Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Gonda 5S, Rm 209, 200 First Street SW, Rochester, MN 55905, USA
* Correspondence to: Dr. Verghese Mathew, Associate Professor of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Gonda 5S, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 507 538 1469; fax: +1 507 266 9142 (E-mail: mathew.verghese{at}mayo.edu).
This editorial refers to "DECOPI (DEsobstruction COronaire en Post-Infarctus): a randomized multi-centre trial of occluded artery angioplasty after acute myocardial infarction"; by P.G. Steg et al. on page 2187
The benefit of prompt reperfusion for ST-segment elevation myocardial infarction (STEMI) using either mechanical or pharmacologic modalities has been convincingly demonstrated. Successful reperfusion salvages myocardium, reduces infarct size, improves left ventricular function (although not uniformly so), and subsequently leads to better survival. This benefit is critically time-dependent within the first three hours after symptom-onset, with sustained but lesser degrees of benefit in the 312 h window after symptom-onset.1,2 The benefit of reperfusion in the 1224 h period after symptom-onset is less pronounced, but likely to be beneficial in patients with signs or symptoms of ongoing ischaemia,3 and likely holds true even after 24 h in such patients.
If all eligible patients with STEMI received prompt and durable reperfusion therapy, a debate over the late revascularization of occluded arteries would be moot. However, in reality, many eligible patients with STEMI do not receive primary reperfusion therapy; additionally, thrombolysis, the most widely available reperfusion modality, is often associated with significant residual stenosis, re-occlusion and/or re-infarction even among patients in whom successful reperfusion is achieved initially. Importantly, sustained late patency of the infarct-related artery (IRA) is required for persistent benefit; subsequent re-occlusion of a reperfused IRA is associated with worse outcome than if the IRA remains patent.4 This realization, along with the 'open artery concept', which postulates potential late benefits on the electrical, mechanical, and ischaemic milieu, independent from the time-dependent issue of initial myocardial salvage, has sustained interest in the strategy of angiography followed by revascularization in asymptomatic post-MI patients with occluded IRAs. Although experimental studies have been quite persuasive regarding the late benefits of an open IRA, a convincing clinical benefit remains to be established.
The observations that (1) survival in STEMI could be improved by IRA reperfusion without significant improvement in left ventricular ejection fraction (LVEF) during follow-up,5 and (2) that in some patients receiving reperfusion therapy for STEMI, mortality was surprisingly low despite the presence of substantial left ventricular dysfunction6 suggests that the improvement in survival after reperfusion for STEMI may be the consequence of factors other than the degree of myocardial salvage and ejection fraction 'the open-artery concept'. This intriguing hypothesis is certainly plausible and the bulk of evidence, clinical and experimental is supportive. Nonetheless definitive proof of the clinical value of establishing late patency in the absence of on-going ischaemia remains unproven. Moreover the mechanisms of benefit remain however speculative, and are probably multi-factorial with favourable effects on the mechanical, electrical, and ischaemic substrates.
The additional observation that late ventricular remodeling in non-reperfused patients with an occluded IRA compared to those with a patent IRA7 suggests that attenuation of ventricular remodelling may indeed be a relatively time-independent benefit of very late reperfusion on an occluded IRA. Another time-independent effect of reperfusion appears to be improved electrical stability. Inducible, sustained ventricular arrhythmias and subsequent clinical events are lessened in patients having undergone thrombolysis (with a presumed patent IRA).8,9 Additionally, a significant decrease in the frequency and severity of late potentials on signal-averaged electrocardiograms has been shown in MI patients undergoing late reperfusion and in patients with a documented patent IRA,10 although this is not a consistent finding.11 Another theoretical benefit of a patent IRA is that it may provide collateral supply in the event of a subsequent MI in another territory. Lastly, and perhaps the least sufficiently evaluated, is the hypothesis that a patent IRA may eliminate the mortality, including lethal ventricular arrhythmias, associated with residual silent ischaemia in the infarct-related territory. Significant inter-patient variability in the extent of residual myocardial viability beyond an occluded IRA may exist in the context of a dynamic thrombotic process that may result in intermittent periods of occlusion and recanalization via intrinsic fibrinolytic mechanisms. This may result in varying degrees of ischaemic pre-conditioning and recruitment of collaterals that may be relatively protective, preserving a greater degree of myocardial viability than might be assumed based on the angiographic appearance of an occluded IRA and an akinetic ventricular wall. As measures of myocardial viability have evolved over the last decade or more from perfusion scanning and echocardiography to positron emission tomography (PET) scanning and magnetic resonance imaging (MRI), these more sophisticated and sensitive modalities may allow us to better select patients that demonstrate substantial viability and define a group of patients that may be more likely to benefit from late revascularization of their IRA.
As provocative and enticing as the 'open artery concept' may be, most randomized studies,1214 with the exception of one,15 have not been able to demonstrate a benefit of late revascularization of an occluded IRA after MI. However, all these trials were small and most certainly undersized to be able to detect a significant difference in outcome. Moreover, these trials antedated the widespread use of stenting and were as such limited by a high rate of re-occlusion. The DECOPI trial by Steg et al. in this issue of the European Heart Journal,16 as the investigators themselves acknowledge, also unfortunately suffers from the lack of sufficient sample size.
DECOPI randomized 212 stable patients without spontaneous or provocable low-level ischaemia after a first Q-wave MI to percutaneous coronary intervention (PCI) vs medical therapy of the occluded IRA, which by protocol had to be a proximal occlusion in a ⩾2 mm vessel. A minority of patients had received thrombolytic therapy, and the left anterior descending artery (LAD) was the IRA in less than 30% of the population. Most patients had single vessel disease and the mean ejection fraction (EF) was normal. Angiography was performed at least 48 h after MI (56 days on average), and PCI performed 215 days after symptom onset. DECOPI was planned to enrol 720 patients in order to have sufficient power to demonstrate a 33% reduction in the composite endpoint, assuming a 15% event rate in the medical therapy arm, although limited funding and slow enrollment resulted in early termination of the study. At six months, PCI patients were more likely to have a patent artery (82.8% vs. 34.2%), although angiographic restenosis was 49.4%. Ejection fraction was higher at 6 months for PCI patients compared to medical therapy patients, although patients with a patent IRA at six months experienced a similar increase in EF at six months regardless of treatment assignment, and patients with a closed artery had no improvement in EF. However, at a mean follow-up of 34 months, the primary endpoint of cardiac death, non-fatal MI, or ventricular arrhythmias was similar in both the PCI and medical groups, as was the secondary composite endpoint that included admission for heart failure; costs were also higher in the PCI group.
Although DECOPI is the largest published randomized trial to date testing the open artery hypothesis, the small sample size limits meaningful conclusions, particularly since the event rate in the medical therapy arm was far lower than anticipated. As the investigators point out, this was indeed a low risk population; all patients were stable and had survived for at least two days post-MI, most without receiving reperfusion therapy acutely. Additionally, most patients had single vessel disease with preserved EF. A post hoc analysis of the angiographic data suggested that 6 month patency of the IRA was strongly associated with better EF and lower mortality in the long term, which does indeed support the concept of a beneficial effect of an open IRA independent of initial therapy aimed at myocardial salvage.
In addition to a low risk population, what other factors may have masked the benefit of late IRA reperfusion in DECOPI, if indeed such exists? To have lasting benefit, late reperfusion of an occluded IRA must result in sustained, long-term patency. In DECOPI, 12% of opened IRAs were occluded at the time of angiographic follow-up and 49% were restenotic (of which approximately half were re-treated), despite 80% stent utilization. This increased incidence of re-occlusion and restenosis has also been demonstrated in other similar trials, and it appears that this subgroup of patients may be more prone to re-occlusion and restenosis than other patient/lesion subsets. It has been demonstrated that angiographic evidence of thrombus, which would be common in such cases, although correlated with worse short-term outcomes does not predict higher rates of revascularization during follow-up.17
If the presence of thrombus alone does not explain the higher degrees of re-occlusion/restenosis, perhaps an impairment of microvascular function may contribute to this increased frequency of late events. Although an intact microvasculature may become impaired due to distal embolization of atherothrombotic material at the time of PCI, extensive microvascular dysfunction due to plugging or prolonged hypoperfusion of the distal vascular bed from the initial occlusion, may lead persistently to absent tissue perfusion despite restoration of epicardial blood flow. Poor distal outflow increases the likelihood of re-occlusion of the treated vessel, and if re-occlusion or significant restenosis occur, the benefit of reperfusion likely will be attenuated. In the trial by Horie et al.,15 restenosis was treated aggressively with repeat PCI, which may be one factor why this trial was the only trial which demonstrated a beneficial effect of PCI of occluded IRAs after MI.
It is of course possible that achieving late patency of an occluded IRA is not clinically beneficial; the available studies are all too small to provide a definitive answer. The Occluded Artery Trial (OAT),18 which plans enrollment of 3200 asymptomatic patients 328 days post-MI with an occluded proximal large vessel or EF<50% for non-proximal occlusion should certainly address the issue of sample size. The composite endpoint of death, MI, and Class IV congestive heart failure will be measured over three years, and should contribute importantly to our understanding of the clinical correlation of the open artery hypothesis.
What do we stand to lose by routinely performing angiography and attempting PCI of occluded IRAs after MI? Other than the consumption of resources and availability of catheterization facilities, it should be understood that there are potential risks, both real and perceived. Failure to restore patency of the IRA occurred in 4.6% of patients, and although the incidence is not explicitly stated in the DECOPI manuscript, peri-procedural adverse events may indeed occur both with and without successful recanalization of the occluded vessel. Additionally, distal embolization of atherothrombotic material during PCI may potentially impair a previously intact microcirculation, and collaterals may be lost. If a vessel does not appear amenable to PCI or PCI is unsuccessful, the procedural risk of bypass surgery need also be considered in the context of the anticipated benefit.
If the open artery hypothesis is to translate into measurable clinical benefit, it is important that the chances of successful, durable revascularization are maximized. As such, it is essential to intervene on such patients in the days to weeks after MI; a delay of many weeks or months allows for organization and fibrosis of the lesion, reducing the chance of successful PCI. Additionally, the relative benefit of flow restoration may not be entirely time-dependent, and restoration of flow weeks to months after the initial occlusion may or may not afford any improvement in the electrical or mechanical parameters of interest. If a significant thrombus burden is present, the use of glycoprotein IIb/IIIa inhibition and/or mechanical thrombectomy may improve the chance of acute procedural success. With regard to durability, although not explicitly studied in this patient or lesion subset, the use of drug-eluting stents to enhance long-term patency may play an important role. The utility of some of the strategies in this patient/lesion subset may also be tested in observational studies, in addition to the awaited randomized outcome data from OAT. In summary, the open-artery concept is intriguing and logical, yet remains unproven. The burden of proof remains an elusive but worthy objective.
Footnotes
; doi:10.1016/j.ehj.2004.10.019.
References
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