Antiplatelet, Anticoagulation, and Fibrinolytic Therapy in NSTEMI: Mechanisms and Clinical Application
Core Principle
In NSTEMI, all patients require dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor) combined with anticoagulation, while fibrinolytic therapy is contraindicated and causes harm. 1
Antiplatelet Therapy: Preventing Platelet Aggregation
Mechanism and Rationale
Antiplatelet agents inhibit platelet activation and aggregation, which is the initial step in thrombus formation on ruptured atherosclerotic plaques. 1 In NSTEMI, subtotal thrombotic coronary occlusion involves platelet aggregation as a central pathogenic mechanism. 1
Specific Agents and Targets
Aspirin (Cyclooxygenase-1 Inhibitor):
- Irreversibly blocks COX-1 within platelets, preventing thromboxane A2 formation and diminishing platelet aggregation through this pathway. 1
- Administer 162-325 mg loading dose immediately upon presentation, followed by 75-100 mg daily maintenance. 2, 3
- Represents the cornerstone of NSTEMI therapy with the strongest long-term prognostic evidence available. 1, 2
P2Y12 Inhibitors (Clopidogrel, Ticagrelor, Prasugrel):
- Block the P2Y12 adenosine diphosphate receptor on platelet surfaces, inhibiting platelet activation through a different pathway than aspirin. 1, 4
- Clopidogrel requires a 300 mg loading dose followed by 75 mg daily. 3, 4
- Ticagrelor is preferred over clopidogrel for patients undergoing early invasive or ischemia-guided strategies. 1
- The combination of aspirin plus clopidogrel reduces cardiovascular death, MI, or stroke by 20% relative risk reduction (from 11.5% to 9.3%). 3
Glycoprotein IIb/IIIa Inhibitors (Eptifibatide, Tirofiban):
- May be considered in intermediate/high-risk patients (positive troponin) undergoing early invasive strategy with dual antiplatelet therapy. 1
- Provide additional platelet inhibition at the final common pathway of platelet aggregation. 1
Anticoagulation: Inhibiting the Clotting Cascade
Mechanism and Rationale
Anticoagulants antagonize thrombin-activated fibrin formation, which works alongside platelet aggregation to create coronary thrombi. 1, 5 The rationale is to inhibit the ongoing clotting cascade both during the acute phase and during percutaneous coronary intervention. 5
Mandatory Use
Anticoagulation is required for ALL NSTEMI patients in addition to antiplatelet therapy, irrespective of initial treatment strategy. 1
Specific Agents and Mechanisms
Unfractionated Heparin (UFH):
- Indirect thrombin inhibitor with anti-IIa activity. 1
- Loading dose: 60 IU/kg (maximum 4000 IU), followed by 12 IU/kg/hour infusion (maximum 1000 IU/hour), adjusted to maintain therapeutic aPTT. 1
- Continue for 48 hours or until PCI is performed. 1
- Preferred in patients with history of subdural hemorrhage due to short half-life and reversibility. 2
Enoxaparin (Low Molecular Weight Heparin):
- 1 mg/kg subcutaneous every 12 hours (reduce to once daily if creatinine clearance <30 mL/min). 1
- Continue for duration of hospitalization or until PCI. 1
Bivalirudin (Direct Thrombin Inhibitor):
- 0.10 mg/kg loading dose followed by 0.25 mg/kg/hour infusion. 1
- Only for patients managed with early invasive strategy, continued until diagnostic angiography or PCI. 1
Fondaparinux (Factor Xa Inhibitor):
- 2.5 mg subcutaneous daily for duration of hospitalization or until PCI. 1
- Critical caveat: If PCI is performed while on fondaparinux, an additional anticoagulant with anti-IIa activity (UFH or bivalirudin) must be administered due to risk of catheter thrombosis. 1
Fibrinolytic Therapy: Contraindicated in NSTEMI
Mechanism
Fibrinolytics (tissue plasminogen activators) dissolve existing thrombi by converting plasminogen to plasmin, which breaks down fibrin clots. 6
Class III: Harm Recommendation
Intravenous fibrinolytic therapy should NOT be used in patients with NSTEMI (without ST-elevation, true posterior MI, or left bundle-branch block not known to be old). 1
Evidence of Harm
- No benefit for mortality or myocardial infarction in NSTEMI patients. 1
- Intracranial hemorrhage, fatal MI, and nonfatal MI occur MORE frequently with fibrinolytic therapy in NSTEMI. 1
- Meta-analysis showed no benefit and actually increased risk of MI. 1
Why the Difference from STEMI?
NSTEMI involves subtotal (not complete) coronary occlusion, where the primary pathology is platelet-rich thrombus on ruptured plaque rather than complete fibrin-rich occlusive thrombus seen in STEMI. 1, 7 The risk-benefit ratio is unfavorable because fibrinolytics increase bleeding without improving outcomes in this setting. 1
Integrated Treatment Algorithm
Step 1: Immediate Antiplatelet Therapy
- Aspirin 162-325 mg loading dose immediately. 2, 3
- P2Y12 inhibitor (clopidogrel 300 mg loading dose) for most patients, though may be delayed until after angiography in specific circumstances. 2, 3
Step 2: Immediate Anticoagulation
- Select one anticoagulant based on patient factors and planned strategy:
Step 3: Risk Stratification
- High-risk features (positive troponin, ST-segment changes, hemodynamic instability) warrant early invasive strategy within 24 hours. 1, 3
- Consider adding GP IIb/IIIa inhibitor for high-risk patients undergoing early invasive strategy. 1
Step 4: Never Administer Fibrinolytics
- Fibrinolytic therapy causes harm in NSTEMI without providing benefit. 1
Critical Pitfalls to Avoid
Do not use fibrinolytics in NSTEMI under any circumstances - this is a Class III: Harm recommendation with Level of Evidence A. 1
Do not use fondaparinux alone during PCI - always add UFH or bivalirudin to prevent catheter thrombosis. 1
Do not use prasugrel in patients with prior stroke or TIA - this is an absolute contraindication. 1, 2
Do not withhold aspirin even in patients with bleeding history - aspirin remains the cornerstone therapy and should be continued at the lowest effective dose (75-81 mg daily after loading). 2
Avoid concomitant omeprazole or esomeprazole with clopidogrel - these significantly reduce clopidogrel's antiplatelet activity by inhibiting CYP2C19 metabolism. 4