Thrombus aspiration during primary percutaneous coronary intervention (PCI) has been extensively studied. Conflicting results have consistently emerged, hence, no clear guidance has been produced. The authors have examined several key clinical trials and meta-analyses, and discovered, arguably, major flaws within the designs of most trials, thus, accounting for the persistently discordant results. The authors conclude that there is some evidence to support the selective use of thrombectomy in primary PCI but a large-scale trial with the appropriate patient selection criteria is needed in order to substantiate or refute the argument.
Introduction
The use of thrombus aspiration in primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) has been subject to intense scrutiny and debate over the last decade. Clinical trials have been undertaken, using varying randomisation methodologies, aiming to objectively quantify the impact of the practice, while several subsequent meta-analyses have been conducted with conflicting results. Uncertainty remains and no exclusive guidance has been internationally agreed regarding the definitive usefulness, or otherwise, of the practice. The use of thrombectomy in PPCI has become ad hoc or, at best, discretionary, with different interventional cardiologists having differing rules as to when to perform it, reflecting the conflicting evidence that currently exists.
This article aims to critically review the available evidence and compare the relationship between thrombus burden and existing lesion severity with the extent of myocardial damage and complications in STEMI patients. The authors argue that the severity of the underlying coronary lesion in the infarct-related artery (IRA) is an independent predictor of infarct size, no-reflow and mortality in selected STEMI patients. Furthermore, the extent of thrombus burden within the lesion only becomes clinically significant if the underlying lesion itself was non-flow limiting prior to the event. The authors conclude that thrombus aspiration is mostly beneficial if performed early in IRA lesions that were non-flow limiting prior to the event, but have recently occluded with a large thrombus burden. In contrast, thrombectomy provides little or no benefit if attempted in IRA lesions that were severely flow-limiting to begin with. The authors conclude that clearer guidance needs to be devised regarding thrombectomy in PPCI to highlight that thrombus aspiration, (figure 1) while not routinely recommended in all STEMI cases, should, nevertheless, be considered in those whose IRA has a large thrombus burden that has developed within a non-flow limiting coronary lesion.
The evidence
We reviewed 17 randomised-controlled trials that evaluated the role of thrombectomy during PPCI in STEMI patients between 2004 and 2015. The total number was 22,222 patients. Trials adopted differing randomisation methodologies and designs. Six trials randomised a total of 12,509 patients to thrombectomy versus conventional PPCI before coronary angiography was undertaken, thus relying purely on symptoms and electrocardiogram (ECG) criteria. The remaining 11 trials studied a total of 9,713 patients and randomised them after coronary angiography. Thirteen meta-analyses have been conducted, and we have taken their findings into consideration on writing this review.
This article elaborates on each of these clinical trials and meta-analyses, discusses the flaws in the evidence and details the reasoning for the authors’ argument that new guidance should be devised to encourage the use of thrombectomy in selected PPCI cases.
Studies where randomisation was done before coronary angiography
REMEDIA
The REMEDIA1 (Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus-aspiration in Primary and Rescue Angioplasty) study (2004) was one of the first clinical trials to examine the feasibility of unselected use of manual thrombus aspiration during PPCI in STEMI. Only 100 patients were randomised. No angiographic criteria were used. Multi-variate analysis demonstrated that thrombus aspiration was a significant independent predictor of myocardial blush grade (MBG) ≥2 and ST-segment resolution (STR) ≥70% (p=0.013). The investigators concluded that manual thrombus aspiration in unselected STEMI patients undergoing primary or rescue percutaneous coronary intervention (PCI) was clinically feasible and would result in better angiographic and ECG myocardial reperfusion rates, in comparison with standard PCI. The main study limitations were its small size and lack of clinical outcome end points. Therefore, the findings could not be generalised to the wider STEMI population.
DEAR-MI
In another randomised study, Silva-Orrego et al.2 (2005) tested the usefulness of thrombus aspiration in 140 STEMI patients. No angiographic criteria were used. The incidence of in-hospital clinical events was similar in both arms, but the multi-variate analysis revealed significant STR and MBG improvement in the thrombectomy arm, plus reduction in no-reflow and creatine kinase mass band fraction release. Once more, the study size was too small to generalise, but findings seemed to replicate those of the REMEDIA study, adding further credibility to its conclusion.
VAMPIRE
The VAMPIRE3 (VAcuuM asPIration thrombus REmoval) study (2007) was larger and multi-centre, randomising 355 STEMI patients to thrombectomy versus direct PPCI. Its findings demonstrated a trend towards better myocardial perfusion and lower clinical events in the thrombectomy arm that did not reach statistical significance (p=0.07). The study suggested that those presenting after six hours of symptom onset benefit the most from thrombus aspiration (slow flow rate: 8.1% vs. 37.6%, p=0.01). The results seemed to support the two aforementioned studies, albeit with no statistical significance.
TAPAS
The TAPAS4 (Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study) trial (2008) was a single-centre, yet larger, study, wherein 1,071 STEMI patients were randomised to thrombectomy versus direct PPCI. MBG and STR were significantly improved in the thrombus aspiration arm. Rates of death and adverse events at 30 days inversely correlated with MBG and STR, demonstrating for the first time that thrombus aspiration had a positive impact on survival and morbidity irrespective of the baseline angiographic characteristics. Furthermore, cardiac death remained significantly lower in the thrombus aspiration group at one year5 (3.6% vs. 6.7%, p=0.02), as did combined cardiac death and non-fatal re-infarction (5.6% vs. 9.9%, p=0.009).
Liistro et al.
In 2009, Liistro et al.6 randomised 111 STEMI patients to thrombectomy versus direct PPCI. End points, including STR, thrombolysis in myocardial infarction (TIMI) flow, myocardial contrast echocardiography score index, course of wall-motion score index and left ventricular ejection fraction, were all significantly improved in the thrombectomy arm. The small number of patients was a limitation, but the findings, nevertheless, supported the use of thrombectomy. Therefore, for some subsequent years, the general consensus remained in favour of routine thrombectomy usage in PPCI, until 2015 when the TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI) study findings were published.
TOTAL
TOTAL7 was by far the largest randomised trial studying manual thrombus aspiration versus routine PPCI, recruiting 10,732 STEMI patients. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction (MI), cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days. The results revealed no significant difference between the two arms in the primary outcome (p=0.86, 0.34 and 0.95, respectively), but there was a significant difference in favour of the PPCI-alone group in the incidence of stroke within 30 days (p=0.02). It was concluded that routine manual thrombectomy, when compared with PPCI alone, did not reduce the risk of cardiovascular death, recurrent MI, cardiogenic shock, or NYHA class IV heart failure within 180 days, but was associated with an increased rate of stroke within 30 days. This served as a landmark study reversing the then popular trend of routine thrombus aspiration during PPCI. The practice has since become discouraged, and, at best, discretionary in current practice.
Studies where randomisation was done after coronary angiography
Parallel to the above trials, other similar studies were being conducted wherein STEMI patients had to satisfy additional angiographic criteria before randomisation.
Antoniucci et al.
Antoniucci et al.8 (2004) randomised 100 acute myocardial infarction (AMI) patients to rheolytic thrombectomy versus IRA stenting. Pre-randomisation coronary angiography served solely to determine the IRA and to confirm the need for PCI. The primary end point was early ST-segment elevation resolution, and the secondary end points were corrected TIMI frame count, infarct size, and one-month clinical outcome. The primary, and most other, end points were shown to be significantly better in the thrombectomy arm (p=0.022, 0.032, 0.032 and 0.010, respectively), apart from the one-month clinical outcome, where no major adverse cardiac events (MACE) were recorded in either arm, attributable to the small number of participants.
XAMINE ST
The XAMINE ST9 (X-sizer in AMI for Negligible Embolization and optimal ST resolution) trial (2005) randomised 201 AMI patients with TIMI flow grade 0–1 to either X-sizer thrombectomy or direct PPCI. The primary end point was the magnitude of STR after PCI. Thrombus scoring (0–5) was performed as an additional angiographic inclusion criterion, together with TIMI flow grade 0–1 in de novo IRA lesions. It is unclear, however, whether patients had been excluded upfront if their IRA thrombus score was zero, which is a study limitation. Nevertheless, there was a significant difference in STR and myocardial perfusion in favour of the thrombectomy arm. Yet, there was no significant difference between the two groups in the rate of major adverse cardiovascular and cerebral events (MACCE) at one and six months.
Kaltoft et al.
Subsequently, Kaltoft et al.10 (2006) randomised 215 STEMI patients to either thrombectomy or standard PPCI. The primary end point was myocardial salvage measured by sestamibi single-photon emission computed tomography (SPECT) after 30 days. Secondary end points included final infarct size, STR, and troponin T release. In the thrombectomy arm, the final infarct size was increased (p=0.004). Therefore, the investigators concluded that routine thrombectomy during PPCI could worsen the final infarct size. However, while coronary angiography was performed as a pre-requisite for randomisation, patients’ eligibility for participation in the study was stated to have been determined if PCI was indicated and the treating physician found the IRA suitable for thrombectomy, a rather vague way of randomisation. No thrombus burden quantification method was documented to have been used.
EXPIRA
Later, the EXPIRA11 (Thrombectomy with Export Catheter in Infarct-related Artery during Primary Percutaneous Coronary Intervention) study (2009) randomised 175 STEMI patients to manual thrombectomy versus direct PPCI. A thrombus score ≥3 was clearly stated as an inclusion criterion, together with TIMI flow grade ≤1, IRA diameter ≥2.5 mm, in addition to other standard STEMI symptoms and ECG criteria. In the thrombus aspiration arm, both MBG and STR were found to be significantly better (p=0.001 and 0.001) together with a lower incidence of cardiac death (p=0.02). Despite a smaller study size, detailed IRA thrombus scoring had been undertaken, and only those with a significant thrombus burden were included in the study, introducing the concept of selective, rather than routine, thrombectomy in PPCI.
PIHRATE
The PIHRATE12 (Polish-Italian-Hungarian Randomized Thrombectomy) trial (2010) randomised 196 STEMI patients to thrombectomy versus routine PPCI, the primary end point being ECG STR. Secondary end points included: direct stenting rate, final TIMI grade 3 flow, corrected TIMI frame count (cTFC), final MBG grade 3, peri-procedural angiographic complications, combination of STR ≥70% and MBG 3, and in-hospital MACE. The primary and other end points were significantly better in the thrombectomy arm, but death and re-infarction at six months were similar in both groups. The investigators concluded that thrombectomy in PPCI improved both coronary flow and myocardial perfusion but had no effect on mortality or re-infarction. The study is limited by its small size and its assessment criteria for IRA thrombus burden, which lacked clarity and objectivity. One third of patients had little or no visible thrombus, yet they were still randomised into either arm.
Ciszewski et al.
In 2011, Ciszewski et al.13 published the results of their study that recruited 137 patients randomised to thrombectomy or direct PPCI. Angiographic evidence of thrombus was an inclusion criterion, and, therefore, patients with no visible thrombus were excluded. The primary end point was myocardial salvage index (MSI) as assessed by 99mTc-sestamibi SPECT imaging. In the thrombectomy arm, MSI was larger (25.4% vs. 18.5%, respectively, p=0.02) and the final infarct size was smaller (23.1% vs. 28.9%, p=0.002). The investigators concluded that thrombectomy improves myocardial salvage with angiographic evidence of thrombus. Although the angiographic inclusion criteria were reasonably clear, particularly in relation to the presence of visible thrombus, the small study size and the fact that it was a single-centre study casts doubt on its reproducibility.
MUSTELA
The MUSTELA14 (MUltidevice thrombectomy in acute ST ELevation Acute myocardial infarction) study (2012) randomised 208 STEMI patients with a high thrombus load to thrombectomy versus direct PPCI. Cardiac magnetic resonance imaging (cMRI) at three months was performed to quantify the infarct size, its transmurality and microvascular obstruction (MVO). Primary end points were STR >70% at 60 minutes and three-month infarct size. There was a higher STR rate and final MBG grade 3 in the thrombectomy arm (p=0.004 and 0.03, respectively). MVO was significantly less in the thrombectomy group (p=0.02), but there was no difference between the two groups in infarct size or transmurality.
INFUSE-AMI
The larger INFUSE-AMI15 (Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction) study was conducted in 37 sites, and its findings were published in 2012. There were 452 high-risk STEMI patients randomised into four arms: bolus intracoronary abciximab, manual thrombectomy, both intracoronary abciximab and manual thrombectomy, and direct PPCI alone. The primary end point was infarct size at 30 days. Patients randomised to intracoronary abciximab compared with no abciximab had a significant reduction in 30-day infarct size (p=0.03), while patients randomised to aspiration thrombectomy versus no aspiration had no significant difference in infarct size at 30 days (p=0.51). It was concluded that intracoronary abciximab was beneficial in reducing the infarct size at 30 days but aspiration thrombectomy was not. The same conclusion was reached after one-year follow-up.16 The study did not specify any angiographic inclusion criteria related to thrombus load or visibility, which represents a methodology flaw, as further discussed below.
TASTE
The TASTE17 (Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia) study (2013) was a much larger multi-centre trial that randomised 7,244 STEMI patients (pulled from the Swedish Registry) to manual thrombectomy and PPCI versus PPCI alone. The primary end point was all-cause mortality at 30 days. Coronary angiography was performed to confirm patients’ eligibility for PPCI. However, no IRA thrombus burden quantification was undertaken, nor were patients without evidence of thrombus excluded from the trial. In addition, there was a significant cross-over between the two arms after randomisation, involving 16% of patients. Notwithstanding those limitations, the results demonstrated better absolute figures in favour of thrombectomy, but statistical significance could not be reached. Death from any cause occurred in 2.8% of patients in the thrombectomy arm (103 of 3,621) compared with 3.0% in the PCI-only arm (110 of 3,623) (p=0.63). The rates of hospitalisation for recurrent MI at 30 days were 0.5% and 0.9%, respectively, in the two arms (p=0.09), and the rates of stent thrombosis were 0.2% and 0.5%, respectively (p=0.06). Stroke and neurologic complications were similar in both arms (p=0.87). The investigators concluded that routine thrombus aspiration before PCI, as compared with PCI alone, did not reduce 30-day mortality among patients with STEMI. The results remained the same after one year.18
Pyxaras et al.
Also in 2013, Pyxaras et al.19 published the results of their retrospective registry, in which 644 STEMI patients were randomised to four arms: conventional PPCI alone; PPCI and abciximab; PPCI and thrombectomy; and PPCI, abciximab and thrombectomy. The primary end point was the composite of overall mortality, MI, target vessel revascularisation, and major bleeding at one year. MACEs at one year in arms 1 to 4 were 29%, 22%, 19% and 13%, respectively (log-rank p=0.001). It was, therefore, concluded that a combination of pharmacologic and mechanical antithrombotic treatment was associated with better one-year clinical outcome. Although the study design was somewhat similar to that of INFUSE-AMI, the results have been discordant as far as thrombectomy was concerned. Furthermore, no clear method for thrombus burden assessment was documented as part of the eligibility criteria.
Onuma et al.
Finally, a small study was conducted by Onuma et al.,20 in which 141 STEMI patients were randomised to PPCI versus thrombectomy. The primary end point was the minimum flow area post-procedure, and the study concluded that it was similar in the two arms.
Meta-analyses reviews
Several meta-analyses have been conducted to further scrutinise the evidence, albeit with similarly conflicting conclusions.
Brodie21 concluded that the evidence did not support routine thrombectomy during PPCI, but adjunctive thrombectomy was beneficial in patients with large IRA thrombus. Later, De Luca et al.22,23 reached a similar conclusion after having meta-analysed 21 randomised trials. The reviews also agreed that mechanical thrombectomy was associated with a higher incidence of stroke and mortality.
Three further meta-analyses24-26 have collectively examined 61 randomised-controlled studies and concluded that thrombectomy in PPCI improved mortality and reduced adverse clinical outcomes. Conversely, two other meta-analyses27,28 collectively reviewed 43 trials and concluded that aspiration thrombectomy in PPCI was not associated with any clinical benefit, and might increase the risk of stroke.
Other meta-analyses29-31 have reached a neutral conclusion, stating that thrombectomy improved early markers of reperfusion, but had no demonstrable impact on 30-day post-MI mortality, re-infarction or stroke.
Ischaemic pre-conditioning
Towards the end of the 1990s, ischaemic pre-conditioning (IPC) has become conceptualised as a powerful form of endogenous protective mechanism against MI. Animal studies have demonstrated that transient ischaemia results in a smaller infarct size when the myocardium is subsequently subjected to permanent cessation of coronary blood flow. The same concept has been shown to exist in isolated human cardiomyocytes.
Due to understandable ethical constraints, no randomised-controlled studies have been conducted in humans, but observational human data, obtained from patients undergoing PCI and coronary artery bypass grafting surgery (CABG) where no collateral blood supply was present have indicated that IPC does exist in humans.32 In 2009, the CRISP Stent (Cardiac Remote Ischemic Preconditioning in Coronary Stenting) study33 assessed the ability of remote IPC on the magnitude of cardiac troponin I release in 242 patients randomised to standard elective PCI versus remote IPC plus PCI, and demonstrated that remote IPC significantly reduced chest discomfort and procedure-related troponin I release. After six years of follow-up,34 the MACCE rate continued to remain significantly lower in the remote IPC group.
More recently (2016), Liu et al.35 randomised 119 STEMI patients to remote IPC prior to stenting versus direct PPCI, demonstrating the alleviation of ischaemic reperfusion injury in the remote IPC group, with resultant significant reduction in infarct size (p=0.042).
Discussion: the flaw within the evidence
One main reason as to why the multiple above randomised studies have continued to reach conflicting conclusions is that not all relevant clinical variables have been considered. The methodologies of most trials have implicitly presumed that the variability in STEMI outcomes was solely dependent on the IRA site (left main stem, left anterior descending, left circumflex or right coronary), the IRA acute occlusion location (proximal, mid or distal), the door-to-balloon time, and the affected myocardium size. Furthermore, those methodologies have presupposed that STEMI patients, in whom the above variables are similar, should be expected to pursue closely similar post-MI courses and final outcomes.
The authors argue that additional factors substantially influence both the immediate and longer-term STEMI outcomes, such as the IRA lesion severity prior to the index STEMI event, the size of thrombus contained within the IRA, and the presence of IPC or pre-established collateral blood supply to the IRA territory. Those factors are variable and interdependent across a continuum of STEMI spectrum patients who otherwise may be considered similar.
On one end of the STEMI spectrum, an acute occlusive thrombus forms within a tight flow-limiting coronary stenosis whose myocardial territory is already trained for ischaemia, with established IPC and/or collateral blood supply. As such, the occlusive thrombus (within the tight IRA lesion) is often small in size and barely visible on angiography. Therefore, performing thrombus aspiration in such patients is unlikely to result in any tangible benefit compared with direct PPCI, because there is virtually no thrombus to aspirate, and because of the protective anti-ischaemic effects of IPC and/or collateralisation. The authors also argue that STEMI patients at this end of the spectrum tend to end up with smaller infarct sizes and fewer MACCE outcomes.
On the other end of the STEMI spectrum, the occlusive thrombus forms within a non-flow-limiting coronary lesion whose myocardial territory neither has ischaemic preconditioning nor collateral blood supply. The thrombus is often large in size and clearly visible on coronary angiography. The affected myocardium is often poorly resistant to ischaemia. Performing thrombus aspiration in such patients is likely to result in a significant benefit compared with direct PPCI, because aspiration will help remove the bulk of the occlusive material (the thrombus), and reduce the risk of no-reflow and distal coronary embolisation. The authors also argue that STEMI patients at this end of the spectrum tend towards larger infarcts and more MACCE outcomes.
With the exception of the three small studies: EXPIRA, MUSTELA and the study conducted by Ciszewski et al.; none of the aforementioned thrombectomy trials used objective thrombus burden quantification methods in its eligibility criteria to ensure that only STEMI patients with visible coronary thrombi were included and randomised. Furthermore, neither the IRA lesion severity prior to the STEMI event, nor the presence of IPC and/or collateralisation has been taken into consideration during the design or the undertaking of any of the above described randomised clinical trials. Therefore, patients from within the entire range of the STEMI spectrum ended up being simply randomised to thrombectomy versus no thrombectomy. Thus, it was left to pure chance whether some STEMI patients with large thrombi ended up being randomised to direct PPCI, while other STEMI patients with virtually no thrombi ended up being randomised to thrombus aspiration. As such, the final statistical results have either regressed to the mean and showed no net benefit for thrombectomy, or revealed conflicting results of seemingly similarly designed trials, thereby, leading to more confusion.
Conclusion
Notwithstanding the large number of clinical trials that have investigated the role of adjunctive thrombectomy in PPCI, confusion about the usefulness of the practice remains. Repeated major design and methodology flaws have led to conflicting results and have fuelled confusion within the realm of interventional cardiology. The missing piece in this jigsaw is a large clinical trial that only randomises STEMI patients with large visible IRA thrombi. The trial should collect data on the culprit lesion degree of severity, and on the presence, or absence, of IRA territory collaterals. The assumption being that tight IRA lesions indicate the presence of IPC and vice versa. The authors anticipate that, if conducted properly, the trial shall unequivocally confirm that thrombectomy confers significant benefit in selected STEMI patients with visible thrombi and not-so-tight IRA lesions, paving the way for clear international guidance. Until such a study is undertaken, the evidence remains deficient. It is premature to decisively conclude in favour of either PPCI strategy, and for the time being the discretionary use of thrombus aspiration is likely to continue.
Key messages
- Most clinical trials that examined thrombectomy use in primary percutaneous coronary intervention (PPCI) had no objective means of infarct-related artery (IRA) thrombus burden quantification, thus, randomising some thrombus-free vessels to thrombectomy, and vice versa, creating confusing results that are difficult to interpret
- An appropriately designed large-scale clinical trial is required to provide definitive answers as to the usefulness of thrombectomy in PPCI. Until then, thrombectomy use should continue to remain discretionary
Conflict of interest
None declared.
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