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(Circulation. 2003;108:2828.)
© 2003 American Heart Association, Inc.

Focused Perspectives

Selecting the Best Reperfusion Strategy in ST-Elevation Myocardial Infarction

It’s All a Matter of Time

Robert P. Giugliano, MD, SM; Eugene Braunwald, MD

From The TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and the Department of Medicine, Harvard Medical School, Boston, Mass.

Correspondence to: Eugene Braunwald, MD, TIMI Study Group, 350 Longwood Ave, Boston. MA 02115. E-mail ebraunwald{at}partners.org

Key Words: Editorials • myocardial infarction • reperfusion • angioplasty • fibrinolysis

	Introduction

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The primary goal of treatment of acute coronary occlusion is the achievement of early, complete, and sustained epicardial and myocardial reperfusion. Fibrinolytic therapy was first attempted in 1958,¹ and, until recently, constituted the dominant approach for reperfusion. Primary coronary intervention (PCI) is now being used as an alternative to fibrinolysis with increasing frequency. This approach is supported by a recent comprehensive meta-analysis of 23 trials that demonstrated reductions in death, recurrent myocardial infarction, and stroke of 2, 4, and 1 per 100 patients treated through 30 days, respectively.² Attempts to improve the efficacy of the standard pharmacological reperfusion regimen consisting of aspirin, unfractionated heparin, and front-loaded tissue plasminogen activator using more fibrin specific fibrinolytic agents, bolus preparations, more potent antithrombotic drugs, and platelet glycoprotein IIb/IIIa inhibitors have not reduced mortality.³ In contrast, a meta-analysis of clinical trials that compared prehospital fibrinolysis to hospital administration demonstrated a 17% relative reduction in mortality when time to treatment was reduced by an average of 1 hour.⁴

See p 2851

Thus, it became logical to compare these 2 improvements in reperfusion therapy in the Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial infarction (CAPTIM) trial,⁵ in which the median time from symptom onset to therapy for patients receiving prehospital fibrinolysis was 130 minutes, and was 60 minutes longer in the primary PCI group. There was no difference at 30 days in the primary composite of death, non-fatal reinfarction, and non-fatal stroke (8.2% for fibrinolysis versus 6.2% for PCI, P=0.29) or in mortality alone (3.8% versus 4.8%, P=0.61). Furthermore, as described in a provocative analysis by Steg et al⁶ in the current issue of Circulation, there was a strong trend toward lower mortality (2.2% versus 5.7%, P=0.058) and a reduction of cardiogenic shock (1.3% versus 5.3%, P=0.032), but no difference in the primary triple endpoint (7.4% versus 6.6%, P=0.86) in patients treated with prehospital fibrinolysis within 2 hours of symptom onset. Thus, the above-described superiority of PCI over fibrinolysis appears not always to be present in a small but important subgroup of patients, ie, those who can receive treatment in the first 2 hours after symptom onset.

	Reassessment of the Golden Hours

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Restoration of epicardial flow, regardless of the method used, can abort infarction within the first 30 minutes after coronary occlusion (Figure), and the benefit of fibrinolytic therapy compared with placebo is considerably higher in patients treated within 2 hours after symptom onset than in those treated later.⁷ By reducing the time to treatment by 30 to 60 minutes, prehospital fibrinolysis results in earlier ST-segment resolution⁸ and increases the frequency of aborted infarction. Although successful reperfusion between 30 minutes and 2 hours can result in considerable myocardial salvage, only a minority of patients comes into contact with medical personnel within this time interval. Indeed, a large US registry showed that the combination of delays in patient presentation and those inherent in an interventional strategy result in only 8% of patients receiving primary PCI within 2 hours of symptom onset.⁹

View larger version (8K): [in this window] [in a new window]   Time Dependent Benefit of Reperfusion. The effects of reperfusion at different times from onset of symptoms varied and were as follows: <0.5 hours, prevention of infarction; 0.5 to 2 hours, substantial myocardial salvage with additional long-term benefit from an open IRA; 2 to 6 hours, less and progressively diminishing salvage, with most benefits derived from an open IRA (may be >6 hours in patients with coronary collaterals, persistent pain, and ST-segment elevation); and >6 hours, little or no myocardial salvage, with the benefits from an open IRA. The benefits of myocardial reperfusion are maximal during the first 30 minutes and then decline irrespective of the method of reperfusion. It is postulated that some benefits of an open IRA persist even when there is no myocardial salvage. IRA indicates infarct related artery.

	Benefits of Reperfusion After 2 to 3 Hours

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With successful reperfusion more than 2 to 3 hours after symptom onset, myocardial salvage is reduced¹⁰ (particularly with fibrinolytic therapy¹¹), preservation of the myocardium is dependent on preexisting collateral flow,¹⁰ and recovery of left ventricular function is modest.¹² Primary PCI with adjunctive glycoprotein IIb/IIIa inhibitor may improve myocardial salvage compared with pharmacological reperfusion.^11,12 In 1989, we expanded the then standard paradigm (early reperfusion smaller infarct improved survival) to include other potential benefits of an open infarct-related artery, which include perfusion of hibernating myocardium, improved healing, the prevention of infarct expansion, and of ventricular remodeling.^13,14 Because PCI is very effective (>90%) at restoring epicardial flow and improving microvascular flow even hours after the onset of coronary occlusion, it is especially well suited to reap these purported benefits of arterial opening in patients who present relatively late. Although progressively longer delays in time to presentation are associated with higher rates of complications after fibrinolysis, the same pattern appears less evident for primary PCI.¹⁵

	A Rational Approach to Reperfusion Therapy

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Given the overall superiority of primary PCI over hospital-administered fibrinolysis,² the former has emerged as the treatment of choice when the facilities and a high-volume, experienced operator and team are readily available and the coronary anatomy is suitable. The definition of "readily available" is somewhat uncertain, although recent data suggest that outcomes with primary PCI remain superior to fibrinolysis if the added delay is less than 60 to 90 minutes.¹⁶ Longer delays in door-to-balloon time are associated with higher mortality,¹⁷ even after adjustment for differences in baseline characteristics.⁹

When PCI is not available or when the delay between presentation to a hospital and primary PCI is anticipated to be in excess of 90 minutes (which is more likely to occur in low-volume centers, in patients requiring transfer to a second facility or presenting between 6 PM and 8 AM), fibrinolytic therapy should be considered in patients who can be treated within 2 to 3 hours of symptom onset and who are not at high risk for intracranial hemorrhage. In such patients with fresh thrombus, fibrinolytic therapy is especially effective in opening an occluded infarct artery. Because the time to onset of treatment can be shortened by prehospital treatment, administration of fibrinolytic therapy in the ambulance, if available, is most appropriate in patients who present early. This may be followed by PCI to achieve maximal sustained patency of the infarct artery. Indeed, in the fibrinolytic arm of the CAPTIM trial, an early "rescue" intervention was used in 26% of patients and PCI was carried out in an additional 46% within the first month.⁵ The Southwest German International Study in Acute Myocardial Infarction (SIAM) III trial¹⁸ suggests that even better outcomes might have been obtained had all patients receiving early fibrinolytic therapy undergone early angiography and revascularization, as transfer for stenting within 6 hours after fibrinolytic therapy was associated with a halving (25.6% versus 50.6%, P=0.001) of the composite outcome of death, reinfarction, ischemic events, and target lesion revascularization compared with a strategy of delayed elective coronary angiography at 2 weeks.

Because aging thrombi become more resistant to lysis, the efficacy of fibrinolytic therapy in establishing reperfusion and salvaging ischemic myocardium falls off with time from symptom onset, whereas the efficacy of PCI in achieving complete reperfusion and salvaging ischemic myocardium is far less time-dependent.^11,19 In addition, patients who present later tend to be older, have more comorbidities, and are at increased risk for intracranial bleeding. Patients over the age of 75 years experience a 3-fold increase in death, reinfarction, or stroke after fibrinolysis compared with primary PCI.²⁰ Thus, patients who cannot receive fibrinolytic therapy within 2 to 3 hours of symptom onset, but who can receive PCI within the next 90 minutes, should be offered this therapy, even if this entails transfer to another facility. Patients who present more than 2 to 3 hours after symptom onset with continued ischemic pain and/or ST-segment elevation, but who cannot be treated with PCI within the next 2 hours, should (if they have no contraindications) receive fibrinolytic therapy, as some myocardial salvage may still be achieved. These patients should be considered for immediate adjunctive PCI after fibrinolysis, particularly if they experience continued ischemic discomfort or ST elevation, recurrent ischemia, or have signs of left ventricular dysfunction, or later if they are not at low risk after noninvasive assessment.

Patients presenting more than approximately 6 hours after symptom onset, especially patients whose chest pain and ST elevation have subsided, will demonstrate only modest benefit from fibrinolysis but may be considered for coronary angiography as soon as feasible, as this approach permits risk stratification, allows for PCI when the anatomy is suitable, and identifies patients who would benefit from coronary artery bypass surgery. The window may be longer (up to 12 hours) in patients with preexisting coronary collaterals, persistent pain, and ST-segment elevation. The benefit of even later (>48 hours) opening of an occluded infarct artery is under investigation in the ongoing Occluded Artery Trial (OAT).²¹

	Areas for Future Investigation

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Despite the wealth of data generated in 2 decades of randomized clinical trials on hundreds of thousands of patients with acute ST-elevation myocardial infarction, a number of important questions remain. In patients who present within 2 to 3 hours, does a routine pharmacoinvasive approach²² that includes early fibrinolytic therapy and/or a glycoprotein IIb/IIIa inhibitor followed by immediate PCI result in additional salvage that offsets the expected increase in bleeding? Are noninvasive markers of early reperfusion after pharmacological therapy helpful in identifying patients who do not require follow-up mechanical reperfusion? Can pharmacological treatment extend the window of eligibility for PCI? Perhaps most important, how can we most effectively increase the number of patients who present immediately after the onset of symptoms, and how can we provide prehospital fibrinolytic therapy in the United States to maximize the benefit of treatment during the golden hours?

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

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