Pharmacological and Mechanical Revascularization Strategies in<br />
STEMI: Integration of the Two Approaches

Acute ST-segment elevation myocardial infarction (STEMI) usually results from atherothrombosis, a disease process involving the rupture of an atherosclerotic plaque with subsequent thrombosis and coronary arterial occlusion at the site of the plaque.¹ Although this condition is associated with significant cardiac morbidity and mortality, the risks of myocardial damage, left ventricular dysfunction and death are reduced if prompt and sustained reperfusion of the infarct-related artery can be achieved.^2,3
Reperfusion can be attempted pharmacologically using systemic intravenous fibrinolytic therapy, or mechanically, using primary (“direct”) percutaneous coronary intervention (PPCI). Early attempts to combine these two strategies resulted in poor patient outcomes^4–6 and, as a result, the two techniques have traditionally been regarded as mutually exclusive, except in cases where fibrinolytic therapy fails and “rescue” PCI is attempted as a life-saving procedure. Emergency coronary artery bypass graft (CABG) surgery is necessary in only a small minority of patients with STEMI.⁷
Fibrinolytic agents reduce mortality from STEMI. Such benefits are maintained over a 10-year follow-up period as illustrated in two large, randomized, placebo-controlled trials involving more than 28,000 patients.^8,9 After 10 years, fibrinolytic therapy with streptokinase was associated with absolute survival benefits of 19–23 fewer deaths per 1000 patients treated, similar to the benefits observed within the first year of treatment. Recent data, however, suggest improved patient outcomes with PPCI versus fibrinolysis. In a quantitative review of 19 randomized trials involving 6315 patients that compared primary angioplasty with intravenous fibrinolytic therapy, Timmer and colleagues concluded that PPCI was associated with a significant improvement in all major short-term outcomes including mortality at 30 days, nonfatal reinfarction, total incidence of stroke and hemorrhagic stroke.¹⁰ The initial benefit of PPCI appears sustained for at least 6 to 18 months.^11,12
These data suggest that, in appropriate patients, PPCI is the preferred reperfusion strategy. In practical terms, however, PPCI is not available in many facilities and may not be available round-the-clock even in specialized centers. While acknowledging that particular patients may be better suited to either pharmacological or mechanical reperfusion, the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of patients with STEMI emphasize that the reperfusion method is probably less important than its speed of delivery and time to reperfusion.³
The aim of this article is to relate the pathogenic mechanisms of acute atherothrombosis to the outcomes of reperfusion strategies that have been evaluated in major clinical trials involving patients with STEMI.

Time-to-Treatment

The interval between symptom onset and initiation of fibrinolytic therapy is inversely related to treatment success.^2,13,14 Using data from 50,246 patients with acute myocardial infarction (MI), Boersma et al observed an inverse relationship between time-to-treatment and mortality, with the maximum reduction among patients treated within an hour of symptom onset (Figure 1).² The proportional reduction in short-term mortality was 44% in those treated within 2 hours of symptom onset and 20% in those treated after this time.² A similar relationship was seen in a more recent study by Kalla et al, which showed an inhospital mortality rate of 5.1% among patients treated with fibrinolytic therapy within the first 2 hours of STEMI onset, increasing to 28.6% in patients not receiving therapy until 6–12 hours after the onset of symptoms.¹⁴

Time-to-treatment is also a critical determinant of outcome in STEMI patients treated with PPCI. Increases in both door-to-balloon time and symptom onset-to-balloon time are associated with increased patient mortality (Table 1).^15–21 Data from 4278 patients undergoing interhospital transfer for PPCI enrolled in the National Registry of Myocardial Infarction (NRMI) showed a median door-toballoon time of 180 minutes, with only 4.2% of patients receiving PCI within 90 minutes as recommended by national quality guidelines.⁷ Adjustments to hospital and prehospital protocols may produce incremental improvements in door-to-balloon time, but the reductions in delay are likely to be relatively small. In contrast, substantial reductions in the delay between symptom onset and initiation of pharmacological reperfusion can be achieved by prehospital administration of fibrinolytic agents. Prehospital administration of fibrinolytics for facilitated PCI appears to be safe and effective if administered by experienced emergency physicians.²² This strategy, which has been shown to reduce treatment delay by 30–140 minutes,^14,23–27 has been associated with significant reductions in short- and longterm mortality^23,28–30 and with a three-fold increase in abortion of MI.²⁵ Even in areas where prehospital administration of fibrinolytic agents is not adopted, the complexities of preparing patients for mechanical intervention dictate that early initiation of fibrinolytic therapy will usually be a more realistic goal than early commencement of PCI.^3,31 For these reasons, it is important to recognize barriers that may interfere with prompt delivery of early fibrinolytic therapy and remedy delays with coordination among hospital-based and community-based emergency physicians and personnel.³² The Which Early ST-elevation myocardial infarction Therapy (WEST) pilot study showed that early initiation of tenecteplase with rescue PCI within ≤ 24 hours as needed for reperfusion failure was as effective as PPCI in preventing death and subsequent cardiovascular events following STEMI.³³ The current ACC/AHA guidelines for the management of patients with STEMI recommend a door-toneedle time for initiation of fibrinolytic therapy of < 30 minutes or a door-to-balloon time of < 90 minutes.³ If door-to-balloon time is delayed by more than 62 minutes compared with door-to-needle time, the mortality advantage of PPCI begins to dissipate.⁷ Valuable time savings can be achieved with prehospital initiation of fibrinolytic therapy.²⁷ Administration of reteplase by emergency medical services has been shown to save approximately 30 minutes in the door-to-drug time relative to controls who were administered inhospital fibrinolytics (p < 0.0001).

An Integrated Approach to Reperfusion Therapy
Rationale. For patients with STEMI, the ultimate goal of treatment is to restore perfusion to the ischemic myocardium, which results primarily from prompt restoration of flow through the infarct-related artery. However, even if the occluded epicardial artery is rendered patent by catheterbased treatment, perfusion of the infarcted myocardium may continue to be compromised by a combination of downstream embolization of platelet aggregate emboli, microvascular damage and reperfusion injury.³
Microvascular damage results from embolization of platelet microemboli and thrombi that may induce occlusion in the microvasculature either directly or via the release of vasoactive substances. Reperfusion injury consists of the accumulation of oxygen-derived free-radicals, neutrophil accumulation, cellular edema, apoptosis and intracellular calcium overload upon brisk reperfusion, leading to increased tissue damage and capillary occlusion.^3,34 These pathological processes can compromise the outcome even for patients in whom the infarct-related artery has been successfully reperfused. For example, in a magnetic resonance imaging-based study of 44 patients who had survived STEMI, Wu and colleagues found that increased microvascular obstruction was a strong predictor of future cardiovascular risk,³⁵ independent of infarct size. The ideal reperfusion strategy should thus combine flow restoration in the involved epicardial artery with a cell salvage agent that would minimize microvascular damage and prevent further extension of the infarct.³

Fibrinolytic and Antiplatelet Therapy

Aspirin. Coronary thrombi consist of a central core of aggregated platelet surrounded by a fibrin-thrombin mesh. Fibrinspecific agents expose additional thrombin as they “peel” through the clot surface, hence promoting further thrombin formation and platelet aggregation.36 Platelet-rich thrombi have high binding affinity for plasma α2-antiplasmin, the main inhibitor of plasmin, and hence are more resistant to further fibrinolysis. This effect is further compounded by the release of plasminogen activator inhibitor-1 (PAI-1), a potent endogenous inhibitor of fibrinolysis released by platelet α-granules. Therein lies part of the biological rationale for combining fibrinolytic agents with antiplatelet agents.³⁶

The success of combining antiplatelet agents with fibrinolytic therapy has been established for some time. For example, in the Second International Study of Infarct Survival (ISIS-2), patients randomized to treatment with aspirin (160 mg/day for 1 month) with fibrinolysis with streptokinase (single 1.5 MU infusion) showed significant improvements in both short- and longterm outcomes compared with patients randomized to either treatment alone (Figures 2A and B).³⁷ Interestingly, aspirin yielded the same mortality benefit as streptokinase, but the two had an additive effect when combined.³⁷ The use of aspirin as the only antiplatelet agent is suboptimal, however, because cyclo-oxygenase inhibition alone does not prevent platelet activation via the thromboxane A2-independent pathways of platelet activation. There is therefore a rationale for combining other antiplatelet agents with aspirin in fibrinolytic- treated patients.
Platelet Glycoprotein IIb/IIIa Antagonists. Initial pilot studies of antithrombotics plus glycoprotein IIb/IIIa inhibitors (GPIs) were encouraging. The results of the Strategies for Patency Enhancement in the Emergency Department (SPEED), the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM), and the Global Use of Strategies To Open coronary arteries (GUSTO) V studies had demonstrated the success of administering a GPI, in addition to aspirin, in combination with reteplase, streptokinase or tissue-plasminogen activator (t-PA) in patients with acute STEMI.^38–41 To date, however, the short-term benefits of combination fibrinolytic/GPI/aspirin therapy have not been clearly associated with a decrease in mortality during follow-up periods of between 30 days and 1 year.^38–40 Furthermore, the addition of a GPI to aspirin plus fibrinolytic therapy may increase the risk of bleeding events.^38–41 Unfortunately, these promising early trials have been contradicted by additional studies. More recent studies have shown that combining fibrinolytics with GPIs is no more effective than GPIs alone in patients referred for PPCI.^42,43 In the Bavarian Reperfusion Alternative Evaluation (BRAVE) trial, treatment with reteplase in combination with abciximab did not reduce infarct size, the primary endpoint, as compared to abciximab alone in patients referred for PCI.⁴³ The Addressing the Value of Facilitated Angioplasty After Combination Therapy or Epti fibatide Monotherapy in Acute Myocardial Infarction (ADVANCE MI) trial showed similar trends.⁴² In this study, compared with patients receiving eptifibatide alone, those treated with eptifibatide plus 50% of standard-dose tenecteplase had a higher incidence of death and new/worsening severe heart failure (primary endpoint) at 30 days both in the “as-treated” (3% vs. 10%) and the “as-randomized” (1% vs. 11%) groups, although definitive conclusions cannot be made due to the small sample size. Interestingly, artery viability and myocardial tissue viability were improved with eptifibatide plus tenecteplase on pre-PCI angiography; however, bleeding complications were two-fold higher in this treatment group. In fact, recent meta-analyses have confirmed that that there is no significant improvement in clinical efficacy of GPI plus fibrinolytic therapy when compared to GPI therapy alone,^44,45 and strongly recommend against the use of GPI and fibrinolytics.
Results from the Controlled Abciximab and Device Investigation to Lower Later Angioplasty Complications (CADILLAC) study showed that stenting with or without abciximab therapy was more effective than PCI with or without abciximab following an acute myocardial infarction.⁴⁶ At 6 months, the primary endpoint, a composite of death, reinfarction, disabling stroke or revascularization of the target vessel, had occurred in 11.5% of patients after stenting, and 10.2% after stenting and abciximab compared with 20.0% after PCI, and 16.5% after PCI and abciximab (p < 0.001).
Thienopyridines. An alternative mechanism by which platelet aggregation can be reduced is via blockade of the platelet adenosine diphosphate (ADP) receptor. This mechanism is exploited by thienopyridines such as ticlopidine and clopidogrel, with the latter agent showing promise as an adjunctive treatment in the management of STEMI. In the recent Clopidogrel as Adjunctive Reperfusion Therapy — Thrombolysis In Myocardial Infarction (CLARITY TIMI) 28 trial, addition of clopidogrel to standard fibrinolytic therapy (fibrinolytic, aspirin, ± heparin or low-molecular-weight heparin) reduced ischemic complications and improved arterial patency following STEMI.⁴⁷ In this randomized, double-blind, placebo-controlled study, which enrolled a total of 3491 patients, clopidogrel (300 mg loading dose followed by 75 mg once daily) was associated with a 36% odds reduction (95% CI 24, 47%; p < 0.001) compared with placebo for the primary endpoint of occluded infarct-related arteries on angiography, or death or MI recurrence before angiography. Clopidogrel treatment also led to a 20% reduction (11.6 vs. 14.1%; p = 0.03) in major cardiovascular events (cardiovascular death, recurrent MI or recurrent ischemia requiring urgent revascularization) within 30 days of presentation (Figure 3). There was no significant increase in the incidence of TIMI-defined major bleeding in the clopidogrel group (1.3% vs. 1.1% for placebo; p = 0.64), and the rates of minor bleeding and intracranial hemorrhage were also similar. This contrasts with the increased incidence of bleeding events observed with the addition of a GPI to aspirin plus fibrinolytic therapy.^38–41

A substudy, PCI-CLARITY, showed that clopidogrel was also effective in reducing major cardiovascular events, and did not increase the risk of bleeding in the 1,863 patients who underwent PCI after fibrinolysis.⁴⁸ Of note, these were elective PCI cases, not rescue or facilitated PCI.
Similarly, positive results were reported when clopidogrel was added to aspirin in the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study ( COMMIT/ CCS- 2).^49,50 This placebo-controlled trial evaluated the effects of daily doses of clopidogrel 75 mg (there was no loading dose in this study) in 45,852 patients in China with suspected MI who were receiving aspirin 162 mg/day. Half the patients received fibrinolytic therapy (this was not randomized), but PPCI was an exclusion criteria. After a mean follow-up period of 16 days, patients receiving clopidogrel showed a 9% reduction in the relative risk of the composite of death, reinfarction or stroke, compared with placebo (9.2 vs. 10.1%; p = 0.002), and a 7% reduction in the coprimary endpoint of all-cause mortality (7.5 vs. 8.1%; p = 0.03). There was no significant increase in the combined risk of fatal, transfused or intracranial bleeding in the clopidogrel group, including among those patients who received fibrinolytic therapy. The combination of clopidogrel and aspirin thus appears to represent an effective and safe adjunctive therapy in STEMI patients undergoing fibrinolytic treatment. While the CLARITY trial excluded patients over the age of 75 years, no such age limit was specified for COMMIT, and 26% of study participants were 70 years of age or older. This gives us some indirect assurance that clopidogrel (at least without a loading dose) is safe in elderly STEMI patients.

Fibrinolytic and Antithrombin/Anticoagulant Therapy
As discussed above, fibrinolytic therapy results paradoxically in increased thrombin levels and development of a procoagulant state. It is therefore essential that patients receiving fibrinolytics (± antiplatelet therapy) also receive optimal antithrombin/anticoagulant therapy. The efficacy of such treatment combinations has been investigated in several major clinical trials. For example, the International Study Group randomized 20,891 patients who had received fibrinolytic treatment to a regimen that either did or did not include heparin.⁵¹ Most patients also received aspirin. A similar comparison was performed by the Third International Study of Infarct Survival (ISIS-3) Collaborative Group, which randomized half of a cohort of 41,299 fibrinolytic- and aspirintreated patients to heparin treatment.⁵² In both trials, the heparin-treated patients showed nonsignificant reductions in the short-term risk of death and myocardial reinfarction. When data from both trials were combined, the effect of heparin on mortality was significant, but only during the period of actual heparin treatment;⁵² after a period of 6 months, mortality rates were similar in the heparin and nonheparin groups.⁵³ It should also be noted that major bleeding complications were more frequent in the three-drug combination group in both trials.^51,52
One alternative antithrombotic agent for STEMI patients undergoing fibrinolysis is the low-molecular-weight heparin, enoxaparin. The ASSENT-3 trial compared the efficacy and safety of tenecteplase plus enoxaparin with tenecteplase plus unfractionated heparin in 6,095 patients with recent acute MI.⁵⁴ The enoxaparin-treated group showed a significant reduction in the risk of cardiovascular events (30-day mortality, inhospital reinfarction or refractory ischemia).⁵⁴ A third treatment group in this trial received half-dose tenecteplase, low-dose unfractionated heparin, and the platelet glycoprotein IIb/IIIa receptor inhibitor, abciximab. The overall efficacy and efficacy plus safety outcomes of this group were almost identical to those of the tenecteplase plus enoxaparin group.⁵⁴ However, STresolution was more rapid and complete with tenecteplase plus abciximab and reinfarction was less frequent among patients with ≥ 70% ST resolution who were receiving tenecteplase plus abciximab or tenecteplase plus enoxaparin, than those treated with tenecteplase with unfractionated heparin.⁵⁵ The incidences of thrombocytopenia, bleeding episodes (total, major and minor), and blood transfusions were higher in the abciximab group than the enoxaparin group (total bleeding episodes: enoxaparin, 25.6%; abciximab, 39.7%). The use of antiplatelet and anticoagulant agents was essentially equal between treatment groups, with 95–97% of patients receiving aspirin, 28–32% receiving a thienopyridine and 4.3–5.2% receiving oral anticoagulants.⁵⁴
The Acute Myocardial Infarction — streptokinase (AMISK) study demonstrated that better angiographic patency, improved ST-segment resolution, and lower rates of reocclusion can be achieved with enoxaparin compared with unfractionated heparin as an adjunctive agent to streptokinase.⁴ In this randomized noncomparator-controlled study, the addition of enoxaparin to streptokinase led to fewer clinical events (death or recurrent MI or angina), but was also associated with a nonsignificant increase in major bleeding rates (4.8% vs. 2.5% for placebo with streptokinase; p = 0.2).
Benefits were also observed for enoxaparin relative to unfractionated heparin in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction (ExTRACT)- TIMI 25 trial, which enrolled more than 20,000 STEMI patients undergoing fibrinolysis.⁵⁶ Compared with unfractionated heparin, enoxaparin significantly reduced the relative risk of the primary endpoint of death or nonfatal recurrent myocardial infarction at 30 days (-17%; p < 0.001). At the same time, enoxaparin was associated with an increased incidence of major bleeding episodes relative to unfractionated heparin (2.1 vs. 1.4% of patients; p < 0.001).
A PCI substudy showed similar findings among the 4,676 patients in the ExTRACT-TIMI 25 trial who went on to receive PCI following thrombolysis.⁵⁷ Enoxaparin reduced the risk of death or nonfatal myocardial infarction by 23% relative to unfractionated heparin (p < 0.001), and unlike in the parent study, was not associated with an increased incidence of bleeding episodes (1.4 vs. 1.6% of patients with unfractionated heparin).
Fondaparinux is another low-molecular weight heparin that has shown promise in patients with STEMI.⁵⁸ The Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-6) trial showed that when initiated early and administered for up to 8 days in patients not undergoing primary PCI, fondaparinux was superior to initial treatment with unfractionated heparin (for up to 48 hours) for the prevention of death or reinfarction at 30 days (hazard ratio 0.82; 95% CI 0.66, 1.02; p = 0.08) and at final follow up after 3 or 6 months (hazard ratio 0.77; 95% CI 0.64, 0.93; p = 0.008), but showed no benefit in patients undergoing primary PCI. There was a tendency toward fewer severe hemorrhages for patients treated with fondaparinux compared with usual care (placebo or unfractionated heparin, 61 vs. 79 events; p = 0.13). In addition, significantly fewer cases of cardiac tamponade were reported with fondaparinux at 9 days (48 vs. 28; p = 0.02).

Primary and Facilitated
PCI As discussed previously, clinical trials have shown that primary mechanical perfusion is generally superior to pharmacological reperfusion.^10,12,59 However, the conditions under which these results were obtained should be borne in mind. For example, many of the clinical trials were conducted in the pre-stent era. Furthermore, these trials are usually performed at specialized hospitals committed to performing primary mechanical reperfusion. However, results from more recent studies show that the greater benefits of PCI are maintained among patients requiring transfer before undergoing the procedure and in hospitals without on-site cardiac surgery.^60–63
While certain studies, such as the Vienna STEMI Registry,¹⁴ suggest that the advantage of PCI over pharmacological reperfusion in patients without contraindications to fibrinolytic therapy may be lost if treatment is initiated within 2 hours of symptom onset, other studies, such as the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA),⁶⁴ show that PPCI maintains its superiority even within the 2 hour window.
It is now recognized that mechanical and pharmacological reperfusion strategies need not necessarily be mutually exclusive. After PCI, the injured artery and/or the stent surface are potentially thrombogenic, and thrombus-related platelet activation, fibrin-bound thrombin, and exposure of subendothelial tissue factor and collagen may contribute to rethrombosis. There is thus a rationale for providing pharmacological therapy in conjunction with PCI, a strategy termed “facilitated PCI”.
The primary aim of facilitated PCI is to achieve reperfusion by pharmacological means prior to performing mechanical reperfusion.¹¹ A number of observations contribute to the rationale for this approach. For example, the delay between symptom onset and initiation of reperfusion is substantially greater in those treated using PPC^I3, and total ischemic time remains the most critical component in regard to treatment outcomes.⁶⁵ The principal function of facilitated PCI is to use pharmacologics in order to overcome additional injury while a patient is transferred to a specialized PCI facility.
Facilitated PCI uses prehospital or inhospital pharmacological reperfusion prior to intervention. Pretreatment with fibrinolytics, antiplatelet agents or both also mitigates the thrombogenic effects of mechanical reperfusion. Facilitated PCI was thought to offer patients a combination of advantages that could not be achieved using either pharmacological or mechanical reperfusion alone: earlier reperfusion, definitive mechanical reperfusion, improved epicardial flow prior to PCI, improved microvascular perfusion and limitation of the thrombogenic effects of mechanical intervention.¹¹ However, failure of the ASSENT-4 protocol to show benefit from facilitated PCI,⁶⁶ followed by the convincing failure of the facilitated PCI approach in the FINESSE study,⁶⁷ likely means that no further large-scale studies of this strategy will be pursued.

Conclusions
For patients with STEMI, the probability of a successful outcome is maximized if prompt and complete reperfusion of the infarcting myocardium can be achieved. Reperfusion can be attempted using pharmacological or mechanical techniques (i.e., fibrinolysis or PPCI). Current clinical trial results suggest that PPCI is the preferred technique, but this treatment option is associated with a number of logistical disadvantages. Most notably, treatment delays are almost universally greater for PPCI than for fibrinolysis, which may be associated with a lessening of the relative advantage of mechanical reperfusion. Furthermore, skilled interventional cardiologists are not available in many hospitals, and only at certain times of day in others.
For these reasons, fibrinolysis is the chosen reperfusion strategy for many patients. However, the realization that fibrinolytics promote thrombogenesis and platelet aggregation — thereby actually inhibiting continuing and necessary fibrinolysis — has led to the use of antiplatelet and antithrombin/anticoagulant therapy in conjunction with fibrinolytic agents. This strategy has been successful: agents that have been shown to improve patient outcomes when combined with fibrinolytic agents include abciximab, clopidogrel, heparin and enoxaparin.
As understanding of the pathogenic mechanisms that operate during atherothrombosis and reperfusion has improved, new treatment strategies have evolved. Clinical trials suggest that the current emphasis on combining antiplatelet and antithrombin/anticoagulant agents with fibrinolytic therapy yields improved outcomes for patients. Emergency physicians without ready access to PPCI should be comfortable with these pharmacologic approaches, as should those who work in emergency departments with onsite catheterization labs, as sometimes unanticipated delays in transition to the lab may occur. Prehospital and emergency medical service personnel should routinely assess patients with STEMI for contraindications to fibrinolytic therapy immediately upon recognition of the diagnosis. Where available, prehospital fibrinolysis may further improve outcomes. Acknowledgment. The author would like to thank Jackie Campbell and Jennifer M. Kulak for their editorial support in preparation of this manuscript. This assistance was funded by Bristol-Myers Squibb/Sanofi-Pharmaceuticals Partnership. No financial compensation was received for this work.

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