Munich, Germany - TheBavarian Reperfusion Alternatives Evaluation (BRAVE) trial, suggesting that primary PCI is beneficial for patients arriving at the hospital more than 12 hours after symptom onset, has been published in the June 15, 2005 issue of the Journal of the American Medical Association [1]. The results were first presented, as reported by heartwire, at the American College of Cardiology meeting earlier this year.

The study found that that performing primary PCI with stenting and adjunctive use of abciximab (ReoPro, Centocor, Eli Lilly) reduces infarct size in ST-elevation MI (STEMI) patients without persistent symptoms presenting 12 to 48 hours after symptom onset. The authors, led by Dr Albert Schömig (Technische Universität, Munich, Germany), say this finding "increases the level of evidence in support of the invasive strategy" for these patients "and deserves consideration when current treatment guidelines for this category of patients are reassessed." An accompanying editorial says the results do not yet justify a revolution in clinical practice but do probably warrant a IIa indication (weight of evidence in favor of usefulness) for PCI in this group of patients [2].

In the paper, Schömig et al note that treating acute-MI patients presenting more than 12 hours after symptom onset is a challenging and as-yet unresolved problem and that until now there has been no evidence to support a reperfusion strategy in the majority of these patients.

The BRAVE trial included 365 STEMI patients who were not eligible for reperfusion treatment because they arrived at the hospital more than 12 hours after symptom onset. They were randomized to either an invasive strategy consisting of immediate diagnostic angiography/PCI or a conservative medical-treatment strategy.

Results showed that the final left ventricular infarct size was significantly smaller in patients assigned to the invasive group than the currently recommended conservative strategy and there was also a trend toward fewer clinical events in the PCI arm.

The authors say that the trend toward a better clinical outcome in the invasive group should be interpreted with caution because of the limited number of patients in the study, but they point out that scintigraphic infarct size is recognized for its accuracy as a marker of reperfusion efficacy in trials of patients with acute MI. They note that several mechanisms may explain the finding of a reduced infarct size in the invasive group; they also note that their results lend credit to the theory that viable myocardium can be found late after symptom onset and that this myocardium might be salvaged if an effective reperfusion strategy is applied.

In the accompanying editorial, Drs Raymond Gibbons (Mayo Clinic, Rochester, MN) and Cindy Grines (William Beaumont Hospital, Detroit, MI) describe the results of the BRAVE-2 trial as "provocative," noting that SPECT-sestamibi infarct size is a well-validated prognostically meaningful end point and that the 5% difference in median infarct size is likely to be clinically significant.

Gibbons and Grines point out that residual antegrade blood flow—due to incomplete occlusion, intermittent reopening, or both—and collateral flow are important determinants of infarct size and clinical outcomes. In this study, half the patients had some antegrade flow to the infarct zone at initial angiography, and many of those with no antegrade flow had some collateral flow. "Only 27% of patients in the PCI group had an initial TIMI flow grade of 0 and an initial collateral flow grade of 0. Residual flow may have preserved myocardial viability in the remaining 73% of the patients and permitted treatment benefit from late PCI," they suggest.

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? Gibbons and Grines say, "Probably not yet." They note: "Although it seems reasonable to consider acute PCI in all patients with STEMI who present 12 hours or more 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, at the very least, confirmation by a second small trial using infarct size as an end point, and preferably by a large trial using clinical end points."

But they do believe that the results justify expanding the class IIa indication for PCI, which currently covers patients with ongoing symptoms after 12 hours, saying that on the basis of BRAVE-2, it would seem appropriate to expand this class IIa indication to patients without symptoms.

In answer to the question: "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?" Gibbons and Grines again say, "Probably not." They point out that although this trial proceeded with urgent PCI in the invasive group, the results do not clarify whether this urgency was justified. "The time course of myocyte death appears to be slower in these patients, perhaps owing 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," they say.

The editorialists conclude: "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. 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, beta blockers, angiotensin-converting enzyme (ACE) 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."

Dr Adnan Kastrati (Deutsches Herzzentrum, Technische Universität), senior author of the BRAVE-2 study, was accepting of these views. He commented to heartwire: "The suggestion of the editorialists to move patients such as those included in the BRAVE-2 trial from a class III (disfavor) to a class IIa (favor) indication for PCI represents a strong call for change in medical practice." He added: "Although a revolution in clinical practice might take some time after this and subsequent studies in the field, the greatest service of the BRAVE-2 study will be to challenge the almost prevailing belief in cardiology that heart muscle is irreversibly damaged after 12 hours of symptom onset and that any reperfusion attempt is unable to salvage heart muscle after this time."