NSTEMI : Early Medical Management Pearls

Antiplatelet therapy

Aspirin

• 2-4 non-enteric coated chewable baby aspirins (81 mg each) – buccal absorption is the fastest for platelet inhibition.
• Initial dose: 150 mg – 325 mg
• Daily dose: <150 mg
• For patients unable to take oral medications: Rectal suppository 325 mg
• Avoid in acute MI: Enteric coated preparations – delayed GI absorption and antiplatelet effects

Clopidogrel (ADP inhibitor)

• Initial loading dose: 300 mg
• Daily dose: 75 mg (continued for atleast 9 months)
• Hold if catheterization within 24-48 hours and/or CABG possible
• Should be discontinued 5-7 days before elective CABG

Ebtifibatide (GpIIb/IIIa inhibitor)

Initial dose: 180 mcg/kg

Continuous infusion: 2 mcg/kg/min (upto 72 hours) – decrease to 1 mcg/kg/min if serum creatinine >2

Approach to antiplatelet therapy

Offer aspirin as soon as possible to all patients and continue indefinitely unless contraindicated by bleeding risk or aspirin hypersensitivity.

For patients with aspirin hypersensitivity, clopidogrel monotherapy should be considered as an alternative treatment.

Offer a loading dose of 300 mg clopidogrel in addition to aspirin to patients with a predicted 6-month mortality of more than 1.5% and no contraindications (e.g. high bleeding risk).

1. High risk (Prolonged refractory chest pain, ST depression or dynamic ST segment shifts, Elevated Troponin and CK-MB) with expected long delays for angiography:

• Aspirin + Clopidogrel + Ebtifibatide

Dynamic ST segment – different from baseline ECG or changing over time)

2. High risk patients planned for early invasive management:

• Aspirin + Ebtifibatide (avoid in severe renal dysfunction)

3. Other patients before angiography:

• Aspirin + Clopidogrel or Ebtifibatide

Prasugrel (ADP antagonist) has been FDA approved for the treatment of moderate to high risk ACS patients who are managed with PCI.

Abciximab (GpIIb/IIIa inhibitor) must be used in ACS only when PCI is clearly planned.

Low Molecular Weight Heparin (LMWH)

Benefits of LMWH over Unfractionated heparin (UFH):

1. Higher anti-Xa to anti-IIa activity: LMW heparins have more anti-Xa activity and less anti-IIa activity than Unfractionated heparins (UFH).
2. Enhanced bio-availability and more reliable anticoagulant effect: No need to monitor aPTT
3. Reliable anticoagulation via subcutaneous route: Ease of administration
4. Lack of inhibition by platelet factor IV
5. Lower risk of heparin induced thrombocytopenia (HIT)

Possible disadvantages of LMWH over UFH:

1. Increased risk of minor bleeding (risk of major bleeding is same).
2. Less effect of protamine on reversal of anticoagulant effects of LMWH than UFH.

Enoxaparin

Indicated as primary medical therapy for NSTEMI

Dose: 1 mg/kg s.c. q12h (normal renal function) and q24h (CrCl <30) X 2-8 days

Contraindications:

1. Active major bleeding
2. Thrombocytopenia with positive antiplatelet antibody tests
3. Hypersensitivity

Caution:

1. Uncontrolled hypertension
2. Diabetic retinopathy
3. Creatinine clearance <30 ml/min
4. Increased risk of bleeding

Monitoring:

1. Platelet count: baseline, twice weekly
2. CBC
3. Serum creatinine: baseline, change in renal function
4. Daily clinical evaluation for bleeding (not aPTT or ACT)

Complications:

1. Significant bleeding:

• Last enoxaparin dose ≤8 hours: Protamine 1 mg for each 1 mg of enoxaparin as slow infusion.
• Last enoxaparin dose 8-12 hours: Protamine 0.5 mg for each 1 mg of enoxaparin as slow infusion.
• Last enoxaparin dose >12 hours: Protamine may not be needed.

2. Thrombocytopenia: Discontinue enoxaparin if:

• Platelet count drops below 1,00,000/cu.mm OR
• Platelet count drops ≥50% from baseline.

3. Renal insufficiency:

• Not approved by FDA for use in dialysis patients.
• If used – dose must be reduced with frequent Xa monitoring.

Fondaparinux (Synthetic Xa inhibitor)

Some studies proved, fondaparinux to be non-inferior to enoxaparin and reduction in risk of major bleeding and 30 day mortality.

1. Fondaparinux 2.5mg S/C daily should be given if angiography / intervention is NOT planned within 24 hours.
2. Where early angiography/intervention is planned unfractionated heparin (UFH) is preferred.
3. Fondaparinux should be given once daily for at least 48 hours after admission up to a maximum of 8 days or until discharge, whichever is sooner.
4. If the patient is undergoing PCI, fondaparinux should be omitted on the morning of the procedure – if not omitted, additional UFH (50-100 unit/kg adjusted to ACT) can be given to reduce the risk of catheter-related thrombosis; although bleeding risk will increase.
5. Fondaparinux should not be used in patients with eGFR < 20 ml/min – use unfractionated heparin instead. No dosage reduction for fondaparinux is required for the treatment of ACS patients with eGFR ≥ 20 ml/min (Note: dose adjustment is required for non-ACS indications for fondaparinux).
6. On cessation of fondaparinux therapy for ACS, all patients should be assessed for risk of venous thromboembolism and initiated on appropriate thromboprophylaxis if needed in line with local guidance.

Unfractionated Heparin (UFH)

Consider use in: Severe renal dysfunction

Dose: 60 U/kg bolus then 12U/kg/hr (target to aPTT of 1.5 to 2.5)

Start immediately and continue for 2-7 days as clinically indicated.

Bivalirudin (Direct thrombin inhibitor) montherapy has been found to be non-inferior to combination of heparin based therapy and GpIIb/IIIa inhibitor with the benefit of significant reduction in major bleeding risk.

Table 1. Antiplatelet and anticoagulant therapies

Drug Category	Early Invasive		Initial Conservative	Postdischarge
Aspirin	Aspirin		Aspirin	Aspirin
Intravenous antiplatelet (glycoprotein IIb/IIIa inhibitors)	Upstream	Periprocedure
	Epifibatide Tirofiban	Eptifibatide Tirofiban Abciximab
Oral antiplatelet (P2Y12 Inhibitor)	Clopidogrel Ticagrelor	Clopidogrel Prasugrel Ticagrelor	Clopidogrel Ticagrelor Prasugrel (trial in progress)	Clopidogrel Prasugrel Ticagrelor
Anticoagulant	Bivalirudin Fondaparinux Enoxaparin Unfractionated heparin		Fondaparinux Enoxaparin Unfractionated heparin	Warfarin Dabigatran Rivaroxaban Apixaban
Other considerations	Dose and timing		Dose and timing	Duration related to PCI vs. no PCI PPIs Patients requiring triple therapy
Abbreviations: PCI = percutaneous coronary intervention; PPI = proton pump inhibitor

Cardioselective Beta Blocker

Start immediately and continue indefinitely unless contraindicated:

1. Heart rate <60 bpm
2. Systolic blood pressure <100 mmHg
3. Moderate or severe left ventricular failure
4. PR interval on ECG >0.24 s
5. 2nd or 3rd degree heart block
6. Cardiogenic shock
7. COPD or asthma

Example:

• IV dose: Metoprolol 5 mg IV q 5 min X 3 doses followed by
• Oral dose: Metoprolol 50 mg PO BD (after 15-20 minutes of last IV dose)

Nitrates

Start immediately and continue with iv infusion if pain persists after 3 doses of sublingual GTN.

Dose: Glyceryl trinitrate (GTN) 0.3-0.6 mg sublingually or translingual spray 400-800 mcg (1-2 sprays) every 5 minutes (maximum 3 doses).

IV infusion: GTN 5 mcg/min intravenously initially, increase by 5-20 mcg/min increments every 3-5 minutes, maximum 200 mcg/min.

Contraindications:

1. History of recent phosphodiesterase-5 inhibitor (e.g. sildenafil)
2. Systolic BP <90 mmHg
3. Concern for right ventricular infarct

Morphine

Start after Beta-blocker and nitrates have been used and pain persists or sooner if anxiety present.

Dose: 2-4 mg IV q5-15 minutes (should not exceed 25 mg in 24 hour period).

Thrombolysis is Not Recommended

The clot in NSTEMI is a platelet-rich clot with a fibrin cap (white clot) which only partially occludes the coronary artery.  In comparison, the pathology is a fibrin-rich clot (red clot) in STEMI.  Thrombolysis or fibrinolysis in NSTEMI may expose and release the underlying platelets into circulation likely leading to further fresh thrombii. Hence, risks of thrombolysis outweigh the benefits in that group of patients.

TIMI Score Mnemonic

Mnemonic: AMERICA

1. Age (greater than 65 years)
2. Markers (raised serum cardiac markers)
3. ECG (ST segment depression ≥0.5 mm at presentation)
4. Risk factors (atleast 3 for coronary artery disease)
5. Ischemia (atleast 2 anginal events previous 24 hours)
6. Coronary stenosis (prior stenosis of 50% or more)
7. Aspirin (use in previous 7 days)

1 point for each risk factor (maximum score 7).

Interpretation:

1. Low risk: 0-2
2. Intermediate risk: 3-4
3. High risk: 5-7

References:

1. ACS Essentials – By Robert M. Califf, Matthew T. Roe

2. Mayo Clinic Cardiology Concise Textbook – By Joseph G. Murphy, Margaret A. Lloyd

3. BMJ Best Practice – NSTEMI – Step by Step Management

4. NICE Guidelines – Unstable angina and NSTEMI: early management

5. NHS – Guidance on use of fondaparinux in UA/NSTEMI

6. Vernon Anderson H, Cannon CP, Stone PH, et al.  One-year results of the thrombolysis in myocardial infarction (TIMI) IIIb clinical trial.  J Am Coll Cardiol. 1995;26(7):1643-1650