Non-STE ACS (NSTEMI/UA)

Abbreviations

  • MACE – Major Adverse Cardiac Effects (mortality, infarction, cardiovascular death, etc)
  • UA – Unstable Angina
  • NSTEMI – Non-ST Elevation MI
  • cTn – Cardiac Troponin
  • NPV – Negative Predictive Value

Diagnosis

History

Helpful Features:

  • Prior MI
  • Risk factors (age, gender, hx of CAD)
  • Deep, poorly localized, chest/arm pain
  • Worse with exertion / emotional stress
 

Features NOT Helpful (studied)

  • Relieved with nitro
    (35% with ACS, 41% without ACS)
  • Relieved with GI antacids like “pink lady”

Features not characteristic

  • Pleuritic 13%
  • Sharp or knife-lung in respiration (22%)
  • Midline or lower abdomen
  • Pain localized with 1 finger
  • Pain reproduced with arm movement or palpation (7%) (high NPV)
  • Brief episodes (few seconds or less)
  • Maximal at onset

NOTE: Historic characteristics increase/decrease likelihood that chest pain is ischemic, but none rule it out

Diagnostic Tests

  • 12-lead ECG (Repeat if diagnosis is unclear) – at 15-30min intervals if high risk of suspicion
    • NSTEMI ECG could have persistent or transient ST depression, transient ST elevation, T-wave inversion, flat T waves, pseudo-normalization of T waves or it can be normal.

Cardiac Biomarkers

    • Serial cardiac Troponin I or T at presentation and at 3-6hrs after SYMPTOM onset (AHA 2014)
      (ESC 2015 promotes 0/3hr from PRESENTATION; 0/1hr algorithms validated for some assays)
      • Additional troponin level can be obtained beyond 6 hours in patients with normal serial troponin levels if there is intermediate/high suspicion for ACS
      • High-sensitivity cTn rises within 1h, and can remain elevated for days/weeks.
      • Repeating troponin levels until they “peak” is not recommended and is not helpful.  Checking the troponin more than 3 times is generally a poor use of resources.
      • However, additional biomarker measurement on day 3 or 4 can help prognosticate and determine infarct size (particularly CK)
      • NOTE: If your institution has Troponin T, assume it is “high-sensitivity.”  Troponin I has many assays, but most modern institutions use high-sensitivity Troponin I assays.
    •  CK-MB
      • Released from myocardium much more rapidly, and “peaks” earlier than troponin.
      • Generally less sensitive than troponin, and less specific for myocardium
      • May correlate better to infarct size
      • May be helpful if you suspect patient is having a second ACS event, and troponin is still rising from the initial event 

Approach to Chest Pain & Classification

Categories of Ischemic Chest Pain
  • Initial assessment of patients should:
    1. Establish likelihood that chest pain is due to myocardial ischemia
    2. Rule out other main causes of chest pain (aortic dissection, PE, pericarditis)
    3. Classify patients into the following categories:
      • STEMI, NSTEMI, unstable angina, low risk chest pain, and stable angina (see below)
    4. Risk stratify the patient into “high risk of MACE” or “low risk of MACE” clinically
      • (NOTE: Does not apply to STEMI, which is always considered high risk)
  • Categories of patients presenting with ischemic chest pain:
    1. STEMI – ST elevations with compatible clinical picture
    2. NSTEMI – Rise and fall of cardiac biomarkers, which meets the Universal Definition of MI
    3. Unstable Angina – New/rest/changing pain without cTn or ECG changes, but “High Risk of MACE” (see below)
      • Generally benefit from admission and aggressive antithrombotic therapy; so treated the same as NSTEMI
    4. Low Risk Chest Pain – New/rest/changing pain without cTn or ECG changes, but “Low Risk of MACE” (see below)
      • Generally benefit less from aggressive/invasive therapy.  These patients can be treated with observation/outpatient management with ASA, nitro spray, activity precautions until further assessment is done
    5. Stable Angina – Predictable retrosternal chest pressure worse on exertion/stress, better with rest/nitroglycerin.  To be “stable,” the pain must remain unchanged for at least 2 months.
      • NOTE: Patients with stable angina who have a change in the pain, such as worsening pain, brought on by less exertion, or pain at rest, should be risk stratified to unstable angina or low risk chest pain. 
  • How do I know if my patient is “Low Risk of MACE” or “High Risk of MACE”?  You must risk stratify them using one or more of the tools below:
      • Clinical picture (Normal ECG? resolution of chest pain? history of CAD? clinically stable?)
      • HEART Score ≤ 3 (New, well-validated, best correlates to 30d risk of MACE)
      • GRACE Score < 140 (Endorsed by ESC Guidelines 2015, better c-statistic than TIMI score)
      • TIMI Score 0-1 (Endorsed by AHA Guidelines 2014)
      • Stress Test (if able to obtain quickly)
  • NOTE: You should know the main categories of the HEART and GRACE scores to quickly risk stratify ACS patients clinically.
 

Low Risk Chest Pain

  • No ST elevation + no cTn change + and deemed low risk through:
    • Clinical assessment OR
    • Scoring tools (i.e. HEART, GRACE, TIMI) – see “Approach” section above
  • There is often diagnostic uncertainty as to the cause of chest pain
  • Risk of MACE is low, and after a period of observation (+/- 3rd cTn) these patients can often be managed in an outpatient setting with close follow-up:
    • ASA is recommended (Class IIB) 
    • Risk factor modification
  • These patients benefit less from intensive anti-thrombotic therapy and revascularization.
    • Those who may benefit may be further selected with non-invasive risk stratification:
      1. Treadmill Stress ECG (functional test)
      2. Myocardial Perfusion Imaging (MIBI) (functional test)
      3. Stress Echocardiography (functional test)
      4. Coronary CT (anatomic test – can exclude ACS/CAD)

Unstable Angina

  • Generally considered to be an ACS (plaque rupture/instability), but amount or duration of ischemia is insufficient to cause myocardial infarction and elevate biomarkers.
  • Classic patient is someone with on/off chest pain that lasts <30-60min at a time. 
  • To call UA, there should NOT be any rise/fall of cTn on serial testing, and there should be concern that the chest pain is “high risk” based on clinical assessment or scoring (HEART, GRACE or TIMI)

Management

  • Hospital admission with medical management is the SAME as NSTEMI to treat plaque rupture/instability (see below)
  • Compared with NSTEMI, there is less benefit with revascularization
    • Patients can be selected for further risk stratification to determine if they will benefit from revascularization through non-invasive tests (i.e. exercise ECG, stress echo, MIBI, Cardiac CT
  • Based on numerous factors, some clinicians may prefer invasive coronary angiography

Practical Tip: New studies indicate that in the modern era of high-sensitivity cTn, negative cTn is excellent at predicting low risk of MACE.  Overall the diagnosis rate of UA is declining.  Most of the cTn-negative patients are classified as “Low Risk Chest Pain.”

NSTEMI

  • Must qualify as “Myocardial Infarction (MI)”, which is based on the Universal Definition of MI

     

  • Patients with NSTEMI should generally be admitted to hospital and treated with antithrombotic therapy (below)
4TH UNIVERSAL DEFINITION OF MI

Rise and/or fall of cTn with 1 of:

  • Symptoms of acute ischemia
  • ECG Changes
  • New Q-waves
  • Loss of viable myocardium (MIBI/Imaging) or new wall motion abnormality on echo
  • Coronary thrombosis directly visualized by CT or angiography

Management: Symptom Management

  • Oxygen: Supplemental only if sat ≤ 90% (routine O2 = poor outcomes)
  • Nitrates:
    • Indications: Chest pain, HF, hypertension
    • Benefit: Symptoms only (no effect on MACE)
    • Doses/Options: Nitro spray 0.4mg q5min x3
      • If pain beyond 3 nitro sprays, start infusion 
      • Infusion Dose: 20 mcg/min IV → increase by 20 mcg/min increments until pain is controlled (max 400 mcg/min)
      • If infusion is not desired or the patient has intermittent chest pain, a nitro patch can be considered (or a low dose infusion): 1.2 mg/hr patch is equivalent to 20 mcg/min infusion
    • Contraindications:
      • PDE Inhibitors: within 24 hours of sildenafil or vardenafil, or within 48 hours of tadalafil
      • Hypotension
    • NOTE: Chest pain refractory to antithrombotic therapy and nitrates is an indication for immediate invasive therapy.
  • Morphine:
    • Indications: Only if pain refractory to all anti-ischemic agents
    • Suggestion of harm – (i.e. interference with anti-platelet agents, risk of HF, etc.)

Management: Antithrombotic Therapy

  • Dual Antiplatelet Therapy
    • Indications: All post-MI patients
    • Benefit: CV mortality, recurrent MI, need for revasc, etc. (MACE)
      • PLATO (ticagrelor), CURE (clopidogrel), TRITON-TIMI38 (prasugrel)
      • Duration > 1yr: PEGASUS-TIMI 54
    • Doses/Options:
      • ASA 160mg chew + 80mg OD thereafter indefinitely
        AND one of: 
      • 1st Line: Ticagrelor 180mg + 90mg BID thereafter (at 1y change to 60mg bid for up to 3y total)
        • 1st Line: Prasugrel (Also considered first-line option, but no longer available in Canada)
      • 2nd Line: Clopidogrel 300mg + 75mg OD thereafter (consider 160mg daily x6d post-PCI)
            Continue 75mg for up to 3y post-MI (CCS 2018)
    • Switching: Switching between ticagrelor and clopidogrel → always reload (CCS 2018)
    • Contraindications:
      • Prasugrel contraindicated if prior TIA/Stroke (not available in canada)
      • Ticagrelor contraindicated if previous intracranial hemorrhage
      • No ticagrelor load if > 75 yo (AHA 2014)
      • Add PPI if has risk factors for GI bleed (prior bleed, etc.)
  • Anticoagulation
    • Indication: ALL post-MI patients
    • Options/Doses:
      • 1st Line: Fondaparinux 2.5 mg SC daily
        • OASIS-5 Trial: Less bleeding than enoxaparin, higher risk of catheter thrombosis (requires heparin load in cath lab)
        • Continue for 8 days, until PCI, or until discharge; usually continue through hospitalization as DVT prophylaxis
      • 1st Line: Unfractionated heparin 60 IU/kg (max 4000 IU) infuse 12 IU/kg (max 1000 IU/kg), target aPTT 
        • Old studies, pre-DAPT era
        • Stop at revascularization, discharge or 48hrs (whichever comes first)
      • 1st Line: Enoxaparin 1mg/kg SC q12h (OD dosing if CrCl < 30 mL/min)
        • Patients for non-invasive approach: ESSENCE Trial: superior to heparin for mortality (continue through hospitalization or until PCI performed). 
        • Patients for invasive approach: Many interventional cardiologists recommend against enoxaparin if patient is undergoing invasive approach (SYNERGY Trial: comparable to UFH in efficacy in pts undergoing invasive approach, but increased risk bleeding)
      • 2nd Line: Bivalirudin (expensive in Canada, generally used in patients with HIT)
    • PRACTICAL TIP:
      • If PCI is planned, guidelines recommend any of the three first line agents but UFH is often preferred. In modern studies, enoxaparin showed similar outcomes but increased in-hospital major bleeding (SYNERGY) and fondaparinux had increased catheter thrombosis during angiography requiring a bolus of heparin (OASIS-5). OASIS-5 results also suggest that patients at high risk of bleeding can be considered for fondaparinux. 
      • If conservative/medical management is planned guidelines prefer fondaparinux or enoxaparin over heparin due to improved outcomes/convenience and decreased bleeding (ESSENCE). Again, in patients at high risk of bleeding, fondaparinux is preferred (OASIS-5)
  • GPIIB/IIIA inhibitors – Only used by interventional cardiology for bailout situations / thrombotic complications.

Management: Adjunctive Therapies

Management: Revascularization

Guidelines

Unlike STEMI, the benefit of revascularization of UA/NSTEMI without “high-risk features” has been controversial. (See “Evidence for revascularization strategies” below.)

Physicians should select an approach based on risks/benefits, and patient/physician preference. 

Available Approaches

  • Routine Invasive: Invasive diagnostic evaluation (angiogram) +/- PCI for ALL patients
    • Early Invasive Strategy -> within 24hrs
    • Delayed Invasive Strategy -> within 25-72hrs
  • Ischemia Guided Strategy: Medical management.  Invasive intervention only if:
    1. Failure of medical therapy (ongoing ischemic chest pain)
    2. High prognostic risk (TIMI/GRACE)
    3. High-risk non-invasive stress test
      • If reasonable, a non-invasive risk stratification test can be used to determine if the patient is “high/intermediate risk” and may benefit from invasive management (most commonly MIBI)
 
AHA 2014 & ESC 2015 (see strategies to the right)
Indications for Invasive Evaluation in UA/NSTEMI

Urgent / Immediate Invasive Strategy

  • Refractory angina
  • Hemodynamic or electrical instability

Early Invasive Strategy (within 24hrs)

  • AHA 2014: If elevated risk of clinical events (see table to the right)
  • ESC 2015: If troponin rise/fall

Ischemia Guided Strategy (Conservative)

  • AHA 2014: Stable patients – reasonable considering clinician and patient preference

(Review the ESC and AHA algorithms to the right)

Summary of Evidence

  • FRISC-II Trial (1999) – Intermediate to high risk patients (FRISC score)
    • Early invasive strategy >> Ischemia-Guided  (fewer recurrent MI and improved long-term survival)
    • Very old trial – poor medical therapy available at that time. 
    • Definition of MI had issues (i.e. Troponin often not used, peri-procedural MI missed)
  • TACTICS-TIMI 18 Trial (2001) – pts with unstable angina and NSTEMI
    • Early Invasive >> Medical Management (only if TIMI > 2)
  • ICTUS Trial (2005) – Pts with elevated troponin.
    • Early invasive = Ischemia Guided
    • Most recent data with relatively modern medical therapy.
  • RITA-3 Trial (2002) – pts with non-ST-elevation ACS
    • Early Invasive >> Medical Management for “refractory angina”, equal for death and MI
  • Meta-Analysis of 7 RCTs: (Bavry JACC 2006)
    • Early Invasive >> Med Mgmt for NSTEMI

Bottom Line:

  • Revascularization appears to consistently confer a benefit in reducing angina, and possibly mortality benefit ONLY in “high/intermediate risk” groups. 
  • Overall, trials controversial due to non-standard risk-stratification methods and variable definitions of MI. 
  • ESC 2015 guidelines recommend routine invasive management if there is a troponin change
  • AHA 2014 guidelines recommend either approach, leaning towards early invasive in patients with high or intermediate risk. (To estimate risk, use GRACE, TIMI, or table above)

References

Highly-Recommended Reading

Optional Reading

  • Primary Author: Dr. Pavel Antiperovitch (MD, FRCPC, Cardiology Fellow)
  • Author/Reviewer: Dr. Atul Jaidka (MD, FRCPC, Cardiology Fellow)
  • Staff Reviewer: Dr. Terrance McPherson (MD, FRCPC[Cardiology])
  • Copy Editor: Perri Deacon (medical student)
  • Last Updated: Feb 26, 2022