Acute PCI for ST-Segment Elevation Myocardial Infarction: Title and subTitle BreakIs Later Better Than Never?

The last 2 decades have witnessed a revolution in acute reperfusion therapy for ST-segment elevation myocardial infarction (STEMI). This therapy has focused on patients who present within the first 12 hours of infarction, in the belief that the benefit of therapy is minimal after that time. However, a significant minority of patients present with STEMI more than 12 hours after the onset of chest pain. In 2 large registry studies,^{1 - 2} patients presenting after 12 hours represented 8.5% and 31.3% of all patients with STEMI. Available randomized trial evidence has until now suggested little role for acute reperfusion therapy in this setting. The Fibrinolytic Therapy Trialist Collaboration³ reported that mortality was not reduced by thrombolytic therapy in patients presenting after 12 hours. Based on these data, existing clinical practice guidelines^{4 - 5} strongly favor the use of acute reperfusion therapy in patients presenting within 12 hours but are more cautious about the potential value of reperfusion therapy in patients presenting later than 12 hours. However, the lack of benefit may, in part, be due to the inability of thrombolytic drugs to restore patency in vessels that have been occluded for several hours.⁶

In the latest of a series of rigorous studies conducted by this group from Munich, the Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2)⁷ trial investigators’ report in this issue of JAMA challenges these existing dogma. In their high quality randomized controlled trial of 365 patients without persistent symptoms who presented 12 to 48 hours after the onset of STEMI, Schömig and colleagues⁷ report a significant reduction in infarct size with primary percutaneous coronary intervention (PCI). After applying appropriate exclusion criteria, 503 patients with STEMI of more than 12 hours duration were eligible and a commendable 365 (72%) were randomized. The primary end point, infarct size by SPECT sestamibi scanning, was available in 349 (96%) of 365 patients randomized, and the median door-to-balloon time was an acceptable 1.7 hours. The trial followed a detailed standardized protocol, with respect to both intervention for the patients who were not treated with acute PCI and adjunctive medical therapy.

The results are certainly provocative. Final infarct size was reduced from a median of 13% of the left ventricle in the group treated conservatively to 8% of the left ventricle in the group treated with PCI. SPECT sestamibi infarct size is a well-validated prognostically meaningful end point.⁸ The difference in median infarct size of 5% of the left ventricle reported by the authors is likely to be clinically significant. Previous studies in larger cohorts⁹ have reported that a 3% difference in infarct size with earlier thrombolysis is associated with a definite reduction in 30-day mortality. Previous trials from this same group^{10 - 11} have found a marked reduction in clinical events in association with a treatment difference of 5.1% and 5.6% of the left ventricle.

The absence of a significant difference in clinical end points in this trial is not surprising, as it was too small to have adequate statistical power to detect such a difference. The 33% relative risk reduction of death, recurrent MI, or stroke at 30 days in the PCI group is at least favorable and provides reassurance that this apparent reduction in infarct size likely does not represent a paradoxical survival bias (ie, an absence of infarct size measurements in patients who die).¹² As noted by the authors, the median infarct size of 13% in the control group is surprisingly small. It is considerably less than the 20% of the left ventricle infarct size that the authors assumed in their sample size calculation and comparable with that reported after treatment with PCI in several recent contemporary trials of PCI.^{13 - 14}

What is the pathophysiological basis for the treatment benefit of late PCI reported in this trial? Although both animal¹⁵ and clinical studies³ have long recognized the time-dependent nature of the benefit of reperfusion therapy, the extent of MI is dependent on the presence of collateral blood flow to the infarct zone.¹⁶ Animal studies have shown an interaction between duration of occlusion and collateral blood flow to the infarct zone.¹⁷ In clinical studies, both residual antegrade blood flow due to incomplete occlusion, intermittent reopening or both, and collateral flow are important determinants of infarct size and clinical outcomes.^{18 - 20} As the authors indicate, a surprising 50% of their patients had some antegrade flow to the infarct zone at initial angiography. Among those patients without antegrade flow, 44% had some collateral flow. Only 27% of patients in the PCI group had an initial Thrombolysis in Myocardial Infarction (TIMI) flow grade of 0 and an initial collateral grade of 0. Residual flow may have preserved myocardial viability in the remaining 73% of the patients and permitted treatment benefit from late PCI.

The modest size of the MIs in the control group is intriguing. It may reflect residual flow to the infarct zone, other factors in patients presenting late, or the use of clopidogrel or ticlopidine in this trial.

Should the next update of STEMI Clinical Practice Guidelines consider PCI to be generally indicated (a class I indication) for all patients presenting with STEMI after 12 hours? Probably not yet. Existing guidelines consider the presence of ongoing symptoms after 12 hours to be a class IIa indication for PCI. On the basis of BRAVE-2, it would seem appropriate to expand this class IIa indication. Although it seems reasonable to consider acute PCI in all patients with STEMI who present 12 hours or longer after the onset of chest pain, regardless of whether they have ongoing pain, this single small trial does not provide sufficient evidence to warrant a class I indication. Such an indication would require confirmation at least in a second small trial using infarct size as an end point or preferably in a larger trial using clinical end points.

Clinicians have used ongoing symptoms in patients presenting relatively late after the onset of STEMI to indicate the presence of ongoing ischemia, and therefore viable myocardium. However, randomized trials of acute reperfusion therapy in STEMI have not generally required ongoing symptoms for inclusion. The BRAVE-2 results are further evidence that the absence of symptoms is a poor indicator of the absence of viable myocardium.

Should patients with STEMI presenting after 12 hours be considered “medical emergencies” requiring acute mobilization of the catheterization laboratory in the middle of the night? Probably not. Although the BRAVE-2 investigators proceeded with urgent PCI in the patients who were included in this trial, the trial results do not reveal whether this urgency was justified. The time course of myocyte death appears to be slower in these patients, perhaps due to the presence of residual blood flow to the infarct zone. Given this slower time-course, it is possible that PCI could be delayed for several hours and still bring substantial benefit.²¹ This single small trial does not justify the same urgency that is warranted on the basis of multiple large randomized trials in patients who present before 12 hours after the onset of chest pain. However, interventionalists and hospital administrators should realize that current Joint Commission reporting standards will include the door-to-balloon time of any patient with STEMI, regardless of time since the onset of chest pain, who undergoes PCI within 24 hours of admission.

From a public health perspective, it is far more appropriate for practicing physicians to focus on the delivery of acute reperfusion therapy to the 30% of patients with STEMI who present within 12 hours and do not currently receive any reperfusion therapy.^{1 - 2} Clinicians should also focus on quality improvement to reduce the door-to-balloon time in patients with acute PCI treated within 12 hours to an absolute minimum and to make certain that all eligible patients with STEMI receive aspirin, β-blockers, angiotensin-converting enzyme inhibitors, smoking cessation instruction, and lipid-lowering therapy. Finally, clinicians should educate all patients to come to the hospital sooner after the onset of symptoms, so that fewer patients are in the more than 12-hour time-window studied by Schömig et al.⁷

The BRAVE-2 trial results are a noteworthy challenge to existing dogma and an important contribution to current knowledge. However, the results do not yet justify a revolution in clinical practice.