ACS (Acute)

Risk Stratification

• For NSTEMI, use TIMI risk score to determine in-patient risk of CV events.
• Many TIMI trials... finally came up with:

  • TIMI Prognostic Variables (each = one point)
    Age ≥65 years
    ≥3 Traditional CAD risk factors (HTN, DMII, Hyperlipidemia, FMhx, Smoking)
    Documented CAD with ≥50% diameter stenosis
    ST-segment deviation
    ≥2 Anginal episodes in the past 24 hours
    Aspirin use in the past week
    Elevated cardiac biomarkers (CK MB or troponin)
    TIMI Risk Score (Sum of Prognostic Variables)
    0-2 Low risk
    3-4 Intermediate risk
    5-7 High risk

• NOTE: ASA --> highlights having active ischemia despite being on therapy. 
• NOTE FOR U.S. EXAMS: GpIIAIIIB inhibitors
  • Often useful in elevated cardiac markers, and ongoing ischemia (high risk TIMI ≥5)... particuarly useful in early invasive strategy.
  • Rarely used in Canada.

(Source: MKSAP 16)

• In above table, the term "Early coronary angiography" timing is unclear.
  • TIMCS and ISAR-COWL studies have conflicting data. 
  • Usually for clinically stable patients unclear when the best time to do the invasive procedure.
  • No clear indication for benefit of a very rapid vs. delayed strategy (few days after presentation). 

Treatment

• Treat all patients with:

• Tx	Comments	Controls
  ASA-160mg PO chewed	Up to 21% decrease in mortality	Antiplatelet
  B-blocker Usually metoprolol PO 25mg BID In past used IV as well (not anymore)	Not if HR <60-70 or CHF Careful with conduction problems on ECG If already on B-B give extra dose (Lately: controversial, IV dose can increase incidence of cardiogenic shock in MI pts).	B-blocker
  Heparin UFH if >75, obese or sig renal failure LMWH otherwise Fondaparinux also an option	Bivalirudin can be used if history of HIT. For UA or NSTEMI: Enoxaparin for 8 days or until discharged [ESSENCE trial] - preferred to UFH UFH x 48hrs if not revascularized (longer if still chest pain) For STEMI: UFH or LMWH (no difference) if NOT reperfused UFH preferred over LMWH for PCI or lytic therapy	Anticoag.
  Second Antiplatelet Plavix (Clopidogrel)   (Given with ASA - dual anti-plt)    - NSTEMI: 300mg load + 75mg     po daily    - STEMI: 600mg load. OR Prasugrel OR Ticagrelor	Proven with STEMI when added to ASA The only issue is if you suspect triple-vessel disease, patient may need CV surgery, do not give plavix (will delay OR).	Antiplatelet
  Gp IIb/IIIa inhibitors	If TIMI ≥5 (in NSTEMI)	Antiplatelet
  Nitroglycerin 0.3mg SL q5min x3 (IF NO RV Infarct!)	Give sublingual nitrates to all patients except pts in inferior MI and evidence of RV involvement. Suspect RV infarct on all inferior infarcts - do 15 lead ECG to confirm (ST elevation in V4R lead) (SEE BELOW) Mechanism: reduce preload, drops venous capacitance, improves coronary flow If continued chest pain, start nitro drip.	Pain
  Morphine(1-2mg IV/SC x1)	Suppresses heightened sympathetic response, helps beyond pain	Pain
  O2 (Only if hypoxemia)	Only if hypoxemia, but all patients end up getting it.

  **Red – Improves survival

  **Green – Symptom Management

  **Blue - Longer Term management:

  •  
• NOTE: No indication for antiarrhythmics (like lidocaine) to prevent ventricular arrhythmias.

Special: RV Involvement

• In RV infarcts, must give lots of volume to push blood through weak RV. (think of it as if it becomes a "passage chamber").  
• Giving nitrates will decreases passage, LV preload, leading to hypotension and cardiogenic shock.  This is called "preload dependent".
• If R-sided HF (high JVP etc) with clear lung fields, hypotension --> suspect RV infarct, give fluids
  • Ask for 15 Lead ECG for V3R and V4R leads (look for 1mm STE)

Mortality Benefit

• 1. ASA + clopidogrel/prasugrel/ticagrelor
• 2. B-Blocker (if heart rate and BP permit)
• 3. Anticoagulation
  • Examples:
    • Heparins (used in low TIMI risk, but provides more benefit in medium+high risk groups).
      • Unfractionated Heparin (early invasive approach,  in setting of kidney disease)
      • LMWH (Twice daily SC injection).
        OR
    • Direct Thrombin Inhibitors (Bivalirudin)
      • Used as an alternative to heparins.
      • ACUITY Trial: evaluated moderate-to-high risk unstable angina or NSTEMI treated with bivalirudin + GIIBIIIA vs. UFH+GpIIBIIIA vs. bivalirudin, undergoing early invasive strategy to evaluate coronary arteries.
        • Rates of death, MI, repeat revascularization was similar, but lower risk of bleeding complications in bivalirudin monotherapy group.
  • Decision to use them based on TIMI risk, timing of cath, consideration of risk of bleed etc.
• Statins
  • Clearly has role in primary and secondary prevention.
  • Benefit of intense lipid lowering in early phase is unknown. 
  • Studies (MIRACL and PROVE IT trials): high dose statin therapy soon after ACS (i.e. within 24-96hrs), reduces long-term CV events at 18mo and 2 years.
  • 80mg of atorvastatin typically regarded as "intensive therapy" with a composite benefit (mortality, CV events etc..)
  • Current consensus: High dose statin, with an LDL target of (<100mg/dL or <2.59mmol/L).
    • I.e. 40 or 80mg of atorvastatin.

Thrombolysis?

• Use of thrombolytics studied, worsens outcomes in NSTEMI.

Timing of Angiography

• Optimal timing unclear for clinically stable patients.
• TIMCS trial and ISARCOOL have conflicting information.
• No clear indication for rapid strategy vs. more delayed (i.e. few days after presentation). 8

Thrombolysis

• Adjunctive therapy to support Thrombolysis
  • ASA 162mg before thrombolysis
  • Clopidogrel 300mg before thrombolysis (75mg dose for pts ≥ 75yo) --> continue for 2w to 1yr
  • Anticoagulation for at least 48hrs
    (duration: until end of hospitalization, up to 8 days, or until revascularized)
    • UFH (weight-based IV bolus + infusion, monitor aPPT 1.5-2.0 times control)
      • Continue x48hrs or until revasc
    • Enoxaparin (weight, age, CrCl dosing) IV bolus then in 15min SC injection
      • Continue for duration of hospitalization or until revasc
    • Fondaparinux initial IV dose, then in 24hrs daily SC injections (if CrCl > 30)
      • Continue for duration of hospitalization, up to 8 days, or until revasc
    • NOTE: All Class I indications evidence level B, but enox has level A.

• Steps After thrombolysis:
  • Did Thrombolytics Work? 

    • Successful Reperfusion Indicators: 1. Resolution of Chest Pain 2. >70% ST-segment resolution on ECG (some say 50%) 3. Reperfusion arrhythmias (such as AIVR)

    • If reperfused:
      • Risk stratify the patient based on risk of future CV events.
      • Arrange transfer to PCI center
      • Poor prognostic features requiring PCI transfer (based on old guidelines):
        • Cardiogenic Shock
        • Severe HF
        • Failed Reperfusion
        • Or other high-risk features (i.e.. low EF, hypotension, HF, shock)
        • (B/c concern large patient myocardium at risk, patient won't tolerate future MI.)  
    • If NOT reperfused
      • Urgent transfer to PCI-capable center for "rescue PCI"

• Transfer to PCI Center:
  • NEW Evidence: Transfer to PCI center whether or not they reperfused, regardless if they have hemodynamic instability etc..
    • NEJM 2009 TRANSFER-AMI Trial --> RCT comparing delayed angiography vs. early coronary angiography post-thrombolysis: early angiography = lower risk of reinfarction and recurrent ischemia (no diff in mortality)

• Fibrinolytic Therapy (Circulation 2004;110:588)
  Absolute Contraindications Any prior ICH Known structural cerebral vascular lesion (ie. AVM) Known malignant intracranial neoplasm Ischemic stroke within 3mo (except acute ischemic stroke within 3h) Suspected aortic dissection Active bleeding (excluding menses) Significant closed head/face trauma in last 3mo
  Relative Contraindications History of chronic/severe/poorly controlled HTN Severe uncontrolled HTN at presentation (sBP > 180 mmHg, or dBP > 110 mmHg) History of ischemic stroke >3mo or known other intracranial pathology Traumatic prolonged (>10min) CPR, or Major Surgery within <3 weeks Recent (<4w) internal bleeding Non-Compressible vascular puncture Pregnancy Active petic Ulcer Current use of anticoagulants (the higher INR, the greater bleeding risk)

Primary PCI

• Adjunctive therapy to support Primary PCI
  • ASA 162mg given before PCI(continue indefinitely post-PCI)
  • P2Y12 receptor inhibitor(continue x1 year regardless of BMS/DES stent)
    • Clopidogrel 600mg --> continue 75mg daily x1 year
    • Prasugrel 60mg  --> continue 10mg daily x1yr  (contraind. if prior stroke/TIA)
    • Ticagrelor 180mg --> continue 90mg bid x1yr
  • Consider IV GP IIb/IIIa (large thrombus burden, inadequate P2Y12 loading)
    • inhibitors before PCI (+/- stent, +/- clopidogrel) who are receiving UFH.
    • Not used with bivalirudin
      • Abciximab, high-bolus-dose tirofiban, or double-bolus ptifibatide
      • Can give them in ED, EMS, cath lab (only if the decision to do PCI is made!!!)
      • intracoronary abciximab can be used
      • Can continue GP IIb/IIIa beyond 1yr in pts with DES
  • Anticoagulation (consider in case-by-case basis)
    • Options:
      • UFH (with boluses to keep aPTT therapeutic) [be careful if GP IIb/IIIa is used]
      • Bivalirudin (with or without prior tx with UFH)
    • If bleeding risk is HIGH, use bivalirudin montherapy instead of UFH+GP IIb/IIIa)
    • NOTE: Do not use fondaparinux (catheter thrombosis risk)

• Angiography in STEMI NOTES:
  • PCI should NOT be performed in non-infarct artery at the time of primary PCI in hemodynamically stable STEMI patients (Class III-B) --> EVIDENCE OF HARM. (conflicting studies) [Unless cardiogenic shock]
  • "No Reflow" Phenomenon --> occurs when poor perfusion despite restoration of epicardial flow
    • Thought to be due to inflammation, endothelial injury, edema, atheroembolization, vasospasm, reperfusion injury 
    • Associated with poor survival rate
    • Possible treatment/prevention: (all have inconsistent effect)
      • Use of GP IIb/IIIa antagonist (abciximab)
      • Vasodilators (nitroprusside, verapamil, adenosine)
      • Metabolism Inhibitors (nicorandil, pexelizumab) 
      • Manual thrombus aspiration (positive studies, but not all showed positive results)
  • Manual aspiration thrombectomy is reasonable undergoing primary PCI (4 studies - Class IIa-B)
  • Do not PCI of CTO (total occlusion) infarct artery >24hrs after STEMI (Class III Level B)
    • If stable, no severe ischemia, and 1 or 2-vessel disease)
    • OAT Trial (Occluded Artery Trial) - higher re-infarction rates if try to open a CTO >24hrs occluded.
  • Non-Infarct Artery PCI: (AFTER primary PCI)
    • DO NOT open at time of primary PCI.
    • Only if spontaneous symptoms of ischemia (Class I, Level C)
    • Intermediate or high-risk findings on non-invasive testing (Class IIA, Level B)

• Other Notes:

• Blood sugar control
  •  Study: Intense glucose control (4.5-6mmol/L) ass'd with increased mortality!!! (hypoglycemica) This is a new guideline: glucose <10mmol/L. (ICU patients, but included ACS)
  • Study: ACS patients with high glucose = worse outcomes.
  • DIGAMI: mortality at 1 year, 28% RRR, and 11% absolute if randomized to aggressive glucose control. (not acute ICU, but for recovery).
  • Hence, this is a long-term outcome measure, acutely can be lenient (<10) but chronically in recovery should be more strict.

• Balloon pumps
  • If cardiogenic shock, or decreased LV function, can put in balloon pump.

Other STEMI Syndromes

• Other disease can give same syndrome:
  • Vasospastic Prinzmetal Angina (uncommon) - Classically at rest associated with transiet ST segment elevation/depression, occurs in normal or near-normal coronary artery segments.
    • Treated with vasodilator therapy long-term such as CCB or long-acting nitrates.
    • Provoked by use of ilict drugs (cocaine, methamphetamine). 
    • Presence of the plaque in coronary artery is a strong precipitant of vasospasm at the same site.
  • Takotsubo
    • Japanese octupus trap that shaped like LV when have apical ballooning. 
    • Aka Stress-Induced Cardiomyopathy - significant impairment of LV contractility in typical pattern (distal anterior wall, apex, distal inferiour wall) with preserved function in basal segments of the heart. 
    • No obstructive coronary lesions....usually present with mild elevation of enzymes, but not to the degree that affects so much of the LV. 
    • Supportive care --> Almost always reversible.

Thrombolytics

• If time to PCI > 120min, and no contraindications, can give thrombolytic threapy:
  • Within 12 hours (Class I, Level A)
  • Within 12-24 hours (Class IIa, Level C) - if ongoing ischemia (ecg or clinical) and large area of myocardium at risk (or hemodynamic instability)
• DO NOT give fibrinolytics to ST depressions
  • Unless posterior (inferobasal) MI suspected, (or associated STE in aVR)

• Adjunctive Therapy
  • All thrombolyzed patients should receive:
    • ASA (162mg) + 80mg daily indefinitely
      AND
    • Clopidogrel (300mg if ≤ 75yo and 75mg if >75yo) + 75mg daily  for at least 14 days (level A) to 1yr. (Level C)
    • Anticoagulation at least >48hrs up to 8 days (or until revascularized)
      • UFH (wt-adjusted IV bolus+infusion to aPTT 1.5-2.0x control) x48hrs or revasc
      • Enoxaparin (age, wt, CrCl) IV bolus + in 15min by SC injection up to 8 days or until revasc.
      • Fondaparinux (if CrCl > 30mL/min) IV dose, followed in 24hrs by daily SC up to 8 days or until revasc.
      • (helps vessel patency, prevents reocclusion)
• Post-Thrombolysis Transfer
  • Immediate transfer to PCI center for angiography if: (SHOCK Trial - STEMI+shock --> revasc improves mort)
    • Acute Severe HF
    • Cardiogenic Shock (Class I Level B)
  • Urgent transfer to PCI center for angiography if:
    • Evidence of failed reperfusion (or reocclusion)  (Class IIA, Level B)
  • Routine Transfer for "routine early coronary angiography" (even if stable, and successful reperfusion)
    • For Angiography within 24hrs (but not within 2-3hrs post-lytics - to monitor for bleeding)  (Grade IIa, Level B)
    • TRANSFER-AMI Trial (less recurrence ischemia/infarction)

• Post-Thrombolysis PCI
  • ASA indefinitely
  • Clopidogrel
    • 300mg load (if no prev load, and within 24hrs of lysis)
    • 600mg load (if no prev load, and >24hrs of lysis)
    • (Followed by 75mg daily)
  • Prasugrel
    • 60mg load (once coronary anatomy is known, and no prev plavix load)
    • DO NOT give within 24hrs of fibrin-specific agent
    • DO NOT give within 48hrs of non-fibrin-specific agent. 
    • Follow by 10mg load. 
    • DO NOT give if prior storke/TIA
  •  

• In absence of contraindications, can give thrombolytic therapy to pts with STEMI and onset of symptoms in previous 12hrs.
  (When antidipcated time to PCI > 120min)
• Patient receiving fibrin-specific fibrinolytics --> also give UFHeparin (prevent re-occlusion of infarct artery).  Half-life of fibrinolytics is short (LMWH can also be used)
• Agents available:

• Adverse effects:

  • Complication	Rate
    Intracranial Hemorrhage (most feared)	0.5 - 1.0 % (risk same with tPA, rPA, and TNK)
    Bleed requiring transfusion	5-15%

    
     
• Thrombolytic reversal: Replete fibrinogen levels with cryoprecipitate (10-15 bags needed) to raise fibrinogen level to 1 g/L
  • Can also infuse FFP up to 6 units for additional fibrinogen and volume!
  • Antifibrinolytic agents such as epsilon-aminocaproic acid (5g over 15-30m IV), discouraged due to widespread thrombosis.
     

Contraindications to Thrombolytic Therapy for ST-Elevation Myocardial Infarction

• NOTE: If has relative contraindications, usually PCI transfer is preferred to lytics.
• "Facilitated PCI" - Sometimes have pre-treatment lytics followed by PCI, but recent studies indicated increased adverse events (bleeding).

CABG for STEMI

• Urgent CABG for STEMI and coronary anatomy not amenable to PCI:
  • IF ongoing or recurrent ischemia, shock, severe HF, or other high risk features (Class I, Level B)
  • IF no shock, not candidates for PCI or lytic therapy --> CABG within 6hrs (Class IIb, Level C)
• CABG is recommended in pts with STEMI if repairing mechanical defects. (Class I, Level B)
• Use of mechanical support is reasonable for STEMI, hemodynamically unstable, and need urgent CABG.
• Managing Antiplatelets around CABG
  • ASA should not be withheld before urgent CABG (Class I, Level C)
  • Clopidogrel or ticagrelor should be d/c at least 24hrs before urgent on-pump CABG if possible (Class I, Level B)
  • IV GP IIB/IIIA
    • Eptifibatide, tirofiban d/c 2-4hrs before urgent CABG (Class I)
    • Abciximab at least 12hrs before urgent CABG (Class I)
  • Urgent off-pump CABG within 24hrs of plavix/ticagrelor can be considered (Class IIb, Level B)
    • (esp if benefits of revasc outweigh risks of bleeding)
  • Urgent CABG within 5 days of clopidogrel or ticagrelor (or 7 days after prasugrel) can be considered (Class IIB, Level C)  [benefits vs. risks]
  • Summary: Plavix+Ticagrelor d/c 24hrs before urgent CABG (Class I) or 5 days before CABG (Class IIb)
    Prasugrel = 7 days. 

Post-STEMI

• B-Blocker within 24hrs (Class I)
  • Continue during and after hospitalization
    • Contra-indications:
      • HF
      • Low output state
      • High risk of cardogenic shock
      • Other (AV block >240ms, asthma, 2nd or 3rd deg AVB)
    • If contra-indicated, re-evaluate later.
  • Acutely: Can consider IV BB if ongoing ischemia (Class IIa, Level B)
• ACEi within 24hrs:
  • Class I, Level B -> Anterior STEMI, HF, LVEF < 40%
  • Class IIa, Level A --> TO ALL PATIENTS WITH STEMI
• ARB if intolerant to ACE.
• Aldosterone antagonist with BB and ACEi if EF < 40% AND:
  • Symptomatic HF
  • DMII
•  

Cardiac Enzymes

• Cardiac Enzyme Types:
  • Myoglobin (old, poor area under curve)
  • CK-MB (MB isoenzyme of Creatine Kinase) - previously gold standard, but 2003 Heart study removed it 
  • Troponin I (cTnI) (more sensitive and specific than CK-MB)
  • Troponin T (cTnT)
• Troponin may not be detectable until 2hrs post-onset of chest pain.  (may not be detectable for up to 12h)
• Some hospitals do the new high-sensitivity troponin (something like that) hsTrp, which goes up earlier?

• Reading:
  • MERIT Study: Collinson PO et al (2002) Heart  (compared biomarkers)

Differential for Troponin Elevation

• Myocardial Infarct
  • Rise and/or fall of cardiac biomarkers (trop) with evidence of ischmia (one of):
         1. Ischemic symptoms
         2. ECG: new ischemic changes or new pathologic Q-waves
         3. Imaging: loss of viable myocardium (MIBI) or wall motion abnormality (Echocardiography).
• Type II:
  • Ischemia due to increase oxygen demand or decreased vascular supply.
    • Increased demand:
      • Arrhythmias, Sepsis
    • Decreased supply:
      • Coronary Spasm, Coronary embolism, anemia, arrhythmias, hypertension/hypotension.