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failure and re‐infarction rates, but has no overall effect on mortality. The MERLIN trial [98], randomized 307 STEMI patients with failed fibrinolysis, as assessed by ECG findings, to emergency coronary angiography or conservative treatment. No difference in 30 day mortality was found (9.8% in the rescue group vs 11% in the conservative group, p = 0.7). However, in the secondary analysis, re‐infarction and clinical heart failure were less common in the rescue group, and there was a decreased need for subsequent revascularization. The REACT trial [99], randomized 427 patients with STEMI who underwent failed thrombolysis by ECG criteria to either conservative treatment, repeated thrombolysis, or rescue PCI (thus three arms in total). The primary endpoint was death, reinfarction, stroke or severe heart failure within six months. The rate of event free survival was 84.6% in the rescue PCI group, compared to 70.1% in the conservative therapy group, and 68.7% in the repeat thrombolysis group (p = 0.004).

      In terms of timing, ESC and ACCF/AHA guidelines recommend proceeding to rescue PCI when fibrinolysis has failed to achieve < 50% ST‐segment resolution at 60–90 mins, or at any time in the presence of worsening ischemia, or hemodynamic or electrical instability [3,4].

      It is important to distinguish facilitated and rescue PCI, and their respective differing evidence bases. Formally, rescue PCI is defined as an intervention performed on an infarct‐related coronary artery after unsuccessful fibrinolysis. Note that the ACCF/AHA guidelines specifically include a recommendation not to proceed to angiogram in the first 1–3 hours following successful fibrinolytic therapy (facilitated PCI). However, this is based on trials performed at a time when radial access was not available, and the recommendation is largely driven due to an increase in bleeding complications [4]. A meta‐analysis incorporating more recent trials performed during the period 2000–2010 revealed no increased risk of bleeding associated with an immediate or early invasive strategy [100]. A further patient level analysis in 2015 revealed that early angiography (<2 h) after fibrinolysis was not associated with increased bleeding, or indeed, an increased risk of 30‐day death or reinfarction [101].

      Fibrinolytic agents

      It should be borne in mind that due to the pharmacological mechanism of action of fibrinolytics i.e. penetration of the thrombus and fracturing the links of the fibrin strands, early interventional is especially critical, and certainly after 12 h, fibrinolysis is of very limited benefit, as it can in most cases no longer effectively penetrate the thrombus [102].

A summary of currently available fibrinolytic agents available worldwide is provided in Table 13.2. The advantages of fibrin‐specific lytics over t‐PA in terms of mortality are small but unequivocal [103], and just as important is their relative ease of administration, e.g. single‐bolus weight‐adjusted tenecteplase [104]. ESC and AHA Guidelines recommend use of a fibrin specific agent [3]. Adjunctive therapy with aspirin [105], clopidogrel [106], and parental anti‐coagulation [107–109] has been shown to be safe and have additive benefits, whereas the adjunct of GP IIb/IIIa inhibitors shows no additional benefit with full dose fibrinolysis, principally due to the much increased risk of hemorrhage [110–112]. Specifically, a retrospective analysis of 548 patients who presented or were referred to the Erasmus Medical Centre, Rotterdam for rescue therapy following failed thrombolysis noted that rates of major hemorrhage with the combination of thrombolysis and GP IIb/IIIa inhibitors were as high as 31% (compared to 11% in rescue strategies that did not use GP IIb/IIIa inhibitors, p = 0.004) [113].

Table 13.2 Fibrinolytic agents in STEMI [4].

Fibrinolytic Agent	Dose	Fibrin specificity	Antigenic
Fibrin specific:
Tenecteplase (TNK‐tPA)	Single IV weight‐based bolus	++++	No
Reteplase (rPA)	10 U + 10 U IV boluses given 30 mins apart	++	No
Alteplase (tPA)	90‐min weight based infusion	++	No
Non‐fibrin specific
Streptokinase	1.5 million units IV given over 30–60 mins	No	Yes

      Where available, pre‐hospital thrombolysis can significantly reduce mortality [114]. The STREAM trial [115] looked at 1892 patients with STEMI who presented within 3 h of symptom onset and who were unable to undergo primary PCI within 1 h, and randomized them to either primary PCI or prehospital fibrinolytic therapy with bolus tenecteplase. Emergency coronary angiography was performed if fibrinolysis failed, otherwise angiography was performed 6 to 24 h after randomization. The primary endpoint was a composite of death, shock, congestive heart failure, or reinfarction up to 30 days. There was no significant difference in the primary endpoint between both groups (relative risk for the fibrinolysis group 0.86, 95% CI 0.68‐1.09; p = 0.21) but more intracranial hemorrhage occurred in the fibrinolysis group (1.0% vs 0.2%; p = 0.04) to the point where the protocol was amended to half‐dose tenecteplase for patients aged ≥ 75 y.

      A meta‐analysis of randomized controlled trials comparing fibrinolysis in the early prehospital setting vs primary PCI revealed that fibrinolysis was consistently associated with similar rates of short term (RR 0.94, 95% CI 0.67–1.31) and 1 year mortality (RR 1.01, 95% CI 0.75–1.34) albeit with an increased risk of hemorrhagic stroke (RR 4.37, 95% CI 1.25–15.26) [117].

      Nonetheless, when expedient transfer to a primary PCI center is possible for patients who initially present to a non‐PCI center, then transfer for PCI has been shown in recent real‐world registries to have a survival advantage over fibrinolysis. In the Catalonia “CODI IAM” network registry of all‐comers (with STEMI) to a non‐capable PCI center with symptom onset to first medical contact <120 min, reperfusion with fibrinolysis rather than transfer to for primary PCI was found to be an independent 30‐day mortality predictive factor (odds ratio 1.91; 95% CI 1.01–3.50, p = 0.04) [119].

      With the advent of more potent P2Y12 inhibitors, the TREAT trial [120], assessed the efficacy of ticagrelor when compared to clopidogrel in STEMI patients treated with fibrinolytic therapy. It enrolled 3799 patients (age <75 years) and randomized them to either ticagrelor or clopidogrel. Decisions as regards the choice of fibrinolytic agent were left to local availability and the discretion of the treating physician. In terms of a primary endpoint of cardiovascular mortality, MI, or stroke, no significant difference was found between treatment groups (HR for the ticagrelor group 0.93; 95% CI 0.73–1.18; p = 0.53). The rates of major, fatal, and intracranial bleeding were similar in both groups suggesting no incremental advantage of ticagrelor over clopidogrel.

Conclusion

      Taken together, the above trials have led to a significant advance in the care of the STEMI patient. Challenges remain in integrating the results of carefully run and well‐resourced clinical trials into our everyday clinical practice, particularly in terms of ensuring as many patients as possible have access to timely primary PCI. In terms of the technical elements of primary PCI, research continues on the most appropriate means of minimizing distal embolization and ensuring the coronary microcirculation remains well perfused peri‐ and post‐procedure, and on the design of the most appropriate

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