The outcomes of patients with ST-segment elevation myocardial infarction (STEMI) have improved in recent years with the more widespread adoption of definitive reperfusion therapies, including rapid recanalisation of the infarct-related artery with percutaneous coronary intervention (PCI). Nonetheless, despite the near universal restoration of normal epicardial flow following primary PCI for STEMI, a relatively large proportion of patients with STEMI have abnormal myocardial perfusion at the end of the procedure. Abnormal myocardial perfusion in STEMI is thought to be related, at least in part, to distal embolisation of thrombotic debris with microvascular plugging and the resultant release of vasoactive substances and myocardial cell oedema in the infarct territory. Distal embolisation may occur spontaneously in STEMI, but can additionally occur as a result of mechanical manipulation of the culprit lesion during PCI. Given the recognised importance of distal embolisation in STEMI, there has been increased interest in strategies to prevent both the occurrence of distal embolisation and the adverse sequelae of this phenomenon. This article will briefly review the pathophysiology of distal embolisation, and will discuss pharmacological and mechanical therapies to prevent distal embolisation and its adverse consequences in patients with STEMI.
Distal Embolisation as a Determinant of Infarct Size
Distal embolisation is a determinant of infarct size and poor reperfusion in patients undergoing PCI for STEMI. The manipulation of atherosclerotic lesions with wires, balloons, atherectomy catheters or stents during primary PCI for STEMI can lead to the embolisation of thrombus and/or plaque debris within the culprit artery. In addition, patients with STEMI may experience spontaneous embolisation from the highly thrombotic and friable lesions that are the hallmark of STEMI, and embolisation from the mechanical force of contrast injections from diagnostic angiography has also been reported.1 Once embolisation occurs, distal emboli can mechanically ‘plug’ the microvasculature, leading to continued ischaemic necrosis of the myocardium, but can also promote local in situ platelet adhesion and thrombosis, provoking microvascular spasm and a local inflammatory reaction that may further complicate recovery.2 Angiographic signs of distal embolisation occur in up to 15% of patients undergoing primary PCI, and have been associated with poor reperfusion, larger infarct size, lower left ventricular ejection fraction and an unfavourable five-year survival.3 However, the true incidence of distal embolisation is likely to be much higher than that observed macroscopically through angiography. Histological analysis from the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) trial demonstrated that visible debris could be retrieved in up to 73% of patients.4
In cases with release of a large embolic burden, embolisation can result in slowed epicardial flow or, in extreme cases, the ‘no reflow’ phenomenon, defined as severely impaired epicardial flow despite the presence of an artery without a significant residual epicardial stenosis. The use of intravascular ultrasound during PCI has demonstrated that greater plaque volume reduction (an indirect sign of plaque embolisation when excluding distal or proximal plaque shifting) is closely associated with slower post-procedural epicardial flow.5 There are many cases, however, where these processes are still present but remain undetected by the traditional thrombolysis in myocardial infarction (TIMI) flow grade classification. In these cases, more quantitative measures, such as the TIMI frame count (TFC), TIMI myocardial perfusion grade (TMPG) or blush grade (MBG),6 may prove more sensitive in detecting abnormalities in epicardial flow. Even in cases where epicardial flow is normal, there can be evidence of inadequate myocardial perfusion in a substantial proportion of patients. Abnormalities in myocardial perfusion can be detected in realtime by means of: electrocardiography – by delayed resolution of ST-segment elevation; angiography – by abnormalities in angiographic blush or TMPG; or flow decrements – measured by coronary Doppler wire.
Other non-invasive imaging modalities – such as myocardial contrast echocardiography, nuclear scintigraphy, delayed enhancement magnetic resonance imaging (MRI) and positron emission tomography (PET) – have also allowed better assessment of microvascular function and myocardial perfusion above and beyond epicardial artery patency.6,7
Therapeutic Strategies to Address Distal Embolisation in ST-segment Elevation Myocardial Infaction – Role of Glycoprotein IIb/IIIa Inhibitors
In a meta-analysis of eight randomised trials of adjunctive abciximab therapy in primary PCI, the use of adjunctive glycoprotein IIb/IIIa inhibition during primary PCI was associated with significant reductions in short-and long-term mortality.8 Further analyses have demonstrated that the mortality benefits of adjunctive abciximab therapy for primary PCI appear to be greatest in high-risk patients.9 Glycoprotein (Gp) IIb/IIIa inhibitors inhibit the ‘final common pathway’ of platelet activation, and may be helpful in STEMI by resulting in dissolution of platelet aggregates at the site of the thrombotic lesion (by reducing the overall embolic burden), or distally within the microvasculature.
Peri-procedural administration of abciximab has been associated with better myocardial perfusion as evaluated by Doppler-flow wire10 and contrast echocardiography,11 with mixed results in a large analysis using angiographic blush grade as the metric of analysis of myocardial perfusion.12 In preliminary series, intracoronary administration of abciximab has been associated with improvements in myocardial perfusion and smaller infarct size.13,14 Similar results have been observed in uncontrolled studies of eptifibatide,15 but larger prospective series are necessary to address the efficacy of intracoronary Gp IIb/IIIa inhibition definitively.
Given their mechanism of action, Gp IIb/IIIa inhibitors are likely to be predominantly effective in addressing the thrombotic component of culprit lesions and emboli, rather than the atheroembolic components, and treatment with these agents is not without risk. In at least 50% of patients with acute STEMI presenting within six hours of onset of symptoms, coronary thrombi – aspirated during PCI and analysed histologically – were days or weeks old.16 Embolised plaque fragments and debris containing an organising thrombus or a more atheromatous plaque component may be poorly responsive to antiplatelet therapies such as Gp IIb/IIIa inhibitors. In a small, non-randomised single-centre study of pre-treatment with abciximab, there was no effect of abciximab on the number, volume or histopathology of PCI-induced embolic particles.17 Finally, Gp IIb/IIIa inhibitors are associated with an increased risk of bleeding complications, which must be weighed against potential ischaemic benefits.
Adjunctive Mechanical Devices to Prevent Distal Embolisation
The use of devices that aim to prevent atherothrombotic particles from embolising into the microvasculature during PCI is another potentially attractive strategy to address PCI-induced distal embolisation in STEMI. If shown to be effective, such an approach would have the theoretical advantage of addressing both the atheromatous and thrombotic components of PCI-induced embolisation. Three basic classes of embolic protection devices (EPDs) exist, categorised according to their mechanism of operation – distal occlusion, distal filter or proximal occlusion.18 Additionally, thrombectomy devices that aim to remove the thrombus from the culprit lesion and distal to it can be viewed as devices that aim to prevent distal embolisation during PCI. Among these categories of devices, the best-studied devices for STEMI have been distal occlusion, distal filter and thrombectomy devices.
Distal occlusive devices aim at preventing distal embolisation by obstructing flow beyond the culprit lesion (by inflation of a balloon distal to the occlusion), followed by aspiration of potentially embolised debris at the end of the procedure. Despite the proven benefit of distal occlusive devices in PCI of saphenous vein grafts and several single-centre reports of efficacy in STEMI, large-scale randomised trial data of distal occlusive devices in native coronary arteries during PCI for STEMI have shown no clinical benefits. In the largest of these trials, the EMERALD trial, a total of 501 patients were randomised to either PCI with the use of GuardWire or conventional PCI without EPD.4 High rates of procedural success were achieved with the device (only 7% of patients had no distal vessel protection) and atherosclerotic debris was collected in 73% of patients. However, the use of the device was associated with no improvements in any of the end-points assessed in the trial, including TIMI flow, myocardial blush, ST-segment resolution, infarct size or clinical outcomes.
Distal filter devices are non-occlusive protection devices that are positioned distally to the culprit lesion in order to capture embolic particles that may be liberated during pre-dilatation and stent implantation. While these devices preserve flow in the culprit artery even when deployed, they typically have larger crossing profiles compared with distal occlusion devices. In the Protection Devices in PCI-Treatment of Myocardial Infarction for Salvage of Endangered Myocardium (PROMISE) trial, 200 patients were randomised to the FilterWire device or conventional PCI. The use of the device did not improve Doppler-assessed myocardial perfusion or infarct as assessed by MRI.19 A pooled meta-analysis of seven trials of distal protection devices (both occlusion and filter devices) demonstrated that, despite benefits in terms of myocardial perfusion (primarily in the smaller studies), no benefits were seen in terms of 30-day mortality.20 Thus, while these devices are theoretically attractive, they have shown very limited benefits in larger randomised trials.
There can be several postulated mechanisms for the failure of these distal EPDs in STEMI. First, embolisation may occur prior to, or during, wire/device crossing, or before these devices can be successfully deployed. Second, native coronary arteries (unlike saphenous vein grafts) have side branches both proximal and distal to the culprit lesion, which may not be protected by devices deployed distal to the culprit lesion. Finally, these devices have a limited ability to address the vasoactive mediators and in situ platelet aggregation that can occur in the distal microvasculature. In order to address the first two deficiencies of distal EPDs listed above (embolisation during crossing and side-branch protection), some have postulated that proximal protection may be the most attractive strategy of embolic protection in STEMI.
Proximal occlusion devices affect balloon occlusion of the vessel proximal to the culprit lesion to prevent forwards arterial flow. These devices are typically deployed before crossing of the lesion, and aspiration is used to capture debris liberated during PCI. While this concept is attractive, particularly in arteries that are already occluded at baseline, such as those being treated in STEMI, prospective randomised trials are needed to confirm the feasibility and safety of these systems in PCI for STEMI. Preliminary data from the Feasibility And Safety Trial for its embolic protection device during transluminal intervention in coronary vessels: a European Registry (FASTER) registry have shown that retrograde blood flow can be achieved during proximal occlusion during PCI of saphenous vein grafts and native coronary arteries.21
The last category of devices that aim to prevent distal embolisation is thrombectomy devices, which work by removal of thrombi from coronary arteries either from simple aspiration or through the more complex means of thrombus removal. Trial results with different devices have been conflicting, but larger multicentre randomised trial data have been largely negative. In the Angiojet Rheolytic Thrombectomy in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction (AIMI) trial, 480 patients were randomised to rheolytic thrombectomy with Angiojet or conventional PCI. Paradoxically, the use of the Angiojet was associated with a larger infarct size and higher mortality in this trial.22 The aetiology of the poor outcomes in this trial is unknown, but may have been due to inclusion of a low-risk population (the observed mortality rate in the control group was 0.8%, with a higher percentage of pre-procedural TIMI 3 flow), and the fact that evidence of thrombus was not an inclusion criterion. In another study of 215 STEMI patients randomised to mechanical thrombectomy or conventional PCI, enzymatic infarct size, paradoxically, was larger in patients randomised to thrombectomy.23 A pooled analysis of 13 randomised trials on thrombectomy devices involving a total of 2,231 patients showed that, despite benefits in terms of post-procedural TIMI 3 flow, myocardial blush and the occurrence of distal embolisation, no benefits were observed in terms of 30-day mortality.20
In summary, the link between the use of device therapies to reduce distal embolisation and improve clinical outcomes has been difficult to demonstrate. Despite some benefits in terms of myocardial perfusion, at least in clinical trials, the use of these devices does not seem to improve short-term survival. However, the observed benefits in terms of myocardial perfusion may have lasting effects on ventricular remodelling and long-term survival.24
Another important issue in the use of these devices is the selection of patients. Most randomised trials testing these devices had strict inclusion criteria that led to the exclusion of high-risk patients, such as those with advanced Killip class and cardiogenic shock. In fact, these patients may be the ones who could derive the most benefit from these devices, given the higher rates of distal embolisation and poor perfusion observed in these conditions. Furthermore, evidence of thrombus was not an inclusion criterion in the majority of these trials. The thrombotic burden and the risk of distal embolisation can be extremely variable across patient groups. It is also possible that adjunctive devices such as EPDs may be efficacious in the setting of a high atherosclerotic emboli risk situation, such as a ruptured plaque image at angioscopy.26 Finally, distal embolisation is not the only determinant of infarct size, poor perfusion and adverse prognosis. Other mechanisms include increased microcirculatory resistance due to neutrophil obstruction and/or constriction of arterioles, myocardial oedema and myocardial injury after reperfusion.2 Because ischaemia time is a major determinant of infarct size and outcome, late reperfusion after several hours of ongoing myocardial injury may not reduce infarct size or improve survival, despite prevention of distal embolisation.27 Thus, adjunctive devices that reduce the embolic burden during PCI cannot be expected to be the only solution for improving myocardial perfusion during primary PCI for STEMI.
Distal embolisation is a relatively common phenomenon in primary PCI of patients presenting with STEMI, and is associated with poor myocardial perfusion and adverse clinical outcomes. Pharmacological strategies as an adjunct to primary PCI have been demonstrated to be associated with improvements in outcomes, particularly in high-risk patients. While EPDs are theoretically attractive, randomised data assessing their clinical efficacy are limited. Pending larger trials with longer follow-up and inclusion of higher-risk patients, the potential benefits of EPDs and thrombectomy devices in primary PCI to prevent distal embolisation in STEMI are as yet unproved.