this is partly because of the high bleeding risk but also because of the more extensive CAD that makes it less likely for fibrinolysis to re-establish perfusion; a half-dose TNK is recommended in patients ≥75 (ESC class IIa).
The mortality benefit is also more striking with the fibrin-specific fibrinolytics (~1% additional mortality reduction).
B. Fibrinolytics: limitations, contraindications, definition of successful response, and definition of TIMI flow (Table 2.1)1,10,20,21
In addition to the classic contraindications, fibrinolysis is contraindicated in a patient with an expected intracranial bleeding risk of >4% (e.g., an elderly [>75] small woman with HTN).20
Consider fibrinolytic therapy successful if: chest pain resolves and initial ST-segment elevation decreases by more than 50% (preferably 70%) at 60–90 minutes after therapy initiation, in the lead showing the worst ST-segment elevation. Also, the occurrence of an accelerated idioventricular rhythm (AIVR) in conjunction with the preceding features is highly specific for reperfusion. In the absence of a response (persistent ischemic symptoms, ST elevation, or both), plan for emergent rescue PCI. It is best to start transferring the patient to a PCI-capable hospital as soon as fibrinolytic therapy is started, so that, if no response is seen at 60 minutes, cardiac catheterization is readily available.
Table 2.1 Limitations and contraindications of fibrinolysis.
| LimitationsPatency of the infarct-related artery (TIMI 2 or 3 flow) is achieved in ~75–80%. TIMI 3 flow is achieved in 55–60% aIntracranial hemorrhage: 0.5–1.5%Major bleeding: ~5%Early recurrent ischemia or MI: 10–20% (within hours or days) Most important absolute contraindicationsAny prior intracranial hemorrhageIschemic stroke <3 months. Ischemic stroke >3 months is a relative contraindicationSevere acute hypertension unresponsive to acute therapyActive bleeding (except menses)Cranial or spinal surgery <2 monthsClosed head or facial trauma <1 month, even without a documented bleed (e.g., recent fall with head trauma) Most important relative contraindicationsIschemic stroke >3 monthsSevere acute HTN (SBP >180 or DBP >110) responsive to acute therapyChronic severe hypertensionRecent major surgery or internal bleed <2–4 weeks. Proliferative retinopathy is not a contraindicationOral anticoagulant therapy, including warfarin with INR >2 (strong relative contraindication) |
a Full patency with <50% residual disease is achieved in only 15–20%.
Figure 2.3 Fibrinolysis cascade and mechanism of action of fibrinolytics. Fibrinolytics activate plasminogen into plasmin, which degrades fibrin. PAI-1, plasminogen activator inhibitor (~ tPA inhibitor); r-PA, reteplase; r-tPA, alteplase; TNK, tenecteplase; tPA, tissue plasminogen activator.
A successful fibrinolysis correlates with TIMI 3 flow on coronary angiography. TIMI grade 0 flow implies the absence of any flow. TIMI 1 flow implies the presence of some flow beyond the obstruction but without full distal perfusion. TIMI 2 flow means that the vessel is fully perfused but the flow is slow compared with a normal artery and/or the contrast material clears more slowly than in a normal artery; TIMI 2 flow is related to a residual mechanical obstruction or to microvascular obstruction from microvascular emboli. TIMI 3 flow means full perfusion of the vessel with normal flow. In fibrinolytic trials, TIMI 3 flow has been shown to be associated with the lowest mortality. TIMI 2 flow is associated with an intermediate mortality, while TIMI 0–1 flow is associated with the highest mortality.22,23 The outcome is improved in patients whose TIMI 2 flow eventually improves to TIMI 3 flow within a few days (this happens two-thirds of the times).24 In a patent artery, TIMI 2 and 3 flow patterns are associated with divergent outcomes and should not be grouped together.
Following PCI and in the absence of any residual mechanical obstruction, the flow may still be TIMI 0–2 flow because of microvascular embolization, spasm, or edema; this is called no reflow, i.e., TIMI 0–2 flow without any residual epicardial stenosis. The term “no reflow” is used only with PCI, not with fibrinolysis.
C. Fibrinolytics: various agents
Fibrinolytics bind to the clot-bound plasminogen and convert it to plasmin, which promotes the degradation of fibrin (Figure 2.3). The old fibrinolytic streptokinase also binds to free plasminogen; thus, in addition to lysing fibrin, it depletes systemic, free fibrinogen and affects systemic coagulation for 12–24 hours.
Alteplase (recombinant tissue plasminogen activator [r-tPA]) binds to the plasminogen entrapped in a thrombus and thus mainly degrades fibrin of a thrombus, rather than systemic fibrinogen (fibrin-specific fibrinolytic). Being more concentrated at the thrombus level, it is a more effective lytic than streptokinase. It generally does not affect the systemic fibrinogen and has a short half-life of only 6 minutes; thus, after the infusion is discontinued and the drug eliminated (~30 min), there is no significant residual effect on systemic coagulation. Therefore, the performance of PCI soon after r-tPA administration is not necessarily associated with a significant increase in bleeding. On the other hand, this short half-life and the lack of residual effect on the systemic coagulation explain the high risk of recurrent thrombosis and the need to start heparin infusion immediately at the end of r-tPA infusion in MI.
In the GUSTO trial of r-tPA vs. streptokinase, r-tPA further reduced mortality by 1% and reduced major bleeding in general, but increased intracranial hemorrhage by 0.25% in comparison with streptokinase.21
Reteplase (r-PA) is a mutation variant of r-tPA. It is slightly less fibrin-specific than r-tPA and has a longer half-life (~15 min), allowing its administration in two boluses rather than an infusion. It has the same mortality benefit and bleeding risk as r-tPA.
Tenecteplase (TNK) is also a mutation variant of r-tPA that is 14 times more fibrin-specific than r-tPA and less likely to be degraded by tPA inhibitors. Thus, TNK is slightly more effective, which explains the higher TIMI 3 flow rate achieved with TNK vs. r-tPA (~65% vs. 60%). It also has a longer half-life than r-tPA, with a duration of effect of ~120 minutes. In the ASSENT-2 trial, TNK was associated with the same overall mortality as r-tPA, but a reduction in major non-cerebral bleeding and a reduction in mortality of patients presenting >4 hours after symptom onset.25
D. Primary PCI is superior to fibrinolytic therapy; importance of time of presentation, door-to-balloon time, and PCI delay
In comparison with fibrinolytic therapy, primary PCI is more effective in re-establishing TIMI 3 flow (95%), and thus reduces 30-day mortality by 2% (7% vs. 9%), recurrent MI by 4% (3% vs. 7%), and stroke by 1%.26–28 However, this superiority of PCI depends on a DTB <120 minutes and PCI-related delay <60 minutes (delay between the expected time of fibrinolytic therapy and the expected time of balloon inflation). In fact, the “90-minute” and “120-minute” cutoffs of DTB have been established in terms of PCI delays beyond which PCI loses its advantage over fibrinolysis (120-min DTB corresponds to equipoise between PCI and fibrinolysis).
DTB is particularly important if the patient presents early, <3 hours after symptom onset, or if the patient is high-risk (anterior
