Acute myocardial infarction claims about 500,000 lives each year in the United States alone. Though the mortality rate for acute MI patients has fallen slightly during the past several years, recent trials with new combination strategies of partial dose clot dissolving medications (thrombolytics) and platelet antagonists, coupled with mechanical interventions including PTCA and coronary stenting, suggest that even greater declines in mortality can be expected. This is even truer when the possibility of pre-hospital thrombolysis is contemplated. We have outlined in the accompanying Cyberounds^® some of these promising new developments. We hope you enjoy it!

-- Richard W. Smalling, M.D., Ph.D., Cardiovascular Editor

Pathophysiology of Myocardial Infarction and Salvage

Defining the optimal treatment for acute myocardial infarction has been aggressively pursued for over 20 years in terms of interventional approaches. Ehrling Falk and his associates have nicely demonstrated that the pathophysiology of acute myocardial infarction is associated with rupture of an atherosclerotic plaque with liberation of the lipid and collagen contents of the plaque into the lumen of the vessel.(1) This intensely thrombogenic milieu subsequently leads to intense platelet activation followed by white and then red thrombus formation. This ruptured, or active, plaque remains thrombogenic even after successful thrombolysis for at least one month after the index event.(2) Performing interventions in vessels with ruptured plaques, or persistent thrombus, may be treacherous and is frequently associated with an increased incidence of late adverse events such as reclosure, re-infarction, and increased mortality.(3) These new mechanistic findings probably help explain the adverse affects seen in early trials of Percutaneous Transluminal Coronary Angioplasty (PTCA) after coronary thrombolysis.(4),(5),(6)

Early work by Reimer and Jennings demonstrated that myocardial necrosis progresses from endocardium to epicardium after abrupt coronary occlusion and this process occurs at such a rapid pace that most of the thickness of the myocardial wall in the risk or ischemic zone is irreversibly damaged within three hours after coronary occlusion. Conversely, if reperfusion can be achieved quickly, the zone of infarction is substantially minimized.(7) The MITI investigators demonstrated that patients treated with intravenous thrombolysis within 70 minutes after onset of chest pain had a dramatic reduction in 30-day mortality, compared to those who were treated somewhat later in their course (1.2 vs. 8.5 percent).(8)

Figure 1. Reduction in Mortality, Infarct Size and Improvement in Ejection Fraction.

Seen in patients receiving thrombolytics within 70 minutes after onset of chest pain.

There is some evidence, in animal models, that reperfusion, relatively late in the course of ischemic injury, can result in additional injury, secondary to white blood cell activation and free radical generation, as well as other mechanisms.(9) Various treatment cocktails have been shown to help minimize this additional damage in animals. However, to date, clinical trials with white blood cell antagonists and free radical scavengers have been disappointing.(10) Thus, the most important strategy for treating acute myocardial infarction patients is early reperfusion, followed by stabilization of the active plaque, in an attempt to achieve optimal myocardial salvage and prevent re-infarction and re-occlusion.

Plateau of Thrombolytic Efficacy

The GUSTO I angiographic investigators demonstrated a link between restoration of normal infarct related artery blood flow (so-called TIMI 3 flow) and improved survival after thrombolysis.(11) Intravenous tissue plasminogen activator achieved an incidence of TIMI 3 flow in 54 percent of patients at 90 minutes after onset of administration of the agent. In contrast, however, intravenous streptokinase achieved only a 32 percent incidence of TIMI 3 flow at 90 minutes.

Figure 2. Infarct Related Artery Patency in the GUSTO I Trial.

The best patency rates were seen with t-PA and i.v. heparin.(11)

This decrease in reperfusion efficacy was reflected by an increase in mortality and a decrease in left ventricular function. Many other investigators have demonstrated similar findings in this linkage between restoration of TIMI 3 flow and both left ventricular function and 30-day mortality. The low success in thrombolysis is disappointing and has led to the development of a number of other so-called "designer" thrombolytic agents.

Reteplase (r-PA) is a deletion mutant modification of the wild type t-PA molecule which was shown to achieve faster and more complete thrombolysis in a large number of patients when studied angiographically.(12),(13) This agent is given by two boluses of 10MU, 30 minutes apart, and, therefore, is relatively simple to give. Despite the impressive angiographic results in the RAPID trials, the large megatrial, GUSTO III, demonstrated identical outcomes in terms of mortality and stroke with t-PA and r-PA.(14) Subsequent angiographic analysis of the r-PA and t-PA patient subsets in GUSTO III suggested that, although r-PA was good at opening arteries quickly, if an emergency or rescue procedure intervention was not done relatively early in the patient's course, the infarct artery was, perhaps, at increased risk for re-closure. At 24 hours, there was an equal incidence of TIMI 3 flow in both patient subgroups receiving r-PA and t-PA. Thus, it would appear that the newer designer drugs may be slightly more efficacious in opening arteries but they may also be associated with a slightly increased risk of early re-closure, which apparently negates their early advantage unless emergency angioplasty is performed or, perhaps, a concomitant Glycoprotein IIb/IIIa receptor blocker is used.

Lanoteplase, or n-PA, is a deletion and point mutation modification of wild type t-PA, which has a longer half-life and is able to be given in a single bolus. Angiographic analyses of patients treated with this agent, compared to t-PA, were also favorable(15) and a large mortality trial is underway. A new multiple point mutation, modified tPA, TNK-PA, has also been evaluated. This agent also can be given as a single bolus but seems to be no faster than wild type tPA in achieving thrombolysis and the percentage of patients with restoration of TIMI 3 flow is not different between wild type tPA and TNK-PA.

Therefore, it appears that despite the best efforts of multiple investigators and pharmaceutical corporations, thrombolytics appear to have reached a plateau of efficacy. While there may be newer hybrid thrombolytics developed in the future, it is clear that, at the present time, a combined approach of thrombolysis, antiplatelet therapy and coronary intervention will most likely be necessary.

PTCA vs. Thrombolysis

The complication of thrombolytic therapy for acute MI that causes the most concern is intracranial hemorrhage. Most physicians who favor PTCA over thrombolysis point out the very, very, rare incidence of intracranial bleeding and stroke, which is observed in patients treated with direct PTCA for acute myocardial infarction. With current technologies in guidewires and PTCA balloons, the success in achieving infarct related artery patency with direct angioplasty for acute myocardial infarction is very high. Recently, several randomized trials have compared direct angioplasty to thrombolysis, with varying results. The PAMI investigators(16) and the group from ZWOLLE in the Netherlands have shown an apparent favorable outcome of PTCA for acute myocardial infarction compared to intravenous thrombolysis.(17),(18) (Figure 3) In a larger trial, the GUSTO IIb investigators found that there was not an apparent advantage of direct PTCA over thrombolysis, despite initial promising results. At six months, GUSTO IIb subgroups with primary PTCA and thrombolysis had identical outcomes.(19) Some have suggested that once direct PTCA for acute MI is taken out of the larger, higher volume, PTCA centers into community-oriented hospitals, the results will not be as favorable.

Figure 3. In-Hospital Mortality in Post-PTCA vs. Thrombolysis in Acute Myocardial Infarction.

This concept seems to be mirrored by the outcome of a large registry of patients treated with thrombolysis or PTCA in the Seattle metropolitan area.(20) Weaver and colleagues have performed a meta-analysis of all the previously published trials, comparing thrombolysis to PTCA for acute MI. This analysis of the randomized trials suggests that there may be a slight advantage of PTCA over thrombolysis but this is not a huge advantage.(21) As stated previously, one of the drawbacks behind direct PTCA of a thrombus laden ruptured plaque is the relatively high incidence of early reclosure and late restenosis.(3) Therefore, other mechanical approaches may be advantageous.

Stenting vs. PTCA

While there are a number of studies underway comparing direct PTCA for acute MI to coronary stenting for MI, the published results, to date, suggest a clear advantage of coronary stenting. Both Antoniucci and associates and the ZWOLLE investigators(22),(23) found an improved result when patients were treated with coronary stenting rather than PTCA for acute MI (Figure 4).

Figure 4. Antoniucci et al. Showed Improved Outcome with Stent Use.

Mechanistically, this makes sense, given the fact that coronary stents seem to remold and partially cover the ulcerated plaque and potentially provide a much larger lumen, which should, in turn, improve blood flow and further reduce the risk of re-thrombosis. Obviously, patients treated with coronary stenting would also receive antiplatelet agents and this may have been part of the reason why the outcomes were better in stented patients compared with those treated by PTCA alone.

Antiplatelet Therapy Plus Stenting

Recent advances in the understanding of blockade of the Glycoprotein IIb/IIIa receptor of the platelet support the concept of a combined assault on the unstable plaque in order to optimize its passivation. Results from the EPIC trial suggested that abciximab (ReoPro^®) markedly reduced the adverse events associated with interventions in patients with complex coronary lesions. This effect was most marked in patients immediately post myocardial infarction or with unstable angina, both patient groups that are most likely to have unstable plaques with lesion associated thrombus.(24) Subsequently, the EPISTENT trial has confirmed that stenting with abciximab is safer and produces much better outcomes then PTCA alone or stenting alone.(25) Other shorter acting IIb/IIIa receptor blockers have also demonstrated promising results; however, they have not been evaluated in the setting of acute intervention for myocardial infarction or unstable angina. Given the prolonged affect of the abciximab, it is unclear how long the infusions of small molecule IIb/IIIa blockers will be needed or, if, in fact, a relatively potent oral antiplatelet agent, such as clopidogrel, will be sufficient after initial intravenous therapy with a short acting IIb/IIIa blocker. Oral IIb/IIIa blockers are also being evaluated and this will be an area that should be closely observed in the coming years for further developments.

Thrombolysis Facilitated PTCA for Acute MI

Despite the attractiveness of direct PTCA for acute myocardial infarction, it still is hampered by the obligate need for mobilization of the catheterization laboratory personnel, as well as an operator skilled in acute coronary interventions. Dr. Allen Ross has proposed a different strategy that relies on a partial dose of thrombolytic on presentation to the emergency department, followed by rapid mobilization to the catheterization laboratory and emergency angiography with possible intervention, as necessary, to maintain the vessel with the maximum TIMI flow status.(26) Preliminary results with this strategy have been very encouraging and suggest that a greater percentage of patients will have open arteries at the time of their acute coronary angioplasty, potentially improving the outcome and reducing the amount of infarcted myocardium in at least a substantial minority of patients. This concept is being further enhanced by very early administration of a thrombolytic, plus a potent IIb/IIIa blocker, such as abciximab. Both the TIMI 14 and the SPEED trial(27),(28) initial results suggest that TIMI 3 flow rates approaching 80 percent at 60 minutes after initiation of therapy are achievable with this strategy. Emergency angiography might be safely delayed until the following morning if a patient were admitted in the middle of the night, given the relatively high probability that the patient would have an open vessel with the hybrid therapy. It is also possible that coronary interventions will not be necessary as frequently, if patency can be restored and the IIb/IIIa blocker can successfully passivate the plaque over the course of several days. This is another area that will receive intense scrutiny in the coming years.

Pre-Hospital Thrombolysis

A number of trials have suggested that pre-hospital thrombolysis can improve the number of patients treated within the so called golden hour of myocardial infarction (the initial first hour) from approximately 20 percent to almost 70 percent. A multicenter trial performed by Weaver and associates suggested that pre-hospital thrombolysis is clearly superior to routine thrombolysis in the emergency department in terms of reducing mortality.(8) It is quite possible that combining pre-hospital administration of a potent antiplatelet agent, as well as a partial dose of a thrombolytic agent, will more promptly restore TIMI 3 flow in the infarct related artery in the majority of patients. Those with persistent ST elevation or pain on arrival at the emergency department could then be sent directly to cardiac catheterization for angiography and possible rescue stenting. This strategy is an attractive one and should be relatively feasible in terms of implementation.

Cardiogenic Shock

Cardiogenic shock is becoming more rare in the thrombolytic era. Nonetheless, approximately seven percent of patients with acute myocardial infarction present with cardiogenic shock. The mortality in this subgroup with thrombolysis alone is uniformly disappointing and not different from patients treated conservatively, at about 80 percent. Antoniucci and associates have suggested that direct coronary stenting (presumably combined with intra-aortic balloon pump counterpulsation) improved the outcome in patients with shock, compared to those that have direct PTCA alone.(29) Studies in our animal laboratory suggest that left ventricular unloading significantly improves infarct salvage in animals when activated prior to coronary reperfusion. Thus, in these patients with cardiogenic shock, the intra-aortic balloon pump should be inserted prior to direct infarct PTCA/stent in order to maximize the outcome. Ideally, the intra-aortic balloon pump should be maintained in position for at least 48 hours to unload the ventricle and give it a chance to recover after the acute intervention. It is quite possible that a combination of left ventricular unloading with the intra-aortic balloon pump, combined with vigorous antiplatelet inhibition with a IIb/IIIa receptor blocker and coronary stent placement in the infarct related artery, should produce an optimal result in patients with cardiogenic shock. This complex and aggressive approach, however, must be performed in institutions with full cardiovascular support and capability.(30)

Summary

The aggressive interventional approach for the treatment of acute myocardial infarction is evolving. Key components, however, now appear to be very early thrombolysis with a partial dose, or reduced dose, of thrombolytic combined with vigorous antiplatelet inhibition utilizing a IIb/IIIa receptor blocker. If prompt ST segment resolution and resolution of pain are not achieved with this approach, then early angiography and coronary stenting of the infarct related artery seem to produce the best results. In the presence of cardiogenic shock, left ventricular unloading, prior to coronary stenting, will produce the best results in terms of infarct salvage and improved survival. It is quite feasible, with the implementation of a pre-hospital treatment strategy, that a combined approach of pre-hospital partial thrombolysis and vigorous antiplatelet therapy, followed by immediate coronary angiography and intervention, have the potential to reduce the mortality from acute myocardial infarction to the one to two percent range from the current level of six to eight percent. These types of therapy, however, require significant organization and, most likely, will necessitate designation of acute cardiovascular centers capable of administering such therapy, similar to Level I Trauma Centers which are certified for taking care of the most critically injured patients.