Catheterization-based strategies for management of STEMI date back to a largely overlooked work performed at Jackson Memorial Hospital by Robert Boucek et al. from the University of Miami.³ The work was initiated in 1959. Boucek was aware of the work of Fletcher and Sherry⁴ with a nonspecific fibrinolytic agent. The Miami investigators performed brachial artery cutdowns, placed nonselective catheters, and infused fibrinolysis in the aortic root of patients with ECG evidence of AMI. They published their work and demonstrated ECG evidence of reperfusion (Figure 30.1). Unfortunately, they were not able to perform selective coronary angiography to actually prove that reperfusion had occurred. Ignatios Voudoukis, a clinical fellow and co-author, explained later that this work was so heavily criticized by the leaders of cardiology in America that Boucek abandoned the work.⁵ Had Boucek known of the work Sones⁶ was conducting in Cleveland with selective coronary arteriography, the entire field might have advanced 20 years earlier.

In 1960 when Boucek was pioneering reperfusion, controversy existed over the role of thrombotic occlusion. Pathologic studies found occluding coronary thrombosis in only 50% of autopsy cases. Cardiac enzyme markers of acute MI did not exist, and clinicopathologic differentiation of ST versus non-ST MI had not occurred yet. A major breakthrough came in 1979⁷ when DeWood et al. demonstrated that thrombotic occlusion was extremely prevalent in STEMI, especially if catheterization occurred within 6 hours of symptom onset. Furthermore, total occlusion was much less prevalent among patients catheterized after 6 hours. This suggested that the body’s own fibrinolytic system was reversing some occlusions. With this information, Rentrop⁸ soon thereafter was able to demonstrate that intracoronary occlusions could be successfully opened with intracoronary streptokinase therapy. Khaja⁹ next proved that streptokinase was superior to placebo in opening occluded arteries. This was the first randomized trial in the field of reperfusion. Kennedy et al. finally demonstrated that intracoronary streptokinase improved 1-year survival as compared to placebo.¹⁰ This group also for the first time linked vessel patency, which they termed “complete” perfusion versus “incomplete perfusion” or no perfusion, to 1-year survival.¹¹ These studies in the early 1980s ushered in the modern era of reperfusion therapy.

At the same time that pharmacologic reperfusion was being introduced, a second parallel cardiovascular intervention also was born: coronary angioplasty therapy. Gruentzig et al. first reported in 1977 that elective angioplasty could be performed in the cath lab on conscious, sedated patients.¹² The University of Michigan group was active in the investigation of intracoronary streptokinase, having collaborated with F. Khaja on the original randomized intracoronary streptokinase trial. Based on their experience with streptokinase, they tested it versus coronary angioplasty in the first randomized trial of thrombolytic therapy versus angioplasty (Figure 30.2). This study ushered in the next phase of investigations into reperfusion therapy: mechanical reperfusion.¹³

Even though intracoronary streptokinase was effective and saved lives, some major drawbacks existed. One of those was the risk of major bleeding, not only at the vascular puncture site, but in remote areas as well. Catastrophic intracranial bleeds occurred in 1% to 2% of cases. These cases were demoralizing especially when this happened in young patients. In addition, angiographic studies revealed severe residual lesions in over 70% of patients in whom successful reperfusion occurred, while in 20% to 30% of cases the therapy was unsuccessful. Coronary angioplasty was an attractive alternative: bleeding risk was lower; intracranial bleeds were unlikely; residual lesions were eliminated; and “complete reperfusion,” now labeled TIMI III (Thrombolysis In Myocardial Infarction) flow, occurred in over 90% of cases.¹³ However, these theoretical advantages had to be proven in the context of randomized trials.

Unfortunately, the field of mechanical reperfusion lost momentum between 1985 and 1995. During this time
investigation focused on the combination of intravenous thrombolytic therapy with coronary angioplasty. The combination was tested in three trials¹⁴, ¹⁵, ¹⁶ and proven to be dangerous. Bleeding risk was higher, stroke risk was higher, and mortality was increased as compared to intravenous thrombolytic therapy alone.

Fortunately during this same time balloon angioplasty became further refined, more operators became trained, and large numbers of catheterization laboratories became proficient in elective angioplasty.

This set the stage for comparative trials of coronary angioplasty versus thrombolytic therapy. Groups in Royal Oak, Michigan¹⁷; Rochester, Minnesota¹⁸; and Zwolle, Netherlands¹⁹ conducted clinical trials which in aggregate demonstrated survival advantage and large reductions in risk of death or reinfarction when angioplasty was used without antecedent thrombolytic therapy. Importantly a 10-fold decrease in the risk of intracranial hemorrhage occurred for angioplasty therapy. The decade between 1995 and 2005 saw 20 further randomized trials conducted, which were summarized by Keeley et al. in a meta-analysis published in 2006.²⁰ In aggregate these trials demonstrated a reduction in mortality (7.4% versus 5.5%, P = 0.0003), reduction in risk of stroke (2% versus 1%, P = 0.0004), reduction in reinfarction (6.8% versus 2.5%, P < 0.0001), and reduction in death or reinfarction (14% versus 8.2%, P < 0.0001) for angioplasty therapy. This summary ushered in the current era of investigation. Mechanical reperfusion had been proven to be safer and superior to thrombolytic therapy. Now the results needed to be optimized. Over the last decade research attention has turned from finding a role for intravenous thrombolytic therapy to optimizing the efficacy, safety, and durability of mechanical reperfusion. The last vestige of hope for a role for intravenous thrombolytic therapy was quashed when Ellis et al. published the Finesse trial²¹ and ASSENT investigators published the ASSENT IV trial²² (Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction). Ellis found that neither facilitation of PCI with retaplase plus abciximab nor facilitation with abciximab alone improved outcomes as compared to PCI alone. The ASSENT IV investigators found that a strategy of full-dose tenecteplase preceding PCI was associated with an increased number of adverse events than was PCI alone. Keeley et al. recently analyzed 17 randomized trials of PCI alone versus PCI facilitated with thrombolytic therapy²⁰ (Figure 30.3). This meta-analysis demonstrated that mortality, reinfarction, intracranial bleeds, and total stroke are significantly increased when intravenous thrombolytic therapy is combined with PCI. This combination is harmful and should not be routinely applied.

Angioplasty-mediated reperfusion therapy has enormous efficacy and safety advantages over intravenous thrombolytic therapy. Its major disadvantage, however, is that specialized catheterization facilities and highly trained operators are required to maximize its efficacy. Each hospital has its own obstacles that will take a reperfusion champion to overcome. Bradley²³ has found that the major difference between successful and marginal reperfusion programs is that in successful programs a reperfusion champion is able to get emergency departments, ambulance services, cath labs, and the cardiologist to buy into a collaboration for timely administration of therapy. Rapid and accurate identification of STEMI patients in the emergency department, rapid mobilization of cath lab staff and rapid response by the interventional cardiologist are all prerequisites for an effective program. Key performance indicators include a 90-minute door-to-balloon time for >90% of cases, final TIMI III flow in >90% of cases, nonshock mortality in <4% of cases, and a shock mortality in <50% of cardiogenic shock cases.

To optimize treatment outcomes, a multipronged approach to the pathophysiology of the clotting system, the coronary lesion, and the ischemic myocardium is required. It is now understood that coronary artery inflammation with macrophage infiltration and destabilization of thin-capped fibroatheroma is the inciting event in vulnerable plaque rupture or erosion.³⁶ This leads to a cascade of platelet activation and aggregation as well as tissue factor-mediated thrombin activation. A platelet-rich, fibrin-laced thrombus quickly develops and totally occludes the affected coronary artery. The local environment of the total occlusion is hostile to
intervention. Clot burden of varying extent occurs, platelet activation is intense, and plaque rupture can cause spontaneous dissections. In some patients even a minor erosion of severe underlying occlusion can totally occlude the vessel. For these reasons, there exists a ceiling of reperfusion for pharmacologic approaches, whereby initial patency rates of <70% occur. Reocclusion rates of 10% to 15% result in a substantial incidence of reinfarction. Thus mechanical opening with pharmacological milieu passivation results in larger numbers of patients with initial successful reperfusion and less reocclusion. Clinical trials have in fact corroborated this superiority. Angioplasty-treated patients are less likely to die or develop shock and less likely to develop reinfarction than those treated with thrombolytic therapy.