Acute Coronary syndrome

Acute Coronary Syndrome
  • Unstable angina (UA),  non–ST-segment elevation myocardial infarction (NSTEMI) and STEMI are among the acute coronary syndromes (ACS). 
  • Stable angina pectoris is characterized by chest or arm discomfort that is reproducibly associated with physical exertion or stress and relieved within 5–10 minutes by rest and/or sublingual nitroglycerin. 
  • Unstable angina describes the occurrence of angina pectoris or equivalent ischemic discomfort with at least 1 of 3 features: 
    • Occurs at rest or with minimal exertion, usually lasting > 10 minutes 
    • Is severe and new onset (i.e., within the prior 4–6 weeks) 
    • Occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than previously) 
  • Non-ST-segment elevation myocardial infarction has the identical clinical features of UA but is also associated with myocardial necrosis, as reflected in elevated cardiac biomarkers. 
Mechanism
Four pathophysiologic processes may contribute. 
  • Plaque rupture or erosion with superimposed nonocclusive thrombus (most common cause) 
  • Dynamic obstruction (e.g., coronary spasm, as in Prinzmetal’s variant angina) 
  • Progressive mechanical obstruction (e.g., rapidly advancing coronary atherosclerosis or restenosis after PCI) 
  • Secondary UA related to increased myocardial oxygen demand (e.g., tachycardia) and/or decreased oxygen supply (e.g., tachycardia, anemia) 
 
Symptoms
  • Chest pain: Typically substernal and frequently radiates to neck, left shoulder and left arm. Occurs with crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than previously) 
  • Angina "equivalents" (occur more often in women, the elderly, patients with diabetes mellitus) are dyspnea and epigastric discomfort. In elderly patients, change in mental status might be the only sign. 
 
Differential Diagnosis 
  • Muscle spasms 
  • Pericarditis 
  • Myocarditis 
  • Expanding aortic aneurysm 
  • Aortic dissection 
  • GERD
  • Peptic ulcer disease 
  • Pleuritis/pneumonia 
  • Pulmonary embolism 
  • Pneumothorax 
  • Chest-wall syndromes like Herpes zoster 
  • Costochondritis 
  • Cervical disc disease 
 
Diagnostic Approach 
Cardiac markers 
  • Biochemical cardiac markers : Troponins (T or I), CK-MB
  • Minor troponin elevations are reported in congestive heart failure, myocarditis, and pulmonary embolism. 
  • With contemporary troponin assays, CK-MB and myoglobin are not useful for diagnosis of ACS. Multiples studies proved this. Refer to data supplements 5.6 and 7 on 2014 AHA guidelines for NSTEMI.  ( Level A evidence by AHA). It may be reasonable to remeasure troponin once on day 3 or day 4 in patients with MI as an index of infarct size and dynamics of necrosis. ( IIb recommendation by AHA). 
  • Solitary elevations of troponin cannot be assumed to be due to MI, because troponin elevations can be due to tachyarrhythmia, hypotension or hypertension, cardiac trauma, acute HF, myocarditis and pericarditis, acute pulmonary thromboembolic disease, and severe noncardiac conditions such as sepsis, burns, respiratory failure, acute neurological diseases, and drug toxicity and chemotherapy. Chronic elevations can result from structural cardiac abnormalities such as LV hypertrophy or ventricular dilatation and are also common in patients with renal insufficiency.  In the diagnosis of NSTEMI, cardiac troponin values must manifest an acute pattern consistent with the clinical events, including ischemic symptoms and electrocardiographic changes.
Diagnostic Procedures 
  • ECG : Changes on ECG in patients with NSTE-ACS include ST depression, transient ST-elevation, or new T-wave inversion. Rightsided leads (V3 R to V4 R) are typically performed in the case of inferior STEMI to detect evidence of right ventricular infarction. If the intial EKG is negative and suspicion is high, repeat every 15-30 mins. 
  • Stress testing : Used to rule out significant coronary artery disease if pain free and markers are negative. 
    • Standard treadmill ECG stress testing , if baseline EKG is normal 
    • Perfusion (sestamibi or thallium) or echocardiographic imaging with stress testing , if baseline ECGs are abnormal (e.g., LBBB or LVH)
    • Pharmacologic stress test for patients who cannot walk 
  • Coronary angiography (for intermediate- and high-risk patients) 
 
Risk assessment: In patients with UA/NSTEMI, the TIMI risk score is a simple prognostication scheme that categorizes a patient's risk of death and ischemic events and provides a basis for therapeutic decision making. A score of more than 4 has atleast 20% mortality risk.  JAMA. 2000;284(7):835-842.
 
GRACE risk score: It is another alternative to assess the risk of death among patients with acute coronary syndrome. The included variables are Age, heart rate, systolic blood pressure, serum creatinine, Killip class ( no CHF vs rales vs pulmonary edema vs cardiogenic shock), elevated cardiac markers, ST segment deviation and cardiac arrest on admission. 
 
TIMI Score Calculation (1 point for each):
  • Age ≥ 65
  • Aspirin use in the last 7 days (patient experiences chest pain despite ASA use in past 7 days)
  • At least 2 angina episodes within the last 24hrs
  • ST changes of at least 0.5mm in contiguous leads
  • Elevated serum cardiac biomarkers
  • Known Coronary Artery Disease (CAD) (coronary stenosis ≥ 50%)
  • At least 3 risk factors for CAD, such as:
    • Hypertension -> 140/90 or on anti-hypertensives
    • Current cigarette smoker
    • Low HDL cholesterol (< 40 mg/dL)
    • Diabetes mellitus
    • Family history of premature CAD
      • Male first-degree relative or father younger than 55
      • Female first-degree relative or mother younger than 65
 
Treatment Approach 
  • Bed rest with continuous ECG monitoring
  • Initial treatment should include aspirin, beta blockers, nitrates, morphine and oxygen. 
  • Hypertension and tachycardia, both of which will markedly increase myocardial oxygen consumption requirements, may be managed with beta blockers and intravenous nitroglycerin. 
  • Patients with unstable angina (UA) or NSTEMI should be treated with an early medical regimen similar to that used in STEMI except for fibrinolytics.   
  • NSAID's (except aspirin) should be discontinued immediately due to an increased risk of cardiovascular events associated with their use. 
  • Routine use of oxygen in patients without hypoxia may increase early myocardial injury and was associated with larger myocardial infarct size assessed at six months. AVOID Study- Am Heart J. 2012 Mar;163(3):339-345.e1
 
Invasive strategy vs conservative strategy 
Early invasive strategy for high-risk patients includes treating with anti-ischemic and antithrombotic agents (aspirin and heparin) , coronary arteriography within 48 hours of admission , coronary revascularization based on coronary anatomy ( PCI or CABG). High risk patients are those who have 
  • Recurrent angina at rest/low-level activity despite treatment 
  • Elevated troponins
  • New ST-segment depression with dynamic EKG changes 
  • Recurrent angina/ischemia with congestive heart failure  
  • LV ejection fraction < 0.40 
  • Hemodynamic instability or angina at rest with hypotension 
  • Sustained ventricular tachycardia
  • Percutaneous coronary intervention within previous 6 months or prior coronary artery bypass grafting (CABG) 
Conservative strategy or delayed invasive strategy for low-risk patients 
  • Anti-ischemic and antithrombotic therapy, followed by watchful waiting 
  • Coronary arteriography if recurrence of: 
    • Rest pain 
    • ST-segment changes 
    • Evidence of high-risk ischemia on stress test (ischemia at stage 1 or 2, >2 mm ST depressions at any stage, hypotension, ventricular arrhythmias, acute pulmonary edema) 
 
Specific Treatments 
 
Nitrates 
Nitrates must be used with caution or avoided in settings in which hypotension is likely or could result in serious hemodynamic decompensation, such as right ventricular infarction or severe aortic stenosis. In addition, nitrates are contraindicated in patients who have taken a phosphodiesterase inhibitor for erectile dysfunction within the previous 24 hours.   
  • Sublingual: Nitoglycerine tablets (0.4mg) given 5 minutes apart, upto 3 doses max
  • IV nitroglycerine: If symptoms not fully relieved with sublingual nitroglycerin, start IV Nitroglycerin, 5–10 μg/min continuous infusion. Increase rate by 10 μg/min every 3–5 minutes (titrated up to 75–100 μg/min) until relief of symptoms or limiting side effects (headache or hypotension with systolic blood pressure < 90 mmHg or > 30% below starting mean arterial pressure) . Side effects include headache and hypotension.
  • Topical or oral Acceptable alternative to intravenous therapy for patients without ongoing or refractory disease. 
    • Transdermal nitroglycerine patch: 0.4–1.2 mg/h for 12–14 hours 
    • Isosorbide dinitrate, sustained release: 10–60 mg PO every 8 hours 
    • Isosorbide-5-mononitrate, oral: 20–30 mg PO bid 
    • Isosorbide-5-mononitrate, oral sustained release: 60–240 mg/d 
Beta blockers 
  • Indications: NSTEMI, STEMI, chronic stable angina 
  • Intravenous beta blockade is preferred intially, followed by oral beta blockade targeted to a heart rate of 50–60 beats/min 
  • B-blockers work by decreasing risk of V. Fib not by controlling heart rate. Give all patients B-blockers unless contraindicated. 
  • Choice of specific agent is not as important as long as they get a beta blocker. 
  • If there is concern about patient intolerance due to pulmonary disease (especially asthma), LV dysfunction, risk of hypotension, or severe bradycardia, administer short-acting agents or lower doses rather than complete avoidance of beta-blocker therapy. Betablockers proven to improve mortality in patients with heart failure from ACS are metoprolol succinate, carvedilol and bisoprolol. 
  • Metoprolol 5 mg by slow (over 1–2 min) IV infusion every 5–10 minutes, to total dose of 15 mg. Then follow in 1–2 hours with 25–50 mg PO every 6 hours 
  • Esmolol Starting dosage of 0.1 mg/kg/min IV. Titrate in increments of 0.05 mg/kg/min every 10–15 minutes as tolerated by blood pressure until the desired therapeutic response is obtained. An optional loading dose of 0.5 mg/kg may be given by slow IV administration (2–5 min) for more rapid onset of action. 
Morphine sulfate 
  • 2–5 mg IV, and can be repeated every 5–30 minutes as needed 
Calcium-channel blockers 
  • Used in patients whose symptoms are not relieved by adequate doses of nitrates and beta blockers , in those who are unable to tolerate these agents and in variants angina 
Statins: High dose statins to aim for reduction in LDL should be started as soon as possible. 
 
Antithrombotic therapy
  • Oral antiplatelet therapy 
    • The combination of aspirin and clopidogrel is recommended for all patients with UA/NSTEMI who are not at excessive risk for bleeding or sensitivity. A P2Y12 inhibitor (either plavix or ticagrelor) in addition to aspirin should be administered for up to 12 months to all patients with NSTEMI , who are treated with either an early invasive or ischemia-guided strategy. ( AHA class I recommendation). 
    • Aspirin, 325mg loading dose, followed by 75mg daily indefinitely. The first tablet should be chewed or crushed to establish a high blood level quickly.  
    • Clopidogrel, 300 loading dose, followed by 75mg daily for atleast a month in bare metal stents but preferably up to an year and for atleast an year in drug alluding stents.  If PCI is planned, 600mg loading dose is given either during or before PCI. Do not give plavix, if CABG is a possibility.  
    • Prasugrel ( Effient ), 60mg loading dose followed by 10mg dailyIt has a more rapid onset of action and is able to achieve higher degrees of platelet inhibition than clopidogrel. In patients with ACS with scheduled PCI, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. N Engl J Med 2007; 357:2001-2015. In patients with ACS but not undergoing PCI, prasugrel did not significantly reduce myocardial infarction as compared with clopidogrel. TRILOGY ACS study- N Engl J Med 2012; 367:1297-1309.  Also, prasugrel given at onset before angiography did not lead to a reduction in the composite primary endpoint when compared with a strategy of administration of prasugrel only at the time of PCI; however, it did lead to an increase in bleeding complications. ACCOAST Trial-N Engl J Med 2013; 369:999-1010.  AHA do not recommend prasugrel as “upfront” therapy in patients with NSTEMI and recommends only giving at the time of PCI.  AHA/ACC gives a Class IIa recommendations to use prasugrel in preference to clopidogrel for patients with NSTEMI, who undergo PCI and not at high risk of bleeding. Prasugrel should not be administered to patients with prior history of stroke or TIA ( Class IIIB recommendation). 
    • Ticagrelor ( Brilinta) , 180mg loading dose followed by 90mg BID — Ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non– procedure-related bleeding. PLATO Study-N Engl J Med 2009; 361:1045-1057 Ticagrelor differs from the thienopyridines (clopidogrel and prasugrel) in that it binds reversibly rather than irreversibly to P2Y12 platelet receptor and has a more rapid onset of action than clopidogrel. Similar to prasugrel, treatment with ticagrelor leads to more intense platelet inhibition than clopidogrel. AHA/ACC gives a Class IIa recommendations to use ticagrelor in preference to clopidogrel for patients with NSTEMI, who undergo PCI/early invasive or ischemia-guided strategy. In patients who had a prior history of stroke, Ticagrelor in comaprision to plavix had higher rates of MI , death and strokes. Circulation. 2012 Jun 12;125(23):2914-21
    • Ticlopidine : Ticlopidine compared to placebo improves outcomes in patients with unstable angina who are not treated with aspirin 
 
  • Intravenous platelet therapy Glycoprotein IIb/IIIa inhibitors are used when the patient is likely to undergo invasive strategy and has intermediate/high risk features. Especially, when there is a potential for CABG, giving plavix might delay the surgery and in those circumstances, short acting drugs like integrillin (Half life is 2.5 hours) should be considered. 
  • Abciximab : Dose: 0.25 mg/kg bolus, followed by infusion of 0.125 μg/kg per min (maximum, 10 μg/min) for 12–24 hours. Duration of action is atleast 12 hours and upto a week. 
  • Eptifibatide ( Integrillin ) : Two 180 μg/kg boluses 10 min apart, followed by infusion of 2.0 μg/kg per min for 72–96 hours. Duration of action is 4 hours. 
  •  Tirofiban : 0.4 μg/kg per min for 30 minutes, followed by infusion of 0.1 μg/kg per min for 48–96 hours 
  • Eptifibatide and tirofiban show benefit for high-risk patients in whom an invasive management is intended. However, for UA/NSTEMI patients in whom an initial conservative strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. 
  • Abciximab has been shown to be beneficial for patients with UA/NSTEMI undergoing PCI. Abciximab should not be administered to patients in whom PCI is not planned. For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit administration of Abciximab, if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier than planned catheterization or PCI.  
  • Anticoagulation: usually given atleast 48 hrs , preferably for the duration of hospitalization, or until PCI. 
    • Unfractionated heparin 
    • Low-molecular-weight heparin : Studies showed LMWH is superior to UFH (BMJ. 2012 Feb 3;344:e712) , ESSENCE Trial: N Engl J Med 1997; 337:447-452
    • Factor Xa inhibitor like fondaparinux 2.5mg SQ daily. When compared to LMWH , fondaparinux was similar in reducing the risk of ischemic events, but it substantially reduced major bleeding and improves long term mortality and morbidity. OASIS-5 Trial- N Engl J Med 2006; 354:1464-1476. If PCI is performed while the patient is on fondaparinux, an additional anticoagulant with anti-IIa activity (either UFH or bivalirudin) should be administered because of the risk of catheter thrombosis. (AHA Class I recommendation). It is excreted by renal pathways and hence, contraindicated if GFR<30. 
    • Direct thrombin inhibitor like bivalirudin or argatroban. It is mainly used in patients with heparin induced thrombocytopenia. Argatroban is metabolized by liver and hence, can be used in renal failure. In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization and stent thrombosis was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. MATRIX Trial- N Engl J Med 2015; 373:997-1009
    • For patients undergoing a non-invasive (conservative) strategy, UFH should be continued for 2-5 days but atleast for 48 hours, and fondaparinux is continued for the duration of hospitalization or 8 days.  
    •  
PCI 
  • Includes percutaneous transluminal angioplasty with stenting 
  • For patients who will be referred to the catheterization laboratory within four hours (usually due to patient instability, refractory angina, heart failure, arrhythmia, or hemodynamic instability), we recommend UFH or bivalirudin as opposed to fondaparinux or enoxaparin. 
  • For patients in whom a conservative (non-invasive) strategy is planned, we recommend either fondaparinux or enoxaparin in preference to either unfractionated heparin or bivalirudin 
  • Usually recommended for patients with 1- or 2-vessel CAD, patients with multivessel CAD with suitable coronary anatomy, with normal LV function and without diabetes
  • Adjunctive use of clopidogrel and aspirin for 1 year after implantation of drug eluting stents to prevent stent thrombosis 
  • Complications include dissection or thrombosis of the vessel and uncontrolled ischemia or congestive heart failure 
CABG 
In patients taking a P2Y12 receptor inhibitor in whom CABG is planned and can be delayed, it is recommended that clopidogrel or ticagrelor be discontinued for at least 5 days and prasugrel for at least 7 days before the planned surgery. Aspirin should be continued until the day of surgery. For urgent CABG, Plavix should be discontinued for atleast 24 hours. 
 
Indications are Severe CAD (left main, 3-vessel disease with impaired LV function), Diabetes with CAD in ≥ 2 vessels and Coronary vessels or vascular access unsuitable for PCI 
 
IABP
IABP can be used in cardiogenic shock due to acute coronary syndrome. IABP counterpulsation increases diastolic BP and coronary blood flow and potentially augments cardiac output while diminishing LV end-diastolic pressure.
 
References: 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes
 
ST Elevation Myocardial Infarction 
 
  1. Reperfusion therapy should be administered to all eligible patients with STEMI with symptom onset within the prior 12 hours. 
  2. Emergency medical services transport directly to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI, with an ideal FMC-to-device time system goal of 90 minutes or less. 
  3. Immediate transfer to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI who initially arrive at or are transported to a non–PCI-capable hospital, with an FMC-to-device time system goal of 120 minutes or less. 
  4. In the absence of contraindications, fibrinolytic therapy should be administered to patients with STEMI at non–PCI-capable hospitals when the anticipated FMC-to-device time at a PCI-capable hospital exceeds 120 minutes because of unavoidable delays. 
  5. When fibrinolytic therapy is indicated or chosen as the primary reperfusion strategy, it should be administered within 30 minutes of hospital arrival. 
  6. Fibrinolytic therapy should not be administered to patients with ST depression except when a true posterior (inferobasal) MI is suspected or when associated with ST elevation in lead aVR. 
  7. Aspirin (162- to 325-mg loading dose) and clopidogrel (300-mg loading dose for ≤75 years of age, 75-mg dose for patients >75 years of age) should be administered to patients with STEMI who receive fibrinolytic therapy. 
  8. Patients with STEMI undergoing reperfusion with fibrinolytic therapy should receive anticoagulant therapy for a minimum of 48 hours, and preferably for the duration of the index hospitalization, up to 8 days or until revascularization if performed 
  9. Fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered because of the risk of catheter thrombosis. 
  10. Urgent CABG is indicated in patients with STEMI and coronary anatomy not amenable to PCI who have ongoing or recurrent ischemia, cardiogenic shock, severe HF, or other high-risk features. 
  11. Aspirin should not be withheld before urgent CABG. Clopidogrel or ticagrelor should be discontinued at least 24 hours before urgent on-pump CABG, if possible. Short-acting intravenous GP IIb/IIIa receptor antagonists (eptifibatide, tirofiban) should be discontinued at least 2 to 4 hours before urgent CABG. Abciximab should be discontinued at least 12 hours before urgent CABG. 
  12. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated 
  13. Emergency revascularization with either PCI or CABG is recommended in suitable patients with cardiogenic shock due to pump failure after STEMI irrespective of the time delay from MI onset. 
  14. The use of intra-aortic balloon pump counterpulsation can be useful for patients with cardiogenic shock after STEMI who do not quickly stabilize with pharmacological therapy. Alternative left ventricular (LV) assist devices for circulatory support may be considered in patients with refractory cardiogenic shock. 
  15. Implantable cardioverter-defibrillator therapy is indicated before discharge in patients who develop sustained ventricular tachycardia/ventricular fibrillation more than 48 hours after STEMI, provided the arrhythmia is not due to transient or reversible ischemia, reinfarction, or metabolic abnormalities 
  16. Aspirin is recommended for treatment of pericarditis after STEMI. Administration of acetaminophen, colchicine, or narcotic analgesics may be reasonable if aspirin, even in higher doses, is not effective. Glucocorticoids and nonsteroidal anti-inflammatory drugs are potentially harmful for treatment of pericarditis after STEMI. 
  17. The duration of triple-antithrombotic therapy with a vitamin K antagonist, aspirin, and a P2Y12 receptor inhibitor should be minimized to the extent possible to limit the risk of bleeding.  
  18.  ST depression in V1-V2 is suggestive of STEMI in posterior wall. 
  19.  Although national door-to-balloon times have improved significantly for patients undergoing primary PCI for STEMI, in-hospital mortality has remained virtually unchanged. Hence, it’s not clear if, past a certain point, door to balloon time matters at all. 
  20.  
 
 
PEARLS: 
  • First Troponin is negative in 16-25% of AMIs 
  • Spontaneous coronary artery dissection remains an unusual cause of acute coronary syndrome. It should be included in the differential diagnosis of acute myocardial infarction, especially when it affects young, healthy females 
  • Diabetes should no longer be considered a risk factor but instead an equivalent to known CAD (Heart 2005;91(3):388) 
  • Patients with end-stage renal disease (ESRD) have high rates of atherosclerotic heart disease and Cardiac troponin I is a reliable marker of myocardial injury even in patients with ESRD on chronic dialysis. (A study by Henry Ford Hospital in Detroit, measured pre- and post- dialysis cTnI in 113 ESRD patients aged 26-92 with no symptoms of acute coronary syndrome who presented for maintenance dialysis. Nearly all of the patients (94.5%) had hypertension and just over half (53.2%) were diabetic. No patient had a cTnI level positive for AMI either before or after dialysis.) 
  • Syndrome X: Angina, positive exercise stress but no lesions on cath.  More common in women than men. 
  • Dressler syndrome: can happen following MI 7-11 weeks. Treat with high dose aspirin 650 mg four – six times per day. 
  • Post Cath complications include groin hematoma, retroperitoneal bleed, compression of femoral nerve from hematoma, femoral artery aneurysm 
  • Hyperoxia from high-concentration oxygen therapy causes a marked reduction in coronary blood flow and myocardial oxygen consumption. These physiologic effects may have the potential to cause harm and are relevant to the use of high-concentration oxygen therapy in the treatment of cardiac and other disorders.
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