secondary to venodilation induced reduction in preload as well as coronary vasodilation and afterload reduction Titrate to relief of chest pain; chest pain = death of myocardial cells No documented mortality benefit

Treatment of ACS; Beta Blockers Beta Blockers reduce myocardial oxygen demand by reducing heart rate, contractility, and ventricular wall tension Administration of beta blockers in ACS reduces cardiac endpoints

Beta Blocker Trials HINT (metoprolol) Beta Blocker Heart Attack Trial (propranolol) Esmolol vs. placebo Carvedilol vs. placebo Propranolol vs. placebo Overall, treatment with beta blockers reduces primary endpoints when compared to placebo

AHA/ACC Guidelines for Beta Blocker Therapy Intravenous beta blockers should be used initially in all patients (without contraindication) followed by oral beta blockers with the goal being decrease in heart rate to 60 beats per minute A combination of beta blockers and nitrates can be viewed as first line therapy in all patients with ACS

Treatment of ACS; Heparin Heparin (unfractionated heparin or UFH) has traditionally been the mainstay of therapy in acute coronary syndromes as its efficacy has been documented in several large, randomized trials

Heparin Trials Heparin/Atenolol Trial The Canadian Heparin/Aspirin Trial The RISC Trial Overall, UFH therapy generally results in an important clinical benefit when compared to placebo. It is more effective when given in continuous infusion rather than intermittent boluses

Treatment of ACS; LMWH More recent studies indicate that low molecular weight heparin is also effective in the reduction of end points such as myocardial infarction or death Some studies report that LMWH, when used in combination with ASA, may be superior to continuous infusion of Heparin

LMWH Trials FRISC TIMI IIB ESSENCE INTERACT EVET

ACC/AHA Guidelines for Heparin Therapy All patients with acute coronary syndromes should be treated with a combination of ASA (325 mg/day) and heparin (bolus followed by continuous infusion with goal of PTT 1-2.5X control) or ASA and low molecular weight heparin unless one of the drugs is contraindicated

Treatment of ACS; ACE-I The best documented mechanism by which these agents act is to reduce ventricular remodeling over days to weeks after myocardial damage. However, there is data that a mortality benefit exists when these agents are used early in the course of ACS Administration of ACE-I in ACS reduces cardiac endpoints

ACE-I Trials GISSI-3 (Lisinopril) ISIS-4 (Captopril) SMILE (Zofenipril) FAMIS (Fosinopril) SAVE (Captopril) TRACE (Trandolapril) AIRE (Ramiripril)

AHA/ACC Guidelines for ACE-I Therapy ACE-I should be administered to all patients in the first 24 hours of ACS provided hypotension and other clear cut contraindications are absent

Treatment of ACS; Statins Statins may be of benefit in ACS Possible mechanisms include plaque stabilization, reversal of endothelial dysfunction, decreased thrombogenicity, and reduction of inflammation

Statin Trials MIRACL (modest benefit in cardiac endpoints, no mortality benefit) SYMPHONY (no benefit) There is no AHA/ACC class I indication for use of statin therapy in ACS

Treatment of ACS; IIBIIIA Inhibitors More potent inhibition of platelet aggregation may be of importance in patients with ACS that is associated with unstable coronary lesion and thrombus formation. This can be achieved by the use of GP IIBIIIA inhibitors Administration of IIBIIIA inhibitors reduces cardiac endpoints

IIBIIIA Trials PRISM-PLUS (Tirofiban – prior to PCI) EPIC (Abciximab – prior to PCI) CAPTURE (Abciximab – prior to PCI) GUSTO IV-ACS (Abciximab – no PCI) PARAGON (Lamifiban – no PCI) PURSUIT (Eptifibatide -- no PCI) RESTORE (Tirofiban – no PCI)

AHA/ACC Guidelines for use of IIBIIIA inhibitors A IIBIIIA inhibitor should be administered to all patients in whom a percutaneous intervention is planned (in addition to heparin/ASA) Eptifibatide or Tirofiban should be administered to patients with ACS in whom PCI is not planned if other high risk features are present (TIMI risk score >3)

TIMI Risk Score Age >65 yrs Daily ASA Therapy (>7 days prior to event) Symptoms of Unstable Angina Documented CAD (stenosis > 50%) 3 or more traditional cardiac risk factors Elevated cardiac enzymes ECG changes

TIMI Risk Score Score of 3 or less = low risk Score of 4-5 = intermediate risk (use IIBIIIA) Score of 6-7 = high risk (use IIBIIIA)

Treatment of ACS; Clopidogrel Clopidogrel is a potent antiplatelet agent It should be administered to all patients who cannot take ASA The CURE trial suggests a benefit to adding Clopidogrel to ASA/Heparin in patients going for PCI Give 300 mg loading dose followed by 75 mg/day

AHA/ACC Guidelines for Clopidogrel Clopidogrel should be administered to patients who cannot take ASA because of hypersensitivity or gastrointestinal intolerance In hospitalized patients in whom an early, noninterventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month and up to 9 months. Do not use clopidogrel if there is any possibility patient may be candidate for CABG

Treatment of ACS; Emergent Revascularization In the setting of STEMI primary PCI is associated with better outcomes than thrombolysis Emergent PCI is also indicated in the setting of a new LBBB

PCI Trials PAMI (PTCA vs. thrombolysis) Netherlands Trials (PTCA vs. thrombolysis) GUSTO IIB (PTCA vs. thrombolysis) DANAMI-2 (stenting vs. thrombolysis) STAT (stenting vs. thrombolysis)

AHA/ACC Guidelines for Primary PCI Primary PCI is indicated as an alternative to thrombolysis when the following criteria are met: –STEMI or new LBBB –Can undergo PCI within 12 hours of the onset of symptoms –The MD doing the intervention does more than 75 PCI’s/yr –The procedure is done in a center that does more than 200 PCI’s/yr and has surgical backup

Conclusions; Approach to Chest Discomfort Good History and Physical (note time and duration of symptoms) Careful evaluation of ECG (compare to previous when possible) Check Cardiac Enzymes Monitor on Telemetry Oxygen

Conclusions; Treatment of NSTEMI/USA ASA NTG (consider MSO4 if pain not relieved) Beta Blocker Heparin/LMWH ACE-I +/- Statin +/- Clopidogrel (don’t give if CABG is a possibility) +/- IIBIIIA inhibitors (based on TIMI risk score)

Conclusions; Treatment of STEMI ASA NTG (consider MSO4 if pain not relieved) Beta Blocker Heparin/LMWH ACE-I +/-Clopidogrel (based on possibility of CABG) IIBIIIA +/- Statin Activate the Cath Lab!!!