6.1 Acute Coronary Syndromes: STEMI & NSTE-ACS Pharmacotherapy

6.1 Acute Coronary Syndromes: STEMI & NSTE-ACS Pharmacotherapy

Pathophysiology & Clinical Spectrum

Acute coronary syndrome (ACS) encompasses a continuum of acute myocardial ischemia triggered by atherosclerotic plaque rupture or erosion. Disruption of the vascular endothelium exposes subendothelial collagen and von Willebrand factor, inducing immediate platelet adhesion via glycoprotein (GP) Ib/IX receptors. Platelet activation triggers the release of thromboxane A2 (TXA2) and adenosine diphosphate (ADP), culminating in conformational activation of platelet surface GP IIb/IIIa receptors and fibrinogen cross-linking. The resulting intraluminal thrombus produces acute coronary luminal compromise:

• ST-Segment Elevation Myocardial Infarction (STEMI): Complete, persistent transmural coronary occlusion requiring immediate reperfusion to prevent transmural myocardial necrosis.
• Non-ST-Segment Elevation ACS (NSTE-ACS): Incomplete, intermittent, or microembolizing occlusion presenting without persistent ST elevations. Subcategorized into Non-ST-Elevation Myocardial Infarction (NSTEMI) (demonstrated by positive cardiac biomarkers such as high-sensitivity cardiac troponin I or T) and Unstable Angina (UA) (ischemic symptoms and electrocardiographic changes without myocardial necrosis biomarkers).

Emergency pharmacotherapy focuses on rapid platelet inhibition, thrombin generation suppression, restoration of myocardial oxygen supply-demand balance, and emergent reperfusion.

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Antiplatelet Pharmacotherapy

Dual antiplatelet therapy (DAPT) combining aspirin with a P2Y12 receptor antagonist represents the standard of care across all ACS presentations.

                         ACUTE ACS ANTIPLATELET CASCADE
  ┌───────────────────────────────────────────────────────────────────────────┐
  │ Aspirin (162–325 mg non-enteric chewed) ──► Irreversible COX-1 Inhibition │
  └─────────────────────────────────────┬─────────────────────────────────────┘
                                        │
                                        ▼
  ┌───────────────────────────────────────────────────────────────────────────┐
  │                         P2Y12 RECEPTOR INHIBITORS                         │
  │  • Ticagrelor (180 mg load): Reversible cyclopentyltriazolopyrimidine     │
  │  • Prasugrel (60 mg load): Irreversible thienopyridine (Avoid if TIA/CVA) │
  │  • Clopidogrel (300–600 mg load): Irreversible prodrug (CYP2C19 dependent)│
  │  • Cangrelor (30 mcg/kg IV + 4 mcg/kg/min): Rapid on/off parenteral agent │
  └───────────────────────────────────────────────────────────────────────────┘

Aspirin

• Loading Dose: 162 to 325 mg non-enteric coated formulation administered immediately upon ED arrival.
• Administration Technique: Must be chewed and swallowed. Chewing promotes rapid buccal and proximal gastric absorption, achieving complete COX-1 suppression and thromboxane A2 inhibition within 15 to 30 minutes. Enteric-coated formulations exhibit erratic, delayed absorption (taking 3 to 4 hours) and must never be swallowed whole in acute presentations.
• Maintenance: 81 mg orally once daily indefinitely.

Oral P2Y12 Receptor Inhibitors

1. Ticagrelor:

   • Loading Dose: 180 mg orally once.
   • Maintenance: 90 mg orally twice daily (lowered to 60 mg twice daily after 12 months in high-risk patients).
   • Pharmacology: Reversible, direct-acting cyclopentyltriazolopyrimidine. Does not require hepatic metabolic conversion. The landmark PLATO trial demonstrated superior reductions in ischemic death and stent thrombosis without excess overall major bleeding compared to clopidogrel.
   • Adverse Effects & Nuances: Self-limiting dyspnea occurs in 10% to 15% of patients (mediated by adenosine reuptake inhibition; typically benign and distinct from acute pulmonary edema), asymptomatic ventricular pauses, and mild hyperuricemia.

2. Prasugrel:

   • Loading Dose: 60 mg orally once.
   • Maintenance: 10 mg orally once daily (reduced to 5 mg orally once daily if body weight is <60 kg; generally avoid if age ≥75 years).
   • Pharmacology: Potent, irreversible thienopyridine prodrug requiring a single-step hepatic CYP450 activation (CYP3A4, CYP2B6). In the TRITON-TIMI 38 trial, prasugrel significantly reduced ischemic events and stent thrombosis compared to clopidogrel.
   • Black Box Warning & Contraindications:
     • History of prior stroke or TIA: Absolute contraindication due to excess fatal and intracranial hemorrhage causing net clinical harm.
     • Age ≥75 years: Generally not recommended due to heightened bleeding risk, except in high-risk clinical subsets (diabetes mellitus or prior MI) where 10 mg or 5 mg daily may be considered.
     • Body weight <60 kg: Increased drug exposure requires dose reduction to 5 mg daily.
     • Pre-treatment Caution: In NSTE-ACS, prasugrel should only be administered after coronary anatomy is defined at diagnostic angiography (ACCOAST trial demonstrated increased bleeding without ischemic benefit from upstream pre-treatment).

3. Clopidogrel:

   • Loading Dose: 300 to 600 mg orally once (600 mg loading dose preferred for primary PCI; 300 mg for fibrinolytic therapy in patients aged ≤75 years; no loading dose for patients aged >75 years undergoing fibrinolysis).
   • Maintenance: 75 mg orally once daily.
   • Pharmacology: Second-generation thienopyridine prodrug requiring two-step hepatic bioactivation involving CYP2C19, CYP1A2, and CYP2B6. Subject to significant pharmacogenomic variability due to CYP2C19 loss-of-function alleles (*2, *3) and drug interactions with potent CYP2C19 inhibitors (e.g., omeprazole, esomeprazole).

Intravenous P2Y12 Inhibitor: Cangrelor

• Dosing: 30 mcg/kg IV bolus followed immediately by a continuous infusion of 4 mcg/kg/min for at least 2 hours or the duration of PCI (whichever is longer).
• Pharmacology: Direct-acting, reversible non-thienopyridine ATP analog. Exhibits instantaneous onset (steady-state platelet inhibition within 2 minutes) and rapid offset (plasma half-life 3 to 6 minutes; normal platelet function restored within 60 minutes of cessation).
• Clinical Indications: Indicated for P2Y12-inhibitor-naive patients undergoing PCI, particularly those unable to take oral medications (intubated, sedated, vomiting, receiving therapeutic hypothermia) or those receiving parenteral opioids (morphine, fentanyl) which delay oral P2Y12 absorption by 2 to 4 hours via gastroparesis.
• Transition to Oral P2Y12 Inhibitors:
  • Ticagrelor: 180 mg loading dose may be administered at any time during or immediately upon discontinuation of the cangrelor infusion.
  • Prasugrel or Clopidogrel: Because cangrelor competitively occupies the P2Y12 receptor, the short-lived active metabolites of thienopyridines cannot bind. Therefore, prasugrel 60 mg or clopidogrel 600 mg must be administered immediately AFTER discontinuing cangrelor, never during the infusion.

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Parenteral Anticoagulant Pharmacotherapy

Parenteral anticoagulation is required for all patients with acute coronary syndromes to suppress thrombin generation and prevent catheter-related or coronary thrombosis.

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Hemodynamic & Symptomatic Adjuncts

Nitroglycerin (Sublingual & Intravenous)

• Mechanism: Endothelial conversion to nitric oxide stimulates soluble guanylyl cyclase, increasing cyclic GMP and inducing systemic vascular smooth muscle relaxation. At low to intermediate doses, venodilation predominates, reducing right and left ventricular end-diastolic volume (preload reduction) and myocardial oxygen demand while improving subendocardial coronary perfusion.
• Administration: Sublingual 0.4 mg every 5 minutes up to 3 doses; intravenous infusion initiated at 5 to 10 mcg/min and titrated by 5 to 20 mcg/min every 3 to 5 minutes based on ischemic chest discomfort and blood pressure.
• Strict Contraindications:
  1. Right Ventricular (RV) Infarction: In patients with inferior STEMI (leads II, III, aVF), an emergent right-sided ECG must be evaluated. ST-segment elevation ≥1 mm in lead V4R confirms RV involvement. The ischemic right ventricle is preload-dependent; venodilation precipitates catastrophic drops in cardiac output and profound shock.
  2. Hypotension: Systolic BP <90 mmHg or a drop ≥30 mmHg below baseline.
  3. Marked Bradycardia or Severe Tachycardia: Heart rate <50 bpm or >100 bpm in the absence of heart failure.
  4. Recent PDE-5 Inhibitor Use: Sildenafil or vardenafil within 24 hours, or tadalafil within 48 hours. Co-administration causes synergistic cGMP accumulation leading to severe, treatment-refractory hypotension and cardiac arrest.

Early Beta-Blockers

• Guideline Direction: Oral beta-blocker therapy (e.g., metoprolol tartrate 25 to 50 mg orally every 6 hours or metoprolol succinate daily) should be initiated within the first 24 hours in hemodynamically stable patients without contraindications.
• The COMMIT/CCS-2 Trial Pitfall: Routine intravenous beta-blockers must be avoided during initial emergency department presentation. The massive COMMIT/CCS-2 trial demonstrated that early IV beta-blockade reduced reinfarction and ventricular arrhythmias but caused an immediate, significant excess of cardiogenic shock and overall mortality, predominantly on day 1.
• Absolute Contraindications to Early Beta-Blockade:
  • Signs of acute heart failure (pulmonary rales, Killip class II or III).
  • Evidence of low cardiac output state.
  • Heightened risk for cardiogenic shock: Age >70 years, systolic BP <120 mmHg, sinus tachycardia >110 bpm or heart rate <60 bpm, and prolonged time from symptom onset.
  • PR interval >0.24 seconds, second- or third-degree AV block.
  • Active reactive airway disease or bronchospastic asthma.

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Reperfusion Strategies in STEMI

                         STEMI REPERFUSION TIMELINE
  First Medical Contact (FMC)
             │
             ├──────────────────────────┬──────────────────────────┐
             ▼                          ▼                          ▼
      PCI Center               Transfer to PCI Center       PCI Unavailable
  (FMC-to-Device ≤90 min)     (FMC-to-Device ≤120 min)    (FMC-to-Device >120 min)
             │                          │                          │
             ▼                          ▼                          ▼
        Primary PCI                Primary PCI           Fibrinolytic Therapy
                                                         (Door-to-Needle ≤30 min)

Primary Percutaneous Coronary Intervention (PCI)

Primary PCI is the preferred reperfusion modality when it can be achieved within ≤90 minutes of FMC at a PCI-capable center, or ≤120 minutes of FMC when interfacility transfer is required.

Fibrinolytic Therapy

When primary PCI cannot be accomplished within 120 minutes of first medical contact, fibrinolytic therapy should be administered within 30 minutes of emergency department arrival (door-to-needle time ≤30 minutes), provided ischemic symptom duration is ≤12 hours and no absolute contraindications exist.

• Tenecteplase (TNK-tPA): Genetically engineered tissue plasminogen activator with 14-fold greater fibrin specificity, 80-fold greater resistance to PAI-1 and a longer half-life (about 20 to 24 minutes initially, versus under 5 minutes for alteplase), so it is given as a single weight-based IV bolus over 5 seconds:
  • Weight <60 kg: 30 mg IV bolus
  • Weight 60 to <70 kg: 35 mg IV bolus
  • Weight 70 to <80 kg: 40 mg IV bolus
  • Weight 80 to <90 kg: 45 mg IV bolus
  • Weight ≥90 kg: 50 mg IV bolus
  • Elderly Dose Adjustment: In patients aged ≥75 years, the STREAM trial established that administering a half-dose tenecteplase bolus maintains reperfusion efficacy while significantly reducing intracranial hemorrhage.
• Absolute Contraindications to Fibrinolysis:
  • Any prior intracranial hemorrhage.
  • Known structural cerebral vascular lesion (e.g., arteriovenous malformation).
  • Known malignant intracranial neoplasm.
  • Ischemic stroke within the preceding 3 months (excluding acute stroke within 4.5 hours).
  • Suspected acute aortic dissection.
  • Active internal bleeding or bleeding diathesis (excluding menses).
  • Significant closed-head or facial trauma within the preceding 3 months.
  • Intracranial or intraspinal surgery within the preceding 2 months.
  • Severe uncontrolled hypertension unresponsive to emergency therapy (SBP >180 mmHg or DBP >110 mmHg).