Systematic Adjunctive Percutaneous Coronary Intervention After Fibrinolysis in the Balloon Angioplasty Era

The initial studies that examined systematic adjunctive PCI after fibrinolysis yielded disappointing results ( Table 2 ). In the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial, 197 patients with STEMI were treated with tissue plasminogen activator. These patients then underwent coronary angiography and were found to have patent, although significantly stenotic, lesions. They were subsequently randomized to receive either immediate angioplasty after fibrinolysis or deferred elective angioplasty 5 to 10 days later. There was no mortality benefit at 7 days with immediate angioplasty, and in fact, there was an absolute increase in death of 3% with immediate angioplasty (p = 0.37). Simoons et al found similar results in a European study of 367 patients with STEMI treated with tissue plasminogen activator, also randomized to either immediate angioplasty or to delayed angioplasty performed just before hospital discharge. The study was terminated early by the data monitoring review board before enrollment of the planned 400 subjects because of higher rates of recurrent ischemia (17% vs 3%) and mortality (7% vs 3%) in the group receiving immediate angioplasty. Later studies demonstrated more neutral effects of angioplasty after fibrinolysis. The Thrombolysis In Myocardial Infarction (TIMI)–IIa study examined the effects of immediate angioplasty compared to delayed angioplasty in STEMI patients treated with fibrinolysis and found no benefit of immediate angioplasty either in the predischarge left ventricular ejection fraction or in mortality at 1 year. Similarly, the Should We Intervene Following Thrombolysis? (SWIFT) study found no difference in mortality between patients randomized to receive early angiography <24 hours after fibrinolysis with anistreplase or to receive only conservative treatment after fibrinolysis (p = 0.60).

There are several hypotheses as to why PCI soon after fibrinolysis for STEMI yielded such unfavorable results in these trials. Autopsy studies in patients treated in this manner demonstrated reaccumulation of thrombus material in the infarct-related artery in conjunction with evidence of endothelial trauma and subintimal bleeding. On the basis of these results, it was hypothesized that balloon angioplasty alone resulted in endothelial trauma, with resulting release of prothrombotic substances, thereby leading to reocclusion of the infarct-related artery. Furthermore, when these trials were conducted, antiplatelet and anticoagulant agent administration was suboptimal: full-strength aspirin was not given immediately to all patients, dosing of heparin was not weight based or guided by activated clotting time or partial thromboplastin time values, and thienopyridines, low-molecular-weight heparins, direct thrombin inhibitors, and glycoprotein IIb/IIIa inhibitors were not available. It is thus unsurprising that balloon angioplasty, which could induce a transient prothrombotic state in an environment with a clotting system that was unsuppressed, might be associated with increased rates of reocclusion of an artery and ultimately increased morbidity and mortality. On the basis of the results of these early trials, the concept of fibrinolysis followed by immediate adjunctive PCI fell out of favor for several years. However, during this time, many advances were made in mechanical revascularization, with the advent of stent implantation, as well as in adjunctive pharmacologic therapy, with the introduction of thienopyridines and glycoprotein IIb/IIIa inhibitors. With these new technological developments, researchers decided to revisit the idea of fibrinolysis followed by systematic adjunctive PCI.

Systematic Adjunctive Percutaneous Coronary Intervention After Fibrinolysis in the Stent Era

In reevaluating the strategy of systematic adjunctive PCI after fibrinolysis in the modern era, several variables need to be taken into account. First and foremost, the timing of when the PCI is performed in relation to the fibrinolysis is critical. The combination of fibrinolysis followed by immediate PCI (i.e., generally within 2 hours), a concept commonly known as facilitated PCI or pharmacoinvasive PCI, as a treatment strategy for STEMI has been examined in several trials. Initial trials were at best hopeful, while subsequent studies established a generally unfavorable risk-to-benefit ratio.

The Bavarian Reperfusion Alternatives Evaluation (BRAVE) study randomized 253 patients to receive either the combination of half-dose reteplase and abciximab or abciximab alone upon presentation with STEMI. Patients were all subsequently taken to PCI within 2 hours. There was no difference in infarct size as measured with single photon-emission computed tomography between the 2 arms of the study. A year later, the Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL-AMI) trial demonstrated more promising results. In this study, 70 patients with STEMI were randomized to either receive tenecteplase alone or to receive tenecteplase followed by PCI <3 hours after randomization (the mean time from fibrinolysis to first balloon inflation was 96 minutes). The primary end point (a composite of death, reinfarction, recurrent unstable ischemia, or stroke at 6 months) occurred less often in the group receiving facilitated PCI (11.6% vs 24.4% with tenecteplase alone, p = 0.04). Rates of major bleeding were similar between the 2 groups (8.1% in the facilitated PCI group vs 7.1%, p = 1.00).

Subsequent trials raised questions regarding the clinical safety and efficacy of facilitated PCI. In the prematurely terminated Addressing the Value of Facilitated Angioplasty After Combination Therapy or Eptifibatide Monotherapy in Acute Myocardial Infarction (ADVANCE-MI) trial, 148 patients with STEMI were randomized to either receive half-dose tenecteplase in combination with eptifibatide or to receive eptifibatide alone before transfer for immediate PCI (the median time from randomization to angiography was 1.4 hours). Although the incidence of TIMI grade 0 flow (occluded infarct-related artery) was substantially lower in the group receiving combination therapy (33% vs 61% in the group receiving eptifibatide alone, p = 0.001), there was a trend toward an increased rate of the primary end point (death or new heart failure) at 30 days (10% vs 3% in the group receiving eptifibatide alone, odds ratio 0.24, 95% confidence interval 0.05 to 1.05, p = 0.09), and bleeding complications were twofold higher in patients randomized to combination facilitated therapy.

More definitive evidence of the risks of immediate PCI after fibrinolysis was provided by the Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention (ASSENT-4 PCI) trial. This trial was designed to assign 4,000 patients presenting with STEMI to either receive full-dose tenecteplase followed by immediate PCI (the median time from fibrinolysis to PCI was 1.7 hours) or to PCI alone. The trial was stopped early by the data safety monitoring board after the enrollment of only 1,667 patients because in-hospital mortality was found to be significantly increased in the group of patients receiving tenecteplase. The primary end point (death, congestive heart failure, or cardiogenic shock at 90 days) was also found to be substantially higher in the group receiving tenecteplase (19% vs 13% in patients receiving PCI alone, p = 0.0045). Tenecteplase was associated with an increased incidence of intracranial hemorrhage (1% vs 0% in patients receiving PCI alone, p = 0.0037) as well as an increase in TIMI minor bleeding (25.3% vs 19% in patients receiving PCI alone, p = 0.0021), although no difference in TIMI major bleeding was noted.

Subsequently, the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE) trial evaluated 2,452 STEMI patients who were assigned to receive abciximab plus half-dose reteplase followed by immediate PCI (the median time from fibrinolysis to PCI was 1.6 hours), abciximab alone followed by immediate PCI, or primary PCI. There was no difference in the composite end point (death from all causes, ventricular fibrillation within 48 hours, congestive heart failure, or cardiogenic shock) among the 3 groups (9.8% for abciximab and reteplase vs 10.5% for abciximab alone vs 10.7% for primary PCI, p = 0.55). When the individual components of the composite end point were examined, there were no significant differences among the groups for any of the secondary end points. In particular, 90-day mortality rates among the 3 groups were not significantly different (5.2% for abciximab and reteplase vs 5.5% for abciximab alone vs 4.5% for primary PCI, p = 0.49). Furthermore, there was a significant increase in TIMI major and minor bleeding in the group receiving combination therapy (14.5% vs 6.9% for primary PCI, p <0.001) Taken together, these results suggest that routine PCI within the 2 hours after the administration of a fibrinolytic drug does not lead to favorable clinical outcomes and is associated with increased bleeding.

Systematic Adjunctive Percutaneous Coronary Intervention After Fibrinolysis in the Stent Era

In reevaluating the strategy of systematic adjunctive PCI after fibrinolysis in the modern era, several variables need to be taken into account. First and foremost, the timing of when the PCI is performed in relation to the fibrinolysis is critical. The combination of fibrinolysis followed by immediate PCI (i.e., generally within 2 hours), a concept commonly known as facilitated PCI or pharmacoinvasive PCI, as a treatment strategy for STEMI has been examined in several trials. Initial trials were at best hopeful, while subsequent studies established a generally unfavorable risk-to-benefit ratio.

The Bavarian Reperfusion Alternatives Evaluation (BRAVE) study randomized 253 patients to receive either the combination of half-dose reteplase and abciximab or abciximab alone upon presentation with STEMI. Patients were all subsequently taken to PCI within 2 hours. There was no difference in infarct size as measured with single photon-emission computed tomography between the 2 arms of the study. A year later, the Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL-AMI) trial demonstrated more promising results. In this study, 70 patients with STEMI were randomized to either receive tenecteplase alone or to receive tenecteplase followed by PCI <3 hours after randomization (the mean time from fibrinolysis to first balloon inflation was 96 minutes). The primary end point (a composite of death, reinfarction, recurrent unstable ischemia, or stroke at 6 months) occurred less often in the group receiving facilitated PCI (11.6% vs 24.4% with tenecteplase alone, p = 0.04). Rates of major bleeding were similar between the 2 groups (8.1% in the facilitated PCI group vs 7.1%, p = 1.00).

Subsequent trials raised questions regarding the clinical safety and efficacy of facilitated PCI. In the prematurely terminated Addressing the Value of Facilitated Angioplasty After Combination Therapy or Eptifibatide Monotherapy in Acute Myocardial Infarction (ADVANCE-MI) trial, 148 patients with STEMI were randomized to either receive half-dose tenecteplase in combination with eptifibatide or to receive eptifibatide alone before transfer for immediate PCI (the median time from randomization to angiography was 1.4 hours). Although the incidence of TIMI grade 0 flow (occluded infarct-related artery) was substantially lower in the group receiving combination therapy (33% vs 61% in the group receiving eptifibatide alone, p = 0.001), there was a trend toward an increased rate of the primary end point (death or new heart failure) at 30 days (10% vs 3% in the group receiving eptifibatide alone, odds ratio 0.24, 95% confidence interval 0.05 to 1.05, p = 0.09), and bleeding complications were twofold higher in patients randomized to combination facilitated therapy.

More definitive evidence of the risks of immediate PCI after fibrinolysis was provided by the Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention (ASSENT-4 PCI) trial. This trial was designed to assign 4,000 patients presenting with STEMI to either receive full-dose tenecteplase followed by immediate PCI (the median time from fibrinolysis to PCI was 1.7 hours) or to PCI alone. The trial was stopped early by the data safety monitoring board after the enrollment of only 1,667 patients because in-hospital mortality was found to be significantly increased in the group of patients receiving tenecteplase. The primary end point (death, congestive heart failure, or cardiogenic shock at 90 days) was also found to be substantially higher in the group receiving tenecteplase (19% vs 13% in patients receiving PCI alone, p = 0.0045). Tenecteplase was associated with an increased incidence of intracranial hemorrhage (1% vs 0% in patients receiving PCI alone, p = 0.0037) as well as an increase in TIMI minor bleeding (25.3% vs 19% in patients receiving PCI alone, p = 0.0021), although no difference in TIMI major bleeding was noted.

Subsequently, the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE) trial evaluated 2,452 STEMI patients who were assigned to receive abciximab plus half-dose reteplase followed by immediate PCI (the median time from fibrinolysis to PCI was 1.6 hours), abciximab alone followed by immediate PCI, or primary PCI. There was no difference in the composite end point (death from all causes, ventricular fibrillation within 48 hours, congestive heart failure, or cardiogenic shock) among the 3 groups (9.8% for abciximab and reteplase vs 10.5% for abciximab alone vs 10.7% for primary PCI, p = 0.55). When the individual components of the composite end point were examined, there were no significant differences among the groups for any of the secondary end points. In particular, 90-day mortality rates among the 3 groups were not significantly different (5.2% for abciximab and reteplase vs 5.5% for abciximab alone vs 4.5% for primary PCI, p = 0.49). Furthermore, there was a significant increase in TIMI major and minor bleeding in the group receiving combination therapy (14.5% vs 6.9% for primary PCI, p <0.001) Taken together, these results suggest that routine PCI within the 2 hours after the administration of a fibrinolytic drug does not lead to favorable clinical outcomes and is associated with increased bleeding.