Acute Coronary Syndrome The Essentials Percy Pentecost, MD University of New Mexico School of Medicine

Acute Coronary SyndromeThe Essentials

Percy Pentecost, MDUniversity of New Mexico

School of Medicine

Acute Coronary SyndromeImpact

• Incidence:

– 3 million people estimated to have acute ST-elevation MI each year

– 4 million people estimated to have non-ST-elevation MI

• A Shift in Populations

– Myocardial Infarction used to be seen predominantly in developed countries, but…

– …it is now becoming increasingly more common in developing countries..


• Why a shift towards developing countries as well?

• Progressive urbanization….

– Increasing rates of obesity– Increasing rates of diabetes– Increasing rates of coronary

heart disease


• Why is this epidemiology stuff important anyway?

• According to the INTERHEART study of over 15,000 patients, 90% of myocardial infarctions were attributable to modifiable risk factors in men, and 94% in women!!!

Acute Coronary SyndromeRisk Factors

• ..modifiable risk factors…such as…

• Smoking• Dyslipidemia • Hypertension• Abdominal Obesity• Diabetes

Acute Coronary SyndromeDefinitions

• Acute Coronary Syndrome describes a spectrum of conditions…

• Unstable Angina• Non-ST-elevation

Myocardial Infarction• ST-elevation Myocardial

Infarction


• Acute Coronary Syndrome describes a spectrum of conditions…

• Unstable Angina• Non-ST-elevation

Myocardial Infarction• ST-elevation Myocardial

Infarction


• Unstable Angina vs. Non-ST-elevation Myocardial Infarction..is there a difference?

• Patients with these two entities often present similarly

• Distinction between the two can be made only many hours to days later when the results of the cardiac enzymes are available…


• Even though, ST-elevation MI’s sound more exciting..they’re not…

• Acute Coronary Syndromes account for 1.57 million hospitalizations each year…– 1.24 million of those are

for Unstable Angina and NSTEMI

– Only .33 million are for STEMI


• Quick Quiz…A 75 y/o man presents to you with new onset exertional chest pain x 1 day…Is this stable or unstable angina?


• So what? …• …unstable angina

implies that there is an unstable or ruptured plaque…which is bad news..

Acute Coronary SyndromePathogenesis

• Disruption of a formed atherosclerotic plaque is central to the initiation of acute coronary syndromes…


• Quick Quiz…– Which type of plaques

are the most vulnerable to rupture – big plaques or small plaques???


• The arterial lesions of patients with unstable angina frequently have complex, eccentric morphologic features on angiography that have been found to represent ruptured plaque with superimposed thrombus…


• Mature plaques are made up of (1) a lipid-rich core and (2) a fibrous cap

• The presence of large, eccentric lipid pools and infiltration of foam cells are most frequently associated with fissured or ruptured plaques


• The majority of these plaques rupture at sites of greatest mechanical stress, notably at the junction of the plaque cap and the adjacent normal intima…or the shoulder regions of the lipid pool…


• Local thrombosis occurring after plaque disruption results from complex interactions among lipid core, smooth-muscle cells, macrophages, and collagen..

• The lipid core is the most potent substrate for platelet-rich thrombus formation, and both smooth-muscle and foam cells within the core increase expression of tissue factor.

http://jnm.snmjournals.org/content/vol45/issue11/images/large/zl70110414120003.jpeg


• So, why is this important??

• Unstable angina is the part of a spectrum of conditions that can lead to complete thrombosis and infarction

• It is paramount to identify patients at high risk early in order to prevent progression of this condition


• And…knowing the pathogenesis will also help you understand the medical therapy for acute coronary syndromes…

• Anti-platelet therapy• Anti-thrombin therapy• Anti-ischemic therapy

Acute Coronary Syndrome

Risk Stratification and Management


• What do we mean by risk stratification?

• The relative instability of a plaque is a huge unknown…

• …so risk stratification helps us delineate how likely it is for a given patient to progress to full infarction, or death…


• The TIMI (Thrombosis in Myocardial Infarction) Trials…

• The TIMI Risk score accurately predicts the risk of an adverse cardiac event in the setting of a suspected Acute Coronary Syndrome…


• The TIMI Risk Factors…• …one point for each…

• Age ≥ 65 years• At least 3 risk factors for CAD• Prior coronary stenosis of ≥50%• ST-segment deviation on ECG

presentation• At least 2 anginal events in prior

24 hours• Use of aspirin in prior 7 days• Elevated serum cardiac

biomarkers


• The TIMI Risk Score– Composite primary

outcome measure = All-cause mortality, recurrent MI, urgent coronary revascularization

The TIMI Risk FactorsScore Component P Value Odds Ratio (95% CI)

Age ≥ 65 <0.001 1.75[1.35-2.25]

≥ 3 CAD risk factors 0.003 1.54[1.16-2.06]

Significant Coronary stenosis

<0.001 1.70[1.30-2.21]

ST deviation 0.005 1.51[1.13-2.02]

Severe angina 0.001 1.53[1.20-1.96]

Aspirin in last 7 days 0.006 1.74[1.17-2.59]

Elevated biomarkers 0.001 1.56[1.21-1.99]


• Case 1…A 75 y/o man with a h/o HTN, DM, and smoking presents with a 2 day history of progressively worsening angina. He has had multiple episodes in the past 24 hours. He takes HCTZ, glyburide, and a baby aspirin daily. On exam, vitals stable, ECG normal. Initial troponin elevated at 1.52.

• What is his TIMI risk score? And what does this mean? – TIMI Risk Factors(5)

• 3 CAD risk factors• Age ≥ 65• ≥2 anginal events in 24°• Aspirin in past 7 days• Elevated biomarkers

– Composite Primary Outcome ~ 26.2% chance of death, MI, or need for urgent revascularization…

Acute Coronary Syndrome• Case 2…A 50 y/o woman with a

history of DM, HTN, and Smoking presents after an episode of angina while walking up a flight of stairs this morning. She has had no further episodes. She takes glyburide. On exam, vitals stable. ECG normal, and cardiac enzymes negative.

• What is her TIMI risk score? – TIMI Risk Factors (1)– Risk ~ 4.7%


• So, the TIMI risk assessment tool helps a clinician estimate the risk involved in an ACS presentation…

• …it also helps guide the initial evaluation and management of ACS…


Initial Therapies and Management

Classification of Recommendation and Level of

Evidence

Classification of Recommendation and Level of Evidence

• To summarize, Recommendations…– Class I – if you don’t do this,

you’re an idiot..– Class II – you should probably

do this too..– Class III – you may find a

reason not to do this…– Class IV – if you do this you’re

an idiot…

• And Evidence…– Class A – lots of great

evidence– Class B – a little bit of

good evidence– Class C – my grandfather

taught me this…

Acute Coronary SyndromeTherapies and Management

• Remember the problem…– …plaque rupture,

platelet aggregation…– Thrombosis…– Occlusion of

vessel..decreased oxygen supply to myocardium

• Helps with the solution…– Anti-ischemic therapy

(reduce demand/ increase supply)

– Anti-platelet therapy– Anti-thrombin therapy


• Anti-Ischemic therapy..

• Bed Rest• Continuous ECG monitoring• Supplemental oxygen• Nitroglycerin• Beta-blockers• IV morphine• IABP for hemodynamic instability• ACE inhibitor for persistent HTN

in patients with persistent systolic dysfunction or CHF



• Bed Rest – Class IC – recommended for all ACS patients on presentation

• Supplemental O2 – Class IB – should be given in ACS patients with O2 sat <90%, respiratory distress, or other high risk features of hypoxemia



• Sublingual Nitroglycerin – class IC – Patients with ACS should receive sublingual NTG (0.4 mg) every 5” for a total of 3 doses after which assessment should be made about the need for IV NTG

• Intravenous Nitroglycerin – class IB – is indicated in the first 48 hours after ACS for treatment of persistent ischemia, CHF, or HTN



• Oral beta blocker therapy – Class IB – should be initiated within the first 24 hours for patients who do not have (1) CHF, (2) low CO, (3) increased risk for cardiogenic shock, (4) evidence of AVB, or (5) reactive airway disease


• Quick Quiz…– What is the estimated

mortality benefit of beta blockers in the setting of acute coronary syndrome?

Yusof et al. JAMA 1988;260:2259-63


• Quick Quiz…Do nitrates improve mortality?


• More questions…what adaptive response occurs within 24 hours of nitrate therapy?



• ACE Inhibitor – class IA – Should be given orally within first 24 hours to ACS patients with pulmonary congestion, or LV EF <40% in the absence of hypotension or other contraindications.

• ARB – Can be administered to ACS patients intolerant to ACE inhibitors.



• Calcium Channel Blockers – class IB – In ACS patients with continuing or recurrent ischemia, and in whom beta blockers are contraindicated, non-dihydropyridine CCB (diltiazem, or verapamil) should be given as initial therapy in the absence of clinically significant LV dysfunction.



• NSAIDS – class IC – because of increased risks of mortality, reinfarction, hypertension, CHF, and myocardial rupture associated with their use, NSAIDs (except ASA) whether selective or non-selective COX inhibitors should be discontinued at the time a patient presents with an ACS.


• What is the issue?

• Just one example…– COX 1 – mediates platelet

production of thromboxane A2 (prothrombotic)

– COX 2 – mediates endothelial cell synthesis of prostacyclin (antithrombotic)

– So selective COX 2 inhibition will result in unopposed thromboxane production by platelets…



• Oxygen – class IIC – it is reasonable to give supplemental oxygen during the first 6 hours after presentation in ACS

• Morphine – class IIB – in the absence of contraindications to its use, it is reasonable to administer morphine sulfate intravenously to ACS patients if there is uncontrolled ischemic chest discomfort despite nitrogylcerin



• Intra-aortic balloon pump (IABP) – class IIC --counter pulsation is reasonable in ACS patients for severe ischemia that recurs frequently despite intensive medical therapy, for hemodynamic instability in patients before or after angiography, and for mechanical complications of MI.



• Nitrates should NOT be given in ACS patients with SBP <90, severe bradycardia, tachycardia in the absence of CHF, or RV infarction (class IIIC)

• Nitrates should not be given to ACS patients who have received a phosphodiesterase inhibitor for erectile dysfunction within 24 hours of sildenafil and 48 hours of tadalafil use (class IIIC)


• Anti- Platelet Therapies

• Aspirin• Clopidogrel• GP IIBIIIA Inhibitors• Heparin


• Antiplatelet therapies…



• Aspirin – class IA – should be given ASAP unless there is known intolerance

• Clopidogrel – class IA should be given to ACS patients who are unable to take ASA



• Glycoprotein IIB/IIIA inhibitors – consistently reduce 30-day relative risk of composite endpoint of death, MI, or need for repeat revascularization (22 to 56%) when given with heparin and aspirin, but not when given alone


• Antithrombin therapy..– What about heparins?

• Unfractionated heparin – evidence shows a 33% lower incidence of MI or death when given in combination with aspirin

• LMWH – TIMI IIB study showed that enoxaparin is superior to UFH in reducing MI and emergent revascularization, but no mortality difference. ESSENCE trial showed that LMWH was superior in all endpoints.


• And finally…Select Management Strategy…

• Initial Invasive versus Initial Conservative Strategy…who will benefit from early catheterization and intervention?


• Back to the TIMI risk score…

• Age ≥ 65 years• At least 3 risk factors for CAD• Prior coronary stenosis of ≥50%• ST-segment deviation on ECG

presentation• At least 2 anginal events in prior

24 hours• Use of aspirin in prior 7 days• Elevated serum cardiac

biomarkers


• It turns out that the TIMI risk score is useful in predicted who will benefit from early invasive therapy…

• Low risk Score – Treat conservatively with medical management

• High risk Score – Treat with early invasive therapy


• The Recommendations…

• Class IB - An early invasive strategy is indicated in ACS patients who have refractory angina, hemodynamic or electrical instability

• Class IA – An early invasive strategy is indicated in initially stabilized ACS patients who have an elevated risk for clinical events per the TIMI risk score


• TACTICS-TIMI-18 Trial– 2,220 patients within 24

hours of ACS– Meds: ASA, heparin,

tirofiban

• Showed decreased death, MI, and rehospitalization for ACS at 6 months for invasive strategy– Benefit in medium and high risk

patients (TIMI risk >3, ST segment deviation, elevated troponin)

– For patients with no high risk features there was equivocal benefit

– Decreased death and MI at 6 months for older patients

– Benefit in high risk women– Low risk women tended to have

worse outcomes

Cannon CP, et al. NEJM 2001;344:1879-87


• In an early invasive strategy, the therapy is a little more aggressive…

• Class IA – antiplatelet therapy in addition to ASA should be initiated before angiography with either clopidogrel or a GP IIB/IIIA inhibitor

• CURE trial showed a decrease in all composite endpoints with clopidogrel but an increased risk of major bleeding as well.

Yusuf et al, NEJM 2001:345:494-502



• PURSUIT trial showed that the IIB/IIIA inhibitor eptifibatide decreased deaths and MI at 96 hours, 7d, and 30 d compared to placebo…

• An additional 11% decrease in events with concomitant heparin

NEJM 1998;339:436-43


• Contraindications to gpIIB/IIIA therapy

• Active or recent bleeding (4-6 weeks)

• Severe hypertension • Any hemorrhagic CVA• Any CVA within 30 days to 2 years• Major surgery or trauma within 4-

6 weeks• Thrombocytopenia (<100,000)• Bleeding diathesis/ warfarin with

elevated INR



• Class IA/IB – anticoagulant therapy should be added to antiplatelet therapy in ACS patients ASAP.



• ESSENCE trial – showed that enoxaparin was superior to UFH in reducing death, MI, or recurrent angina at 14d, 30d and 1 year in ACS patients.


• Long term medical therapy

• Class 1– Aspirin– Clopidogrel– Combined ASA + Clopidogrel

for 9 months for NSTEMI– Beta blockers– Lipid lowering agents– Ace inhibitor if LV

dysfunction, HTN, or diabetes– Smoking cessation – Diet/ Lifestyle modification


• One special note about lipid control, and statins…

• Heart Protection Study (20,536 patients with CHD)– Simvastatin vs. placebo

• Decreased total rates of CHD, total stroke, revascularization

• Statins recommended in all patients at discharge regardless of baseline LDL-C

Lancet 2002;360:7-22


• Clinical Question: – What are the blood

pressure, LDL, and Hgb A1C goals in CAD patients?

• LDL goal <100 class IA, and <70 class IIA

• BP goal is <140/90 in CAD patients, and <130/80 in CAD patients with DM, or CKD

• A1C goal is < 7%

The End

References• The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI, JAMA 200; 284:835-842• Chew DP and White HD. Acute Myocardial Infarction. Lancet 2008; 372:570-84• Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable Angina Pectoris. New England Journal of

Medicine. 342(2): 101-114• http://static.flickr.com/56/151606719_95d2a462ed.jpg• http://www.medscape.com/content/2002/00/43/64/436408/art-jic436408.fig1.gif• http://www.panaceia-or-hygeia.com/Images/PlaqueRupture-Thrombus.jpg• http://www.kup.at/kup/images/thumbs/750.jpg• http://jnm.snmjournals.org/cgi/content-nw/full/45/11/1898/F3• http://www.acc.org/qualityandscience/clinical/guidelines/STEMI/Guideline1/Images/table1.jpg• http://www.australianprescriber.com/upload/issue_files/3004_f1_antiplatelet.gif• http://www.fiery-foods.com/ffshow/images/sandia_mountains.jpg

http://static.flickr.com/56/151606719_95d2a462ed.jpg

http://www.medscape.com/content/2002/00/43/64/436408/art-jic436408.fig1.gif

http://www.panaceia-or-hygeia.com/Images/PlaqueRupture-Thrombus.jpg

http://www.kup.at/kup/images/thumbs/750.jpg

http://jnm.snmjournals.org/cgi/content-nw/full/45/11/1898/F3

http://www.acc.org/qualityandscience/clinical/guidelines/STEMI/Guideline1/Images/table1.jpg

http://www.australianprescriber.com/upload/issue_files/3004_f1_antiplatelet.gif

http://www.fiery-foods.com/ffshow/images/sandia_mountains.jpg

Documents

Acute Coronary Syndrome The Essentials Percy Pentecost, MD University of New Mexico School of Medicine