IntroductionContemporary techniques of primary

percutaneus coronary interventions (pPCI) enable the restoration of normal epicardial flow in the infarct related artery, as evaluated by trombolysis in myocardial infarction (TIMI) flow and the corrected TIMI frame count (cTFC)

However, vessel patency does not always translate in microvascular perfusion

Impaired microvascular perfusion, measured by the TIMI myocardial perfusiongrade (TMPG), is associated with increased infarct size and worse clinical outcomes

ST-segment resolution (STR) has also been shown to correlate with microvascular reperfusion after revascularization for ST-segment elevation myocardial infarction (STEMI)

Distal embolization of thrombotic material has been hypothesized as a mechanism microvascular obstruction and injury and provides the rationale for employing thrombus aspiration (TA) during pPCI

previous studies of TA during pPCI for STEMI have been conflicting, andcomparisons have been complicated by the variety of devices used

In this Trial, we evaluated whether there might be an association between the use of manual TA and changes in angiographic,electrocardiographic and clinical outcomes of patients with STEMI undergoing contemporary pPCI.

Material and MethodsThe study randomized 3602 patients with STEMI,

presenting within 12 hours after the onset of symptoms,who were undergoing pPCI

The primary study endpoint was net adverse clinical events (NACE), which includeddeath, re-infarction, ischemic target vessel revascularization (TVR), stroke, or major bleeding.Other outcomes of interest were MACE (including death, re-infarction, ischemic TVR, andstroke), components of MACE, major bleeding not related to CABG, and definite or probablestent thrombosis according to ARC criteria

Angiographically, reperfusion was assessed by thefinal TIMI flow in the infarct artery and the TMPG (16, 18). STR was measured by continuousdigital 12-lead Holter monitoring

Complete STR was considered STR ≥70%. Stent thrombosis wasdefined as definite or probable, using the Academic Research Consortium classification

ResutsThe final study population included 3235

patients, 318 patients (9.8%) who underwent pPCI with upfront use of TA and 2917 patients (90.2%) who underwent PCI alone

Patients treated with versus without TA were younger and had a lower prevalence of hypertension, but a higher prevalence of smoking and prior PCI

Patients treated with TA had shorter symptom-onsetto balloon time, a higher prevalence of single vessel disease, angiographic evidence of thrombus and baseline TIMI flow <3

Direct stenting and post-stent dilatation were used more frequentlyin patients treated with TA

There was no difference between the twogroups in the rates of final TIMI 3 flow and TMPG grade 2-3

At 60 minutes post-procedure, a similar proportion of patients treated with and without TA hadcomplete STR

However, significantly more patients in the TA grouphad complete STR at discharge

At 30-day, 1-year, and 3-year follow-up, the TA and no TA groups had similar rates of MACE, NACE, death, MI, ischemic TVR, and stent thrombosis

There were more strokes and major bleeding events in the TA group at 30 days, but by 3 yearsthe difference was no longer apparent

The cumulative incidence of definite or probable stent thrombosis was similar between the two groups

Late stent thrombosis occurredsignificantly more frequently in the TA group

After multivariate adjustment, the use of manual TA was not associated with anydifferences in long-term outcomes

DiscussionWe found that the quality of reperfusion

attained was similar between the two groups with no significant differences in the rates of final TIMI 3 flow, TMPG 2-3, or complete STR at 60 minutes despite worse initial angiographic presentation among patients in the TA group

There was a higher rate of complete STR in the TA group at hospital discharge

There were nosignificant differences in the rates of MACE, NACE, death, MI, ischemic TVR, or stentthrombosis at 30 days, 1 year, or 3 years in patients treated with or without TA

There was a higher incidence of late stent thrombosis in patients treated with TA

we found that theuse of manual TA was not associated with rates of short- or long-term MACE

Analysis of the results of previous thrombectomy trials is complicated by the variety of devices studied, which can be broadly categorized into mechanical thrombectomy and manual aspiration catheters

Rheolytic thrombectomy using the Angiojet device had until recently been reported inrandomized trials to be of no benefit and to possibly be associated with increased infarct size,MACE, and reduced TIMI flow

Prospective cohort studies and registry data specifically in patients with high-grade thrombus burden have reported improved angiographic and clinical outcomes

The recently published JETSTENT multicenter randomized trial of rheolytic thrombectomy and direct stenting versus direct stenting alone during pPCI with highgrade thrombus burden reported improved STR, but no improvement in the other primaryendpoints including infarct size

There was a significant reduction in the secondary endpointof MACE at 1, 6, and 12 months

Randomized trials of the X-sizer device demonstratedimproved STR, corrected TIMI frame count (cTMC), and reduced distal embolization, but reported no difference in TIMI 3 flow, TMBG, or MACE

Randomized and prospective cohort studies of manual TA, as used in this study, have reported improvements in electrocardiographic and angiographic endpoints

In our study there was noimprovement in post-procedural TIMI 3 flow and TMPG, or in 60-minute complete STR with the use of TA devices, while STR was significantly improved in the TA group at discharge

This may indicate a delayed improvement in microvascular reperfusion following TA in our study population

It should be noted that the TA patients had more visible thrombus and a higher  proportion of TIMI 0/1 flow pre-procedure at baseline, from which they then achieved similar rates of TIMI 3 flow as the no TA patients

While the majority of studies report an improvement in surrogate markers with the use of manual TA, it remains uncertain whether this translates into an improvement in clinical outcomes

One early study suggesting a possible mortality benefit was recently supported by the randomized EXPIRA and TAPAS trials

Manual TA was associated withimprovement in the co-primary endpoints of TMPG and STR

Cardiac death, MACE and infarctsize on MRI were also noted to be reduced, although the study was not powered to detect theseendpoints

Similarly, in TAPAS, manual TA was associated with improved TMPG, STR, cardiac death, and non-fatal MI, but again was not powered for the clinical endpoints

A subsequent meta-analysis of 9 randomized trials, including TAPAS, concluded that manual thrombectomy was associated with improved 30-day mortality

A more comprehensive meta-analysis of 30 randomized trials of alladjunctive devices used in STEMI also reported that manual aspiration was associated withimproved mortality and reduced MACE rates

Contrary to the results of TAPAS and themeta-analyses, we did not observe any difference in MACE or mortality at 1 year with TA, even after adjusting for many important covariates

An important procedural difference between the two groups in our study was a greater use of direct stenting in the TA group than in the no TA group

As already discussed, there have been concerns raised in prior TA trials, including TAPAS, that some of the benefit observed may be due to direct stenting and not to the TA itself

There is, however, some evidencethat the use of TA is an independent predictor of improved angiographic outcomes even in thesetting of direct stenting

In our study, the use of direct stenting was more frequent in the TA group, but the net-clinical effect of this difference in procedural approach would be difficultto assess among a host of potential confounders

We reported an increased rate of stroke at 30 days and 1 year in the TA group

Patients treated with manual TA still had a trend towards anincreased stroke rate at 1 year, but no such difference was apparent at 3-year follow-up, and our finding should be regarded as an association of clinical interest

This finding is partly consistent with results from the meta-analysis of randomized trials of thrombectomy and embolic protection devices

That study demonstrated a trend towards increased stroke following manual or mechanical thrombectomy.

It is hypothesized that this could be due to dislodgement and embolization of thrombus from the coronary ostium or aspiration catheter

We found a higher incidence of late stent thrombosis in the TA group at 1-year follow-up

This clearly raises concern that TA, possibly due to endothelial disruption and impaired endothelialization, may induce a higher incidence of late stent thrombosis

we also observed a trend towards less sub-acute stent thrombosis in our TA group, raising the possibility that the use of aspiration catheters may affect the time of occurrence of stent thrombosis

Another important consideration in our study isthat patients treated with manual TA were more likely to have visible thrombus, and there isevidence in STEMI patients that large thrombus burden is an independent predictor of infarct-related artery stent thrombosis

However, at 3-year follow-up, the rate of late cumulativestent thrombosis did no longer differ between the two groups, suggesting that slowing down of vascular repair by TA may be a temporary phenomenon, but this assumption should be regardedwith caution, due to many potential confounders that cannot be corrected for

ConclusionsIn the HORIZONS-AMI trial, manual TA was

associated with improved STR at discharge,whereas final TIMI flow and TMPG were unaffected

There were similar rates of NACE, death,cardiac death, re-infarction, ischemic TVR, major bleeding, and MACE at 30 days, 1-year, and3-year follow-up

Further multicenter randomized trials are required to clarify the safety andefficacy of routine TA in patients with STEMI undergoing pPCI