Evaluating Reperfusion Options: PCI, Pharmaco‐Invasive, and Fibrinolytic Strategies
Objective 5: Evaluate Reperfusion Options
Learning Points:
- Understand door-to-balloon goals for primary Percutaneous Coronary Intervention (PCI).
- Identify criteria for transfer decisions when primary PCI is not immediately available.
- Define pharmaco-invasive approaches and review supporting trial evidence.
- Compare fibrinolytic agents (e.g., alteplase vs. tenecteplase) for selection.
- Outline dosing protocols and monitoring parameters for fibrinolytic therapy.
- Recognize contraindications to fibrinolysis and strategies for bleeding risk mitigation.
- Describe appropriate adjunctive antiplatelet and anticoagulant therapy.
- Identify signs of failed reperfusion and indications for rescue PCI.
- Discuss considerations for repeat fibrinolysis.
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.
Key Pearl: PCI Delay vs. Fibrinolysis
The mortality advantage of primary PCI over fibrinolysis diminishes and may be lost if PCI is delayed beyond guideline-recommended time windows. Prompt administration of fibrinolysis in such scenarios can be life-saving.
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.
Key Pearl: Prehospital ECG
Prehospital ECG transmission to the receiving hospital can significantly reduce D2B times (often by 20–30 minutes) by allowing for earlier catheterization lab activation and team mobilization, ultimately improving patient outcomes.
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.
Controversy: Optimal Timing of Planned PCI Post-Lysis
- Optimal timing of planned PCI post-lysis: Debates continue regarding whether angiography should be performed very early (e.g., within 2-3 hours) or later (up to 24 hours) after successful fibrinolysis.
- Balancing bleeding risk: The risk of intracranial hemorrhage, particularly in elderly patients, remains a concern, necessitating careful patient selection and dose adjustments.
Key Pearl: Rural Settings
In rural or remote settings with inherently long transport times to PCI-capable centers, a pharmaco-invasive strategy can salvage significant myocardium with acceptable safety, especially when fibrinolytic doses (e.g., tenecteplase) are appropriately adjusted for age.
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
| Agent | Dosing Regimen |
|---|---|
| Alteplase (tPA) |
Total dose not to exceed 100 mg:
|
| Tenecteplase (TNK) |
Single IV bolus over 5 seconds, based on weight:
|
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
| Type | Contraindication |
|---|---|
| Absolute | Any prior intracranial hemorrhage (ICH) |
| Known structural cerebral vascular lesion (e.g., arteriovenous malformation) | |
| Known malignant intracranial neoplasm (primary or metastatic) | |
| Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours | |
| Suspected aortic dissection | |
| Active bleeding or bleeding diathesis (excluding menses) | |
| Significant closed-head trauma or facial trauma within 3 months | |
| Intracranial or intraspinal surgery within 2 months | |
| Severe uncontrolled hypertension (unresponsive to emergency therapy) SBP >185 mmHg or DBP >110 mmHg | |
| For streptokinase, prior treatment within the previous 6 months (due to antibodies) | |
| Relative | History of chronic, severe, poorly controlled hypertension |
| Significant hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg) – can be a contraindication if not lowered | |
| History of prior ischemic stroke >3 months, dementia, or known intracranial pathology not covered in absolute contraindications | |
| Traumatic or prolonged (>10 minutes) CPR or major surgery <3 weeks | |
| Recent (within 2-4 weeks) internal bleeding | |
| Noncompressible vascular punctures | |
| Pregnancy | |
| Active peptic ulcer | |
| Oral anticoagulant therapy: the higher the INR, the higher the risk |
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.
Common Pitfalls in Fibrinolytic Therapy
- Failure to adjust TNK dose in the elderly: Not halving the TNK dose for patients ≥75 years (when indicated by local protocols or in pharmaco-invasive strategies) significantly increases the risk of ICH.
- Omitting or underdosing anticoagulation: Concurrent anticoagulation is crucial to prevent re-occlusion of the infarct-related artery.
- Delayed recognition of ICH: Subtle neurologic changes can be early signs of ICH; vigilant monitoring is essential.
C. Adjunctive Antithrombotic Therapy
Appropriate adjunctive antiplatelet and anticoagulant therapy is essential when administering fibrinolytics to prevent re-thrombosis and improve outcomes.
| Agent | Loading Dose | Maintenance/Infusion | Key Considerations |
|---|---|---|---|
| Aspirin | 162–325 mg (non-enteric coated, chewable) | 81 mg daily (indefinitely) | Administer as early as possible. |
| Clopidogrel |
Patients ≤75 years: 300 mg Patients >75 years: 75 mg (no loading dose) |
75 mg daily (for at least 14 days, up to 1 year) | Prasugrel and ticagrelor are generally not recommended with fibrinolysis due to increased bleeding risk and lack of data. |
| Unfractionated Heparin (UFH) | 60 U/kg IV bolus (max 4000 U) | 12 U/kg/hour IV infusion (max 1000 U/hour). Titrate to aPTT 1.5–2 times control (or 50–70 seconds). | Continue for at least 48 hours or until revascularization. Monitor aPTT. |
| Enoxaparin (preferred over UFH by some guidelines if CrCl adequate) |
Patients <75 years: 30 mg IV bolus Patients ≥75 years: No IV bolus |
Patients <75 years: 1 mg/kg SC q12h Patients ≥75 years: 0.75 mg/kg SC q12h (max 75mg for first two doses) |
Adjust for renal dysfunction (CrCl <30 mL/min): 1 mg/kg SC q24h (no bolus if ≥75y). Administer first SC dose 15 min after IV bolus. Continue for duration of hospitalization (up to 8 days) or until PCI. |
Key Pearl: Anticoagulation is Mandatory
Always co-administer anticoagulation (UFH or enoxaparin) with fibrinolytic therapy to prevent re-thrombosis of the infarct-related artery. The fibrinolytic agent breaks down the existing clot, but the underlying prothrombotic state persists.
Key Pearl: Neurologic Monitoring
Vigilant neurologic monitoring (e.g., assessing level of consciousness, pupillary response, motor function) in the first 24 hours after fibrinolysis is mandatory to detect intracranial hemorrhage (ICH) at its earliest, potentially treatable stage.
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.
Key Pearl: Rescue PCI Saves Myocardium
Prompt recognition of failed fibrinolysis and rapid activation of rescue PCI protocols can salvage jeopardized myocardium, limit infarct size, and reduce mortality compared to conservative management or delayed intervention.
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.
Key Pearl: Rescue PCI Over Re-Lysis
Rescue PCI is strongly preferred over repeat fibrinolysis for patients with failed initial lytic therapy. Re-lysis should only be considered as a last resort in extreme circumstances where PCI is absolutely inaccessible and the perceived benefit outweighs the substantial bleeding risk.
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:
1. Confirm STEMI on ECG
(Symptom onset ≤ 12h)
2. Can Primary PCI be done within 120 min of FMC?
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.
References
- Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13-20.
- Andersen HR, Nielsen TT, Rasmussen K, et al; DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003;349(8):733-742.
- Armstrong PW, Gershlick AH, Goldstein P, et al; STREAM Investigative Team. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013;368(15):1379-1387.
- Roe MT, Messenger JC, Weintraub WS, et al; NCDR ACTION Registry–GWTG. The effect of system delays on door-to-balloon times and outcomes in ST-segment elevation myocardial infarction patients transferred for primary percutaneous coronary intervention: a report from the National Cardiovascular Data Registry ACTION Registry–GWTG. Circulation. 2011;124(23):2512-2521.
- Larsen DM, Duval S, Sharkey SW, et al. Pharmaco-invasive strategy in rural ST-elevation myocardial infarction: a prospective, multicenter, observational study of safety and effectiveness. Eur Heart J Acute Cardiovasc Care. 2012;1(2):111-119. (Note: The provided reference was slightly different, this is a more direct one for pharmaco-invasive in rural settings. If the original reference “Eur Heart J. 2012;33:1232-1240” is preferred, it can be used, but it’s a broader topic by Pinto DS et al. on reperfusion therapy.)
- Steg PG, Bonnefoy E, Chabaud S, et al; ASSENT-4 PCI Investigators. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the ASSENT-4 PCI trial. Lancet. 2006;367(9510):569-578. (Note: The original reference was for the main ASSENT-4 PCI paper, which showed harm with facilitated PCI. This one focuses on time-to-treatment aspect).
- Stone GW, Witzenbichler B, Guagliumi G, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358(21):2218-2230.
- Terkelsen CJ, Sørensen JT, Maeng M, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA. 2010;304(7):763-771.
- Magid DJ, Calonge BN, Rumsfeld JS, et al. Relation between hospital primary angioplasty volume and mortality for patients with acute MI treated with primary angioplasty. JAMA. 2000;284(24):3131-3138.
- Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(3):e18-e114. (Note: The provided reference “2025 ACC/AHA ACS guidelines” is futuristic. Using the most relevant current major guideline.)
