Plaque rupture and subsequent thrombus formation account for most acute myocardial infarctions (AMIs). Percutaneous coronary intervention (PCI) is considered the preferred treatment for ST-segment-elevation myocardial infarction (STEMI), for evolving non-STEMI (NSTEMI) and for rescue intervention post-thrombolytics.1 The main goals of primary and rescue PCI in AMI include restoration of a normal TIMI 3 antegrade flow, enhancement of myocardial tissue perfusion and achievement of maximal myocardial salvage. However, the reality of acute or rescue PCI for patients with STEMI is quite disturbing as many interventions fail to gain an adequate outcome. The main cause is the presence and insufficient removal of the underlying thrombus. This view is corroborated by careful examination of published data from the Clopidogrel as Adjunctive Reperfusion Therapy Thrombolysis in Myocardial Infarction (CLARITY-TIMI 28) study. Altogether, 3,491 STEMI patients treated with fibrinolytic therapy2 were enrolled. Angiography was scheduled 48–192 hours (median 84 hours after randomisation). Interestingly, a unique angiographic perfusion score (APS) representing the sum of TIMI flow grade and myocardial perfusion grade was used for assessment before and after PCI. Among 1,278 patients who underwent PCI, full perfusion, defined as an APS of 10–12, was gained in only 50%, partial perfusion (APS 4–9) was found in 47% and 3.1% had failed perfusion (APS 0–3). The optimal APS of 10–12 was associated with the lowest mortality, while partial perfusion and failed perfusion were associated with higher mortality at 30 days. Full perfusion was also associated with a lower incidence of recurrent MI, a composite of MI and death, recurrent myocardial ischemia, severe arrhythmias, congestive heart failure and shock. Thus, inevitably, during primary or rescue PCI revascularisation, thrombus, whether visible by angiography or not, frequently presents a formidable obstacle to the attainment of the above-mentioned goals.
PCI in thrombus-containing lesions is associated with an increased risk of acute and long-term complications and remains a predictor of ischemic complications,3 stent thrombosis,4 increased in-hospital complications, six-month MI and death.5 It is apparent that concomitant treatment with standard balloons and stents frequently results in dislodgement of thrombotic material, leading to distal embolisation.6 Emboli of fragmented thrombotic material in the target vessel obstruct flow in its distal segments and side branches, as well as in microvessels in the myocardium. In most instances a resultant ischaemia and necrosis further impair myocardial tissue perfusion, leading to a deleterious effect on recovery and salvage.7
Unfortunately, distal embolisation occurs in up to 15% of patients undergoing primary PCI for AMI and is associated with an up to seven-fold increase in peri-procedural MI. It also significantly increases the need for emergency bypass surgery and the procedure-related death rate compared with revascularisation of lesions without thrombus content.8,9 Altogether, distal embolisation and its sequelae contribute to a significant increase in five-year mortality, reaching a rate of 44% compared with 9% in patients without embolisation.10 Furthermore, it is now recognised that the mainstay treatment modalities for acute coronary syndromes – heparin and IIb/IIIa platelet receptor antagonists – may offer only limited protection from thrombus-related adverse events or are ineffective in an already formed, active thrombus.11 The shortcomings of these standard pharmacological therapies are specifically apparent with regard to resultant suboptimal PCI-induced ST resolution at 60 minutes, inadequate prevention of distal embolisation and insufficient degree of revascularisation of old saphenous vein grafts.12–14 Thus, in order to enhance patient care and improve procedural outcomes with PCI for AMI, a dedicated thrombus removal strategy should be incorporated.15
The histology of the arterial thrombus and its physical properties explain well the challenge it imposes during PCI. The physical structure of thrombus is supported by a scaffolding system made of at least two types of fibrin fibre. Thin fibres yield to external mechanical forces (such as balloon angioplasty), but are not easily susceptible to thrombolytic agents. The thick fibrin fibres can resist external forces of deformation but dissolve appropriately in response to enzymatic digestion by thrombolytics.16
This matrix of criss-crossing fibres attaches red blood cells, platelets, vasoconstrictors and procoagulants. Angioscopy and histology reveal two major types of intracoronary thrombus.17 The first is the red thrombus with its dense surface containing a loose inner core. Transmission electron micrography of this thrombus reveals loosely packed fibrin and many interspersed red blood cells. The second type consists of white thrombus, a dense structure that lacks loose, inner spaces and contains a high concentration of platelets with fibrin and only few red blood cells.18 Frequently, an infarct-related vessel presents an angiographic thrombus that appears to be structurally built of layers upon layers of one thrombus type interspersed with the other. Clinically, a phenomenon termed ‘illusion of reperfusion’ that relates to PCI for AMI is well recognised by interventionalists.19 Essentially, it describes the finding of a marked discrepancy between the initial achievements of optimal TIMI 3 grade flow by primary PCI compared with a disappointing, suboptimal degree of post-procedure myocardial salvage. This is apparent when the blush score is examined at the completion of PCI. The optimal blush score of grade 3 is observed in only 28–35% of patients in whom ‘adequate’ TIMI 3 epicardial flow is gained.20 This marked discrepancy is attributable to the underlying thrombus and its adverse effects in the form of distal embolisation, microvessel obstruction, no reflow and resultant myocardial necrosis. Clearly, patients with no reflow have larger infarct size, significantly worse left ventricular function and a greater risk of non-fatal cardiac events and cardiac death.21,22 Thus, the thrombus’ potential as a hazardous material prone to adverse coronary events and suboptimal outcomes should be taken into consideration during PCI for AMI. This calls for a concentrated effort towards mechanical solutions for removal.23 While a small thrombus is commonly managed by adjunct pharmacotherapy, balloon angioplasty and adjunct stenting,24 management of heavy thrombus burden in the infarct-related vessel is considerably more challenging.25 Intriguingly, most major STEMI studies do not measure or grade thrombus burden,26 despite recognition of the structural complexity of thrombus27 and its significant effect on PCI outcomes.28 Two useful thrombus-grading scales are available. The first grades the thrombus burden along a scale of 0 (no thrombus present) to 4 (large thrombus with ≥2 vessel diameter).29 The other grades from 0 to 5, whereby 5 indicates 100% occlusion of the infarct-related artery. The thrombus is then reclassified to grades 0–4 following initial flow restoration with either guidewire or 1.5mm balloon.30
The role of thrombectomy as a useful adjunctive therapy for removal of underlying thrombus in AMI continues to evolve. Following the recent publication of several landmark studies,4,31 there has been rekindled interest in dedicated mechanical thrombectomy. In a Dutch study,4 the impact of underlying thrombus as an independent predictor of post-procedure major adverse coronary events and stent thrombosis was clearly demonstrated. The TAPAS investigators31 demonstrated that thrombus aspiration is applicable in a large majority of patients with STEMI, resulting in better reperfusion and clinical outcomes than conventional PCI. These findings confirm previous observations from smaller trials and provide credence to the notion that manual aspiration protects the microcirculation during primary PCI. However, it is unclear whether these findings are a direct result of a reduction in thrombus burden, facilitation of direct stenting or a combination of the two.32
Multiple thrombus removal devices are available for PCI in AMI. Based on their internal mechanism of activity, they can conveniently be divided into two main types: aspiration-based catheters and mechanical thrombectomy. We do not subscribe to the traditional approach33 that characterises thrombus-dedicated interventional tools as ‘simple’ devices, i.e. aspiration-based, versus ‘complex’ devices, i.e. mechanically based. Such rigid views erroneously imply a higher level of technical difficulty associated with application of the mechanically based tools, while, in fact, no such limitation should pertain to an experienced interventionalist. Overall, we firmly believe that operators who perform revascularisation for patients sustaining AMI must be familiar with the specific (and simple) technical aspects related to the utilisation of most, if not all, thrombectomy devices. Since these are relatively small devices mostly applied over rapid-exchange platforms, they are actually user-friendly and reduce radiation exposure. Competent operators can comfortably gain complete control of these devices and achieve excellent results. Certainly, attributing ‘complexity’ to these devices may lead to underutilisation and, consequently, less than optimal revascularisation.
Thrombus Aspiration Catheters
Manual thrombus aspiration within the infarct-related vessel has gained intense interest recently as a useful method for rapid reduction of thrombus burden (see Figure 1).34 Most aspiration-based catheters are 6Fr in size, containing an extraction lumen and aspiration syringes. They are easy to manipulate due to a low crossing profile, hydrophilic coating, flexibility and a tapered distal tip.
Among the commercially available aspiration catheters are the Export (Medtronic, Minneapolis, MN, US), Pronto Extraction catheter (Vascular Solutions, Minneapolis, MN, US), Diver CE (Invatec, Roncadelle, Italy), QuickCat (Kensey Nash, Exton, PA, US) and Fetch (Possis, Minneapolis, MN, US). Several prospective studies involving these catheters, such as DEAR-MI35 and REMEDIA,36 demonstrated increased myocardial blush grade of 2–3 and adequate ST-segment resolution of >70% in patients who received this treatment versus those who underwent standard PCI. It is unclear whether one aspiration catheter provides a significant advantage over others. In the prospective single-centre STEMI study RETAMI, Sardella and colleagues found that the use of a certain aspiration catheter before stenting removed more thrombus burden compared with one from another manufacturer, providing a greater post-intervention epicardial flow and microvascular perfusion.37 However, such conclusions strongly depend on operator preference and other factors such as cost. In a study similar to the REMEDIA trial, investigators observed a significant decrease in procedure-related elevation of cardiac enzymes in comparison with patients who did not receive aspiration, as well as only 3 and 15% no-reflow, respectively. Importantly, aspiration catheters do not increase procedural time and offer a safe, straightforward approach for thrombus removal. Follow-up over six months demonstrates a significantly lower occurrence of left ventricular (LV) dilation versus patients who underwent standard PCI.38 A meta-analysis of randomised studies on thrombus aspiration shows a significant benefit of reducing mortality compared with PCI alone: 2.7 versus 4.4% (p=0.05).39 However, it is noteworthy that some investigators did not find any advantage to the routine use of aspiration catheters in STEMI patients,40 observing that this approach does not increase myocardial salvage and, in fact, may increase final infarct size. Among the potential disadvantages of aspiration catheters are difficult delivery to distal segments and risk of dissection/perforation in cases where the guidewire is not precisely located within the lumen. The risk of distal embolisation, especially during a hurried manoeuvre or the inevitable multiple passes required in a large thrombus, cannot be dismissed. Furthermore, the low-level negative pressure during aspiration and relatively small holes render these catheters suboptimal in the presence of a large thrombus volume. Frequently, these devices result in inadequate clot removal, leaving a 30–50% residual thrombus burden behind. Such insufficient thrombus removal also occurs with sequential use of thrombus aspiration catheters and distal protection filters.41
Mechanical Thrombectomy Catheters
The advantages of mechanical thrombectomy devices such as the X-Sizer, AngioJet and Excimer laser are presented in Table 1. At the McGuire Veterans Affairs Medical Center, we have gained experience with each of these devices. These modalities are user-friendly and effective tools in selected patients who receive dedicated treatment for thrombotic lesions, although cost-effectiveness certainly needs to be considered. The question of whether mechanical thrombectomy offers any advantages over standard aspiration catheters is frequently raised, with calls for prospective studies with direct comparison between these two types of thrombus removal technology. However, there is no doubt that the larger the target thrombus volume, the higher the extracting yield of a mechanical thrombectomy device over aspiration catheter.42 This is quite apparent to the extent that some authorities correctly question whether the proposed studies are relevant and even ethical in large thrombus content.43 The X-Sizer thrombectomy system (eV3, Plymouth, MN, US) consists of a helical cutter enclosed within a protective housing attached to a dual-bore catheter shaft containing guidewire and vacuum/extraction lumens. Activation of the handheld controller simultaneously rotates the helical cutter at 2,100rpm, which entraps and macerates soft atherosclerotic plaque and thrombus and channels it to a vacuum collection bottle. The device is available with 1.5, 2.0 and 2.3mm-diameter cutters and is compatible with 0.014-inch guidewires.44Figure 2 represents X-Sizer utilisation in AMI. This device gained recognition mainly in Europe with the publication of several successful clinical experiences.45 Napodano and colleagues studied 92 AMI patients,46 demonstrating that adjunct X-Sizer thrombectomy with stenting during direct PCI for AMI improves myocardial reperfusion as assessed with myocardial blush score and ST-segment resolution. The large, prospective X-AMINE multicentre study that followed demonstrated a device success of 87% and adequate thrombus removal in 95% of the lesions.47 Unfortunately, this device is currently unavailable in the US.
The AngioJet rheolytic thrombectomy system (Possis, Minneapolis, MN, US) is a device fully approved by the US Food and Drug Administration (FDA) for coronary and peripheral interventions. The principle of activation is based on the creation of saline jets inside the catheter that travel backwards at high speed to create a negative pressure zone. Side windows optimise fluid flow, drawing thrombus into the catheter for fragmentation and removal. A new AngioJet console, the ULTRA, was recently introduced featuring automated, rapid set-up and support for a wide range of catheters.
Multiple rapid-exchange 4 or 5Fr flexible catheters are available for various target vessels including native coronary vessels and old saphenous vein grafts. The AngioJet’s ability to provide more effective myocardial perfusion than that obtained with standard balloon and stenting in PCI for AMI has been well documented.48 In the FAST study, AngioJet was applied to extensive thrombotic lesions in 116 AMI patients, leading to significant improvements in perfusion compared with a control group with similar thrombus burden.49 The in-hospital major adverse coronary event (MACE) rate was relatively low at 8%. Further evidence of the excellent safety profile of AngioJet has repeatedly been demonstrated.50,51 Nevertheless, this tool, together with the entire concept of thrombus extraction, sustained a major setback a few years ago when negative results from the AIMI multicentre study were published.52 In perspective, this study was poorly designed. Thrombus presence in the target lesion was not required at all as a criterion for enrolment. Moreover, operators were restricted by an unacceptable technique of device activation that called for pushing the device to the distal end of the target vessel and then activating it in a retrograde fashion. Because the unfavourable results of the AIMI trial continued to haunt this device, the manufacturer recently launched a new prospective international multicentre study. The JetStent AMI study will enrol 500 patients with STEMI and visible thrombus or a totally occluded infarct-related vessel for comparison between AngioJet thrombectomy and standard PCI alone. Operators will use the current thrombectomy technique of antegrade slow activation toward the target lesion followed by slow retrograde thrombectomy. Meanwhile, the Rotterdam group elegantly demonstrated that AngioJet thrombectomy is a significant independent predictor of reduced risk of stent thrombosis and MACE when applied for removal of large thrombus burden in STEMI patients.3 The usefulness of AngioJet in the treatment of AMI induced by late stent thrombosis has been demonstrated as well53 (see Figure 3).
Lasers offer another option of mechanical thrombectomy for revascularisation in AMI.54,55 The ultraviolet pulsed-wave excimer laser has been successfully applied in patients with AMI56,57 (see Figure 4). This device is FDA-approved for physician’s discretionary use in acute coronary ischaemic syndromes related to coronary thrombosis including AMI.58 This device interacts well with several components of the occluding thrombus. The generated acoustic shock waves dissolve fibrin fibres59 and suppress platelet aggregation.60 The clinical and angiographic effects of this laser on thrombus in AMI were further examined by the CARMEL multicentre study.61
This trial enrolled 151 patients who presented in various stages of AMI including ST-segment elevation but also with a late presentation, cardiogenic shock and post-failed thrombolytic therapy. In contrast to most AMI studies, the trial also included patients in whom old saphenous vein grafts were the infarct-related vessel. In addition to angiographic assessment by the operators, unbiased quantitative and statistical analyses were performed by independent core laboratories demonstrating successful laser revascularisation of infarct-related arteries with less than 1% distal embolisation rate. Importantly, the maximal yield obtained with this laser was directly proportional to the thrombus burden, i.e. the larger the thrombus volume at the target lesion, the more effective the induced dissolution. Thus, this study provided the first objective, quantitative proof in the literature for the benefit of a mechanical thrombectomy device in thrombus removal in AMI. A beneficial acute laser gain was achieved mostly in patients presenting later than the ideal six-hour window for treatment post-AMI.62 This selective group commonly exhibits a heavy thrombus burden and unstable haemodynamics, even following timely thrombolytic administration. A separate analysis was performed for patients in the trial who exhibited angiographic total occlusion of the infarc-related artery (attributable to the presence of extensive grade 5 thrombus). As a group, patients frequently arrived at the cardiac catheterisation laboratory in cardiogenic shock (21%), had old saphenous vein graft involvement (26%) and were post-thrombolytic failure (5%). Despite these suboptimal baseline parameters, laser success was obtained in 89%, angiographic success was documented in 93% and procedural success in 86%. Baseline TIMI 0 flow increased to 2.7±0.5 with laser (p<0.001). The final TIMI flow was 3.0±0.2 (p<0.001 versus baseline). Distal embolisation occurred in only 4%, no reflow in 2%, dissection in 4% and a small perforation in 0.6%. Total MACE was relatively low at 13%.63
This approach integrates mechanical thrombectomy with low-dose thrombolytic agents administered selectively into the infarct-related artery. The advantages are elimination of the systemic effects of standard-dose pharmacotherapy and dedicated maceration of the thrombus structure by the mechanical device.64
The last decade has witnessed a growing interest in eradication of intracoronary thrombus during PCI for AMI. Flow-limiting thrombus is frequently found in the infarct-related vessels. It causes deleterious effects on antegrade flow and myocardial tissue perfusion and increases the risk of early and late stent thrombosis. Both light and heavy thrombus burden in an infarct-related vessel require targeted removal. The increased roles of aspiration catheters and mechanical thrombectomy devices in revascularisation of thrombotic occlusions have been recognised and currently are integral parts of contemporary treatment of AMI patients. For large thrombus content, it appears that mechanical thrombectomy provides improved removal. Mechanical thrombectomy creates direct thrombus contact and facilitates stenting, resulting in effective and safe procedures. Ample evidence demonstrates that thrombus removal by dedicated mechanical devices improves ST-segment resolution, enhances antegrade TIMI flow and increases myocardial blush score and corrected Timi frame count (cTFC). While adjunct therapy with pharmacological agents such as IIb/IIIa receptor antagonists and direct thrombin inhibitors is commonly utilised, the role of protection devices needs to be further explored. Combining mechanical thrombectomy with low-dose thrombolytic agents administered selectively into the infarct-related artery is another optional approach termed ‘power thrombectomy’. Interventionalists who treat AMI patients should be familiar and comfortable with the technical aspects related to application of aspiration catheters and be competent with the utilisation of at least one of the above-mentioned mechanical thrombectomy devices.