THE LASER-AMI STUDY - Excimer Laser Versus Manual Thrombus Aspiration in Acute Myocardial Infarction (LASER-AMI)

A Randomized Comparison of Excimer LASER vs Manual Thrombus Aspiration for the Prevention of No-reflow During Primary Percutaneous Coronary Intervention of St-elevation Myocardial Infarction(LASER-AMI Study)

The occurrence of no-reflow phenomenon after recanalization of the infarct related artery in acute myocardial infarction is described in up to 40% of cases. This event is associated with a worse prognosis at follow up and an unfavourable left ventricular remodelling. Two main pathogenetic mechanisms cause no-reflow: distal embolization, ischemia-reperfusion injury and individual susceptibility. In such a context, Excimer Laser (EL) may play an important role in order to reduce the rate of microvascular obstruction. Thus, in this randomized study we will assess the effect of EL versus Manual Thrombus Aspiration for ST elevation MI using ST segment resolution on standard 12 leads ECG as primary endpoint of myocardial reperfusion.

Acute myocardial infarction (AMI) is the leading cause of death in developed countries. In patients with AMI, prompt reopening of an occluded coronary artery is the main goal of reperfusion therapies in order to restore normal blood flow to the myocardium, thus preventing left ventricular (LV) adverse remodelling and occurrence of heart failure. Primary percutaneous coronary intervention (PPCI) represents the pivotal step in the current management of ST-segment elevation myocardial infarction (STEMI) (1). Yet, in a sizable proportion of patients, PPCI achieves epicardial coronary artery reperfusion but not myocardial reperfusion, a condition known as no-reflow (2), that increases the extent of myocardial damage. The proportion of patients who get optimal myocardial reperfusion, among those without cardiogenic shock undergoing PPCI, is about 35% (3). Thus, the prevalence of no-reflow remains extremely high. Furthermore, a series of consistent data has clearly shown that no-reflow has a strong negative impact on outcome, negating the potential benefit of PPCI (4-10). Indeed, as compared to patients without no-reflow, patients with no-reflow exhibit a higher prevalence of: 1) early post-infarction complications (arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure); 2) LV adverse remodelling; 3) late re-hospitalizations for heart failure; 4) mortality. In man, no-reflow is caused by the variable combination of four pathogenetic mechanisms: 1) distal atherothrombotic embolization, 2) ischemic injury, 3) reperfusion injury, 4) susceptibility of coronary microcirculation to injury (3). As a consequence, appropriately designed strategies to prevent or to treat, at the right time, each of these components are expected to reduce the final number of patients with no-reflow. Manual thrombus aspiration (MTA) has been clearly shown to improve microvascular perfusion and survival in STEMI patients treated by PPCI (9,10). Accordingly, in current guidelines of the European Society of Cardiology (ESC), MTA is a 2a recommendation (1). Yet, complete ST-segment resolution (defined as >70%) is obtained in only about 50% of patients (3,6), thus suggesting that microvascular perfusion may be further improved. In such a context, Excimer laser (EL) may play an important role in order to reduce the rate of microvascular obstruction. Coronary lasers are devices emitting electromagnetic energy which, upon absorption within the atherosclerotic plaque, can debulk the target tissue (11-12). Over the past decade, a second generation of pulsed-wave lasers was introduced (13). These devices combine a brief pulse duration of light emission with a long pause interval, thus ensuring prevention of thermal injury and adverse effect on the arterial wall to be laser. The pulsed wave EL (308 nm, ultraviolet wavelength, in the UVB region of the spectrum) is an FDA and EMEA approved device for treatment of atherosclerotic coronary lesions considered "non ideal" for standard balloon angioplasty (14-16). Furthermore, continuous saline flush of saline during laser advancement has allowed to further reduce heat generation and tissue damage. Taken together device improvement and technical advancement have allowed to lower procedural complication rate and to confirm in published registries the safety of the EL assisted angioplasty (17-18). In the setting of thrombotic lesion, EL has the potential to vaporize thrombotic and plaque material, leading to particles smaller than the size of erythrocytes unlikely to plug the microcirculation (19-20), and inhibits platelet aggregation, by inducing platelets stunning (21). Furthermore, laser is able to debulk underlying thrombogenic plaque thus limiting its thrombogenicity (22). EL has been used in the setting of STEMI within registries (23-26) and in a small randomized trial vs balloon assisted PPCI (27), showing a very low rate of myocardial no-reflow, as assessed by angiography (around 5%) and electrocardiography (around 35%). These studies, however, were limited by the small sample size and for most of them by the non-randomized design. Thus, a randomized study of EL assisted PPCI has become necessary in order to evaluate the efficacy of this mechanical strategy for STEMI patients. As MTA-assisted PPCI is nowadays the recommended approach by current guidelines, the effectiveness of EL-assisted PPCI should be evaluated against MTA-assisted PPCI. The goal of this trial, which will be carried out in patients with STEMI undergoing PPCI, is to assess the superiority of EL-assisted vs MTA-assisted PPCI, having as primary end-point the rate of 90-min ST segment resolution>70% and as secondary end-points the rate of angiographic no-reflow, defined as TIMI flow3 and MBG >=2 (28), the evaluation of infarct size, as assessed by the area under the curve of cardiac markers (29) and the rate of adverse remodelling as assessed by echocardiography at 6 months follow-up Description of LASER-AMI trial Study design LASER-AMI is a randomized, open-label, blind-examination (PROBE), active controlled, multinational clinical trial. Patients undergoing PPCI will be randomly assigned to 1 of 2 interventional strategies of reperfusion: MTA-assisted PPCI alone or EL-assisted PPCI alone. Study protocol and procedure The informed consent will be signed before angiography. The randomization process will start after the completion of diagnostic angiography and patients will be allocated to one of the following two arms: MTA-assisted PPCI alone; or EL-assisted PPCI alone. A consecutively numbered and sealed envelope will be opened to have knowledge of the randomization arm. Each enrolling center will receive from the promoting center an exact number of numbered envelopes to use for the randomization. The interventional procedure will be carried out according to usual site's local protocol. The choice of vascular access and stent type will be left to operator discretion. All patients will receive aspirin per os (150-325 mg), clopidogrel (600 mg) or prasugrel or ticagrelor in the emergency department. Anticoagulant therapy in the catheterization laboratory will be left to the operator's choice according to recent ESC guidelines (1); GP IIb/IIIa inhibitors will be considered for bailout therapy if there is angiographic evidence of massive thrombus, slow or no-reflow or a thrombotic complication. After identification of culprit vessel and crossing the lesion by the guidewire, vessel recanalization will start by using either MTA or EL, according to randomization (see appendix 1 about advices for ELCA use). The choice of the MTA devices will be left to each site's usual availability. Complications related to either ELCA or MTA will be recorded (perforation, dissection) as well as failure to restore antegrade flow and lack of crossing culprit stenosis. The use of balloon after MTA or EL is left to operator discretion, even if direct stenting is recommended. In all patients, after MTA or ELCA, intracoronary adenosine (120 µg as fast bolus followed by 2 mg given in 33cc of saline in 2 minutes as slow bolus) will be administered. Vessel recanalization will be completed by coronary stenting. Postdilatation of the stent is left to the operator's discretion, although stent overexpansion is not recommended in order to reduce the risk for no-reflow. Angiographic and electrocardiography analysis Angiographic analysis will be performed off-line by the angio core lab (IsMeTT, Palermo, Italy) and will include: quantitative coronary angiography (31), TIMI flow (32), corrected TIMI frame count (33), MBG (34), combined evaluation of TIMI flow and MBG (27), thrombus score (35), and Rentrop collateral grading (36). Angiographic no-reflow will be defined as a final TIMI flow of < 2 or final TIMI flow 3 with a MBG 0/1 (3,27). These parameters will be assessed according to validated methods (31-36). At 90 minutes after the end of the procedure a 12 leads ECG will be recorded for the analysis of ST-segment resolution as compared to admission ECG. Complete ST-segment resolution will be defined as >70% of ST-segment as compared to baseline in both single lead showing maximum ST-elevation on admission and on the sum of leads showing ST-elevation on admission (37,38) Baseline ECG will be also assessed off-line for number of Q waves and terminal distorsion of QRS (39). ECG analysis will be performed offline by an ECG core lab (Clinica di Cardiologia, UNIVPM, Ancona, Italy). Echocardiographic protocol At day 3 to 5 and at 6-month after the index procedure all patients will undergo comprehensive 2D transthoracic echocardiography examination at rest. End-systolic (LVESV) and end-diastolic volumes (LVEDV), LV ejection fraction (LVEF), presence and degree of mitral insufficiency and wall motion score index (each segment scored from 1= normal/ hyperkinetic, to 4 = dyskinetic, in a 16 segment model of the left ventricle) will be calculated following the recommendations of the American Society of Echocardiography (40). LV volumes and ejection fraction will be measured by modified biplane Simpson's method, and adjusted for body surface area. LV remodeling will be defined as an increase in end-diastolic volume > 20% at 6 months after AMI as compared to in-hospital examination (7). Serious Adverse Events Serious adverse events will be recorded and defined as any untoward medical occurrence that results in cardiac death, vascular death, death, re-infarction, target lesion revascularization, target vessel revascularization, or stent thrombosis. They will be communicated to the Safety Board within 24hours from their occurrence. Blood sampling Blood samples will be collected before the PCI and at 4, 8, 12, 24, 36, 48, and 72 h after the procedure to measure creatine kinase-myocardial band (CK-MB) (mass), troponin-T (mass), and hemoglobin levels. Clinical follow-up The incidence of cardiac death, myocardial infarction, target lesion revascularization and heart failure requiring hospitalization will be assessed at 6 months by interview and clinical check and at 1 year by telephone contact. In line with protocol, interviewers and examiners will not know which drug was administrated at the time of procedure. The accumulation of such end-points will be defined as major adverse cardiac events (MACEs). Study end-point The end-point of the study is the comparison of the rate of ST-segment resolution at 90 minutes post PPCI between patients randomized to MTA-assisted PPCI and EL-assisted PPCI. Thus, the study will test whether EL-assisted PPCI is superior to MTA-assisted PPCI in reducing of the incidence of electrocardiographic no-flow after performing PPCI. Secondary endpoints are: a) angiographic no-reflow defined as a TIMI flow ≤2 or a TIMI flow 3 with a MBG 0/1; b) LVESV, LVEDV, LVEF, and WMSI assessed by in-hospital and 6 months echocardiography; c) infarct size, defined as CK-MB and troponin-I area under the curve; d) MACEs rate in the two groups at 6 and 1 year follow-up. Power calculation LASER-AMI is a randomized, open-label clinical trial, in which patients will be randomly assigned to 1 of 2 interventional strategies (MTA-assisted PPCI; or EL-assisted PPCI). The primary objective of LASER-AMI trial is to test the superiority of EL-assisted PPCI vs MTA-assisted PPCI based on the rate of post-procedural STR>70% after PPCI. The study sample size was powered to demonstrate a significant difference in the primary end point of rate STR >70%, which was around 56% in a previous trial of PPCI with MTA only (10). Starting from such figures and thus assuming an 76% event rate in the control group with an absolute 20% decrease in the experimental group, we calculated that 194 patients (97 per group) had to be enrolled to have an alpha error of 0.05 and a power of 0.80 in a prospective 1:1 randomized study. Statistical analysis All analyses will be planned and conducted according to the intention-to-treat principle, as this approach minimizes the risk of selection bias and alpha error. Continuous variables (presented as mean ± standard deviation) will be compared by the Student t test for normally distributed variables and by the Wilcoxon test for nonnormally distributed variables. Chi-square tests will be used to compare discrete variables (reported as raw numbers [%]). Odds ratios (OR) with 95% confidence intervals (CI) will be calculated to compare event rates in the EL-assisted PPCI group versus those observed in the MTA-assisted PPCI group (considered as the control group). A multivariable logistic regression analysis will be also performed to further assess and confirm the independent predictive value of randomization to EL-assisted PPCI for the achievement of STR>70% (cut-off for entry 0.05, cut-off for removal 0.10). Moreover, infarct size assessment will be perfomed, defined as CK-MB and troponin-I area under the curve, calculated by the linear trapezoidal method (29). If baseline or 72-h values are missing, the value will be set to 0, whereas missing intermediate values will be substituted by linear interpolation. For patients dying in the first 72 h after enrollment, the area under the curve will be set as the largest area under the curve recorded in the study (29). Analyses will be carried out using SPSS for Windows 11.0 (SPSS Inc., Chicago, Illinois). Statistical significance will be defined by two-tailed p < 0.05. In addition, prespecified subgroup analyses by means of multiple logistic regression or multiple linear regression, as appropriate, will be performed according to the following variables: age class, sex, diabetes, anterior myocardial infarction, total ischemic time cutoff, pre-infarction angina, baseline angiographic thrombus score, baseline TIMI flow, number of diseased vessels.

Myocardial Infarction, No-reflow, Primary PCI, Coronary no-reflow phenomenon, Primary percoutaneous coronary intervention (primary PCI)

After wire crossing, Excimer Laser will be performed. Consequently, intracoronary adenosine will be selectively administered through the guiding catheter.

After wire crossing, thrombus aspiration will be performed. The device will removed outside the body, flushed with saline and subsequently reintroduced in the culprit vessel beyond the occlusion site and intracoronary adenosine will be selectively administered.

Inclusion Criteria: Onset of symptoms of MI less than 12 hours prior to enrolment; ST-segment elevation of at least 2 mm in two or more contiguous leads; Vessel and lesion amenable to both coronary laser and manual trhombus aspiration (lack of marked vessel/lesion tortuosity or calcification; reference vessel diameter >2.5 mm in diameter); Written informed consent. Exclusion Criteria: Rescue angioplasty after failed thrombolysis; Stent thrombosis; Culprit lesion located in a bypass graft or in the left main trunk; Cardiogenic shock; Young age (< 18 years); Severe renal failure (creatinine clearance ≤30 ml/min); Concomitant disease resulting in a life expectancy of less than 6 months; Pregnancy; Contraindications to contrast agents not manageable medically, or to study medications, including aspirin, clopidogrel, ticlopidine and heparin; Left bundle branch block, paced rhythm, frequent ventricular ectopy, pre-excitation or other ECG abnormalities interfering with the analysis of ST-segment resolution; Markedly depressed LV function (LVEF <30%); Culprit lesion cannot be identified; Severe left main or triple vessel disease requiring CABG during the index hospitalization; Patients already involved in other ongoing trials; Patients unable or unwilling to give their informed consent.

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