Tabla 1. Baseline clinical characteristics of the population.

Tabla 2. Angiographic and procedural characteristics of the population.

Figura 1. Study design. CECI,Cardiovascular Research Center; STEACS: ST-segment elevation acute coro...

Tabla 3. In-hospital outcomes.

Figura 2. Rate of in-hospital hemorrhagic complications. The chart includes the bleeding BARC defini...

INTRODUCTION

Percutaneous coronary intervention is the strategy of choice to treat patients with ST-segment elevation myocardial infarction when trying to restore blood flow by opening an artery occluded due to a thrombus. The thrombus burden is associated with the rupture of the plaque and platelet activation. In addition, it’s an independent phenomenon that predicts slow flow.1,2 This slow flow is associated with distal embolization or microcirculation, which reduces myocardial perfusion while increasing the rate of malignant arrhythmias, heart failure, reinfarction, and death.3

The use of glycoprotein IIb/IIIa inhibitors (GPIs) is recommended in cases with a high thrombus burden and is used in percutaneous coronary intervention in cases where there is no proper pretreatment with powerful antiplatelet agents with documented clinical benefits but increased bleeding.4-8 Eptifibatide, abciximab, and tirofiban (all GPIs often used) have been tested with clopidogrel. However, there is no evidence from randomized clinical trials with the most powerful ticagrelor or prasugrel.9,10 As a matter of fact, evidence is based on the continuous administration of GPIs both regarding the high thrombus burden, and to reduce the rate of the slow-flow phenomenon. However, there is scarce information on the results of its intracoronary use via catheter whether dedicated or not in terms of efficacy.4,11

The objective of this study was to assess the safety and efficacy profile of the intracoronary use of tirofiban in patients treated with percutaneous coronary intervention due to ST-segment elevation myocardial infarction.

MATERIAL AND METHODS

Study population

The study was based on data from our center as part of the multicenter registry of the Centro de Estudios en Cardiología Intervencionista (CECI). This is an ongoing, open-label, prospective, observational registry of consecutive patients including a network of different cardiology units with cath lab capabilities, and the capacity to perform percutaneous coronary interventions in the metropolitan area in Buenos Aires, Argentina. The analysis included all the patients admitted to the cath lab with a diagnosis of ST-segment elevation acute coronary syndrome achieved at Sanatorio Otamendi from 2016 through 2022. The only exclusion criteria were the impossibility to perform cine coronary angiography at admission, the previous use of thrombolytic agents (angioplasty or bailout angioplasty), and those who received GPIs (tirofiban) in continuous infusion.

Study endpoints and definitions

Patients were categorized into patients who received intracoronary GPIs and those who did not. The intracoronary dose of GPIs was 25 μg/kg in bolus. The study safety primary endpoint was knowing whether the intracoronary use of the drug increased bleeding when used together with the new P2Y12 inhibitors according to the latest definition established by the Bleeding Academic Consortium (BARC).12 Also, the overall bleeding and puncture site-related bleeding were studied. The study efficacy primary endpoint was in-hospital mortality. The study secondary endpoint was the need for new revascularization due to stent thrombosis. The baseline clinical and angiographic characteristics were studied as well. Also, the subgroups of concomitant thrombus aspiration, the thrombus burden based on the TIMI scale, the early TIMI flow, and the rate of no-reflow phenomenon were studied as well.

Regarding the TIMI thrombus grade scale, the one introduced by Rotterdam Thoraxcenter was used (Sianos G, Papafaklis MI, Daemen J, et al. Angiographic stent thrombosis after routine use of drug eluting stents in ST-segment elevation myocardial infarction. The importance of thrombus burden. J Am Coll Cardiol 2007;50:572-83). In conclusion, the method consists of using a guidewire or a 1.5 mm balloon to cross or re-cannulate the lesion in case of TIMI grade-5 flow (acute total occlusion), thus allowing some degree of antegrade flow to expose the thrombus and re-categorize it into small (grades 1 to 3) or large thrombi (grade 4).

The registry followed the rules and regulations set forth in the Good Clinical Practice (GCP) standard and the local legislation.

Statistical analysis

The sample was divided into 2 groups: those who received GPIs, and those who didn’t. Categorical variables were expressed as means (%) while the continuous ones were expressed as means with their standard deviation. The former ones were visually analyzed, and they all had a normal distribution. The Student t test, and the one-factor ANOVA were performed. Categorical variables were compared using the chi-square test and Fisher’s exact test, when appropriate. All were 2-tailed tests. P values < .05 were considered statistically significant. The statistical software package SPSS v.22.0, IBM (United States) was used.

RESULTS

Out of the 235 patients included in the CECI registry from the center, a total of 24 were excluded for analysis purposes (Figure 1). Finally, a total of 211 patients with a definitive diagnosis of ST-segment elevation acute coronary syndrome, 82 patients who did not received GPIs, and 129 who did so were included in the analysis.

Table 1 shows the clinical characteristics of the study population. The mean age was 65 ± 14.9 years being the youngest the group that received GPIs without statistical significance (67.2 ± 14.8 vs 63.8 ± 14.8; P = .10); a total of 78.2% were men. Pain-to-balloon and door-to-balloon times were 265 ± 168 min and 55 ± 51 min, respectively, which was similar in both groups as shown on Table 1. In addition to being younger, patients who received GPIs had a tendency towards smoking more actively (32.6 vs 22.0; P = .09).

No differences were reported between the type of antiplatelet agent used to treat the patient’s thrombus burden and the use, or not, of intracoronary GPIs. However, a significant difference was found when the patient had been anticoagulated prior to his hospital admission for a different preexisting condition. In that case, GPIs were not used (11.0% vs 3.9%, P = .04).

Access site was often the femoral access route without significant differences reported between the 2 groups. There was a tendency towards the culprit artery being the left anterior descending coronary artery (LAD) in the group that received the GPIs (54.3% vs 41.5%; P = .07). Also, the TIMI grade-0-1 flow seen on the cine coronary angiography was more common in the GPI group (86.7% vs 60.5%; P < .001) same as the use of manual thrombus aspiration (25.6% vs 8.5%; P = .002) as Table 2 shows together with other angiographic and procedural characteristics.

Regarding bleeding, no inter-group differences were seen when overall bleeding and the puncture site-related bleeding were compared or in any of the BARC classification categories as shown on figure Figure 2. Also, no differences were seen when the femoral or radial puncture site were discriminated. When the use of GPIs and the new P2Y12 inhibitors was compared no differences were reported either or when these were compared to clopidogrel as shown on figure Table 2.

Table 3 also shows the in-hospital results with no differences regarding cardiac tamponade, acute kidney injury or cardiogenic shock. We should mention that, during the hospital stay, color Doppler ultrasounds were performed on a routine basis after the procedure. A correlation was found between a poor ventricular function measured using Simpson’s rule and the previous use of GPIs (7.3% vs 22.8%; P = .003). A total of 6 patients died during the procedure or the hospital stay, 2 of whom were admitted to the cath lab in cardiogenic shock and another 2 evolved to KK D. One out of the 2 remaining patients developed VT/VF at the cath lab while the second one was a patient who had tested positive for COVID-19 and admitted with an extensive anterior infarction and bilateral acute arterial ischemia that had progressed into acute kidney injury and posterior distributive shock. We should mention that none of the patients who dide had acute stent thrombosis during the hospital stay.

DISCUSSION

Our study shows that the intracoronary use of GPIs in patients with STEACS revascularized with percutaneous coronary interventions was not associated with a higher rate of bleeding regardless of the use of P2Y12 inhibitors or the access site selected. In our population the rate of use of GPIs was 61.1%, a similar percentage compared to the one shown in the TRITON-TIMI 38 STEMI trial (64%), and above other series like the registry conducted by Blanchart et al. (41%), and the PLATO-STEMI (37%) and ATLANTIC (43%) clinical trials.13-16

The use of GPIs is not a common thing in our country both for procedural and financial reasons. Also, the evidence available on their safety regarding intracoronary use together with the most powerful P2Y12 inhibitors is scarce.17 Our study is the first one ever conducted in our country that sheds light on all these issues. We proved that the intracoronary use of only GPIs did not increase the rate of any kind of bleeding regardless of the selection of the dual antiplatelet therapy used. A randomized clinical trial assessed the use of abciximab in bolus plus infusion vs infusion only proving the superiority of the former regarding the infarction size and the ventricular function at 6 months without any clarification being made regarding bleeding.18,19 A Hindu registry assessed a single dose of abciximab in bolus vs standard therapy concluding that the continuous infusion triggered increased bleeding without any differences being reported regarding ischemic events.20

Post-hoc landmark randomized trials showed an increased rate of bleeding when the most powerful antiplatelet agents (prasugrel or ticagrelor) and GPIs were combined. However, in these studies, GPIs were mostly used in continuous infusions. The French registry conducted by Blanchart et al. showed findings similar to ours without increased bleeding.13-16 A review published back in 2021 discussed the use of dedicated catheters for the bolus administration of GPIs. However, no conclusive results have ever been come up on this regard.21

Regarding clinical events, no association between the use of GPIs and in-hospital mortality was ever reported. Also, no association was found between early stent thrombosis and the use of GPIs. The current guidelines recommend the use of GPIs in selected patients with STEACS who did not receive P2Y12 inhibitors. Still, our study did not analyze the moment when these were administered.

This was an exploratory analysis. Therefore, no definitive conclusions should be drawn due to its non-randomized nature. However, it shows us the safety profile of the use of these drugs regarding bleeding and ischemic events, results that can be replicated in other series published. Since this was a single-center study it needs to be interpreted with caution. Although it is a registry of consecutive patients, the size of the sample is small, and the pain-to-balloon and door-to-balloon times were good and similar to those recommended by the international clinical practice guidelines. However, we don’t know what the results may look like with longer times and a larger number of patients. This is something we expect to know when the CECI registry that includes several centers in our country is completed.

CONCLUSIONS

Our exploratory analysis shows that the intracoronary use of GPIs both with clopidogrel and with the new P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction and revascularized with percutaneous coronary intervention is safe and effective.

Dedicated randomized clinical trials are expected to assess appropriately who are the patients that could benefit from this strategy.

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21. Kirresh A, Candilio L, Stone GW. Intralesional delivery of glycoprotein IIb/IIIa inhibitors in acute myocardial infarction: Review and recommendations. Catheter Cardiovasc Interv 2022 Feb;99(3):641-649. doi: 10.1002/ccd.30008. Epub 2021 Nov 12. PMID: 34767293.

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Safety of a single intracoronary dose of IIb/IIIa inhibitors in patients with high thrombus burden and ST-segment elevation myocardial infarction revascularized with percutaneous coronary intervention

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