1. Introduction to Reperfusion Modalities

Timely reperfusion in ST-segment elevation myocardial infarction (STEMI) is critical to limit infarct size and reduce mortality, embodying the principle “time is muscle.” When primary PCI cannot be performed rapidly, alternative strategies such as a pharmaco-invasive approach or direct fibrinolysis can achieve reperfusion. However, these alternatives require careful patient selection and appropriate adjunctive therapy.

• Each 30-minute delay in reperfusion is associated with an approximate 7.5% increase in 1-year mortality.
• Primary PCI is the preferred reperfusion strategy if first medical contact (FMC)-to-device time can be achieved within 90 minutes (or within 120 minutes if transfer is required).
• When the expected PCI-related delay is greater than 120 minutes, fibrinolytic therapy should be administered, followed by transfer to a PCI-capable center.

2. Primary PCI Pathway

Primary PCI offers the highest rates of vessel patency, lower rates of reinfarction and stroke, and improved survival when performed within target door-to-balloon (D2B) times or, more accurately, FMC-to-device times.

• Target FMC-to-device time: ≤ 90 minutes for patients presenting directly to a PCI-capable hospital, or ≤ 120 minutes for patients requiring transfer from a non-PCI-capable hospital.
• System interventions to reduce delays:
  • Prehospital ECG acquisition and interpretation.
  • Advance activation of the cardiac catheterization laboratory by emergency medical services (EMS).
  • Direct transport of patients by EMS to the catheterization laboratory, bypassing the emergency department if appropriate.
• Transfer decision: If the anticipated FMC-to-device time, including inter-hospital transfer, is ≤ 120 minutes, transfer for primary PCI is recommended. Otherwise, fibrinolysis should be considered at the non-PCI-capable facility.

Pharmacist Role in Primary PCI:

• Ensure early administration of aspirin and P2Y₁₂ inhibitor loading doses.
• Assist in selecting and dosing anticoagulants (e.g., unfractionated heparin [UFH] or bivalirudin) based on patient-specific factors like bleeding risk.
• Prepare glycoprotein IIb/IIIa inhibitors for potential use in cases of no-reflow phenomenon or large thrombus burden.

3. Pharmaco-Invasive Strategy

A pharmaco-invasive strategy involves the administration of early fibrinolysis followed by planned PCI, typically within 3 to 24 hours. This approach is reserved for patients presenting early ( ideally ≤ 3 hours from symptom onset) when PCI-related delays are expected to exceed 120 minutes.

A. Definition & Patient Selection

• Eligible patients: STEMI onset ≤ 3 hours, anticipated PCI delay > 120 minutes, and no contraindications to fibrinolytic therapy.

B. Key Trial Evidence (STREAM Trial)

• Compared a strategy of prehospital tenecteplase, clopidogrel, and enoxaparin followed by routine angiography within 3–24 hours, versus primary PCI.
• The 30-day composite endpoint (death, shock, heart failure, reinfarction) was comparable between the pharmaco-invasive group (12.4%) and the primary PCI group (14.3%).
• Rescue PCI for failed reperfusion (defined as <50% ST-segment resolution) was required in approximately 36% of patients in the pharmaco-invasive arm.
• An important finding was that reducing the tenecteplase dose by half for patients aged ≥ 75 years significantly decreased the rate of intracranial hemorrhage without compromising efficacy.

The TRANSFER-AMI and DANAMI-2 trials also support the concept of early transfer for angiography and PCI after fibrinolysis when primary PCI is not rapidly available.

4. Fibrinolytic Therapy

A. Agent Selection

The two most commonly used fibrin-specific lytic agents are alteplase (tPA) and tenecteplase (TNK).

• Alteplase (tPA): Administered as a weight-based bolus followed by an infusion. It has a shorter half-life and requires an infusion pump.
• Tenecteplase (TNK): Administered as a single weight-based bolus. It has greater fibrin specificity and a longer half-life, offering simplicity in administration. It is often preferred due to ease of use and similar efficacy to tPA.

B. Pharmacotherapy Details

Mechanism of Action: Both tPA and TNK are plasminogen activators that convert plasminogen to plasmin. Plasmin then degrades the fibrin matrix of the thrombus, leading to clot dissolution and restoration of blood flow.

Indications: STEMI within 12 hours of symptom onset when primary PCI cannot be performed within 120 minutes of FMC.

Dosing of Fibrinolytic Agents

Monitoring

• Efficacy:
  • Resolution of chest pain.
  • ≥ 50% ST-segment resolution in the lead with maximal elevation at 60–90 minutes post-administration.
  • Reperfusion arrhythmias (e.g., accelerated idioventricular rhythm), though not specific.
• Safety:
  • Frequent neurologic checks (e.g., hourly for the first few hours, then regularly for 24 hours) to detect signs of intracranial hemorrhage (ICH).
  • Monitoring for signs of bleeding (e.g., at puncture sites, gastrointestinal, genitourinary).
  • Hemoglobin and hematocrit levels.

Contraindications to Fibrinolysis

Note: This list is not exhaustive and clinical judgment is paramount.

Comparative Advantages

• Tenecteplase (TNK): Single bolus administration, potentially lower rate of non-cerebral systemic bleeding, no infusion pump required, greater fibrin specificity.
• Alteplase (tPA): More widely available in some regions, extensive clinical experience.

C. Adjunctive Antithrombotic Therapy

Appropriate adjunctive antiplatelet and anticoagulant therapy is essential when administering fibrinolytics to prevent re-thrombosis and improve outcomes.

5. Recognition of Failed Reperfusion & Rescue PCI

Failed fibrinolysis is suspected when clinical or electrocardiographic (ECG) criteria for reperfusion are not met within 60–90 minutes after the administration of the lytic agent. Prompt recognition is crucial as these patients benefit from immediate angiography and rescue PCI.

A. Criteria for Failed Fibrinolysis (at 60-90 minutes post-lytic)

• ECG Criteria: Less than 50% resolution of ST-segment elevation from baseline in the lead showing the most prominent initial elevation.
• Clinical Signs:
  • Persistent or worsening chest pain.
  • Hemodynamic instability (e.g., hypotension, shock).
  • Development or worsening of heart failure.
  • Significant ventricular arrhythmias.

B. Indications for Rescue PCI

• Persistent ST-segment elevation or ongoing ischemic chest pain 60–90 minutes after initiation of fibrinolytic therapy.
• Hemodynamic instability or cardiogenic shock.
• Life-threatening arrhythmias.

C. Pharmacist Role in Failed Reperfusion

• If an infusion (e.g., tPA) is ongoing, ensure it is stopped promptly.
• Coordinate with the medical team for emergent transfer to a cardiac catheterization laboratory.
• Assist in adjusting the antithrombotic regimen to balance the need for potent antiplatelet/anticoagulant therapy during PCI against the increased bleeding risk from recent fibrinolysis. This may involve careful consideration of additional heparin dosing or the use of bivalirudin.

6. Repeat Lysis Considerations

Repeat fibrinolysis (“re-lysis”) is rarely employed in current practice and is generally reserved for highly selected patients with clear evidence of failed initial lysis who do not have timely access to PCI.

A. Timing & Patient Factors

• May be considered if PCI is definitively unavailable and initial fibrinolysis has clearly failed (e.g., persistent ST elevation and pain) usually after a waiting period of at least 60-90 minutes, and sometimes longer (e.g., ≥ 6 hours in some older protocols, though this is not standard).
• Patient factors such as high bleeding risk, advanced age, and recent surgery significantly limit its applicability.

B. Evidence Base

• The evidence supporting repeat lysis is limited, mostly observational, and often associated with higher rates of major bleeding, including intracranial hemorrhage.

C. Alternatives

• The preferred strategy for failed fibrinolysis is rescue PCI.
• If rescue PCI is not an option, optimal medical therapy (including aggressive antiplatelet and anticoagulant therapy as tolerated) and urgent transfer to a PCI-capable facility as soon as feasible are indicated.

7. Clinical Decision Algorithms & High-Yield Pearls

A. Simplified Reperfusion Strategy Algorithm

The following algorithm provides a general guide for selecting a reperfusion strategy in STEMI:

B. Key Clinical Pearls for Critical Care Pharmacists

• Early Antiplatelets: Ensure aspirin and P2Y₁₂ inhibitor loading doses are administered as early as possible, regardless of the chosen reperfusion strategy.
• Tenecteplase Advantages: TNK’s single-bolus, weight-adjusted dosing simplifies administration, especially in prehospital or busy emergency department settings. Remember to halve the dose in elderly patients (≥75 years) when indicated to reduce ICH risk.
• Anticoagulant Selection: The choice of anticoagulant (UFH vs. enoxaparin vs. bivalirudin in PCI settings) should balance the risk of bleeding against the risk of stent thrombosis or reocclusion, considering patient factors and procedural aspects.
• Sustained Vigilance: Neurologic and bleeding surveillance must continue for at least 24 hours post-fibrinolysis due to the ongoing risk of complications.
• Rescue vs. Facilitated PCI: Rescue PCI for failed fibrinolysis is life-saving. However, “facilitated PCI” (routine early PCI after fibrinolysis without clear evidence of failure or high-risk features) has not consistently shown benefit and may increase risks.

C. Unresolved Controversies & Research Gaps

• The optimal time interval between successful fibrinolysis and routine coronary angiography in a pharmaco-invasive strategy remains an area of investigation.
• The role and safety of newer, more potent P2Y₁₂ inhibitors (prasugrel, ticagrelor) in conjunction with fibrinolytic regimens are not well established and generally avoided.
• Developing and implementing strategies to further reduce system delays in STEMI care, particularly in rural and underserved areas, is an ongoing challenge.
• Optimal antithrombotic strategies post-fibrinolysis, especially in patients who subsequently undergo PCI, continue to be refined.