Pre-hospital ticagrelor in patients with ST-segment elevation myocardial infarction with long transport time to primary PCI facility

Abstract

Background

Pre-hospital ticagrelor, given less than 1 h before coronary intervention (PCI), failed to improve coronary reperfusion in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI. It is unknown whether a longer interval from ticagrelor administration to primary PCI might reveal any improvement of coronary reperfusion.

Methods

We retrospectively compared 143 patients, pre-treated in spoke centers or ambulance with ticagrelor at least 1.5 h before PCI (Pre-treatment Group), with 143 propensity score-matched controls treated with ticagrelor in the hub before primary PCI (Control Group) extracted from RENOVAMI, a large observational Italian registry of more than 1400 STEMI patients enrolled from Jan. 2012 to Oct. 2015 ( ClinicalTrials.gov id: NCT01347580 ). The median time from ticagrelor administration and PCI was 2.08 h (95% CI 1.66–2.84) in the Pre-treatment Group and 0.56 h (95% CI 0.33–0.76) in the Control Group. TIMI flow grade before primary PCI in the infarct related artery was the primary endpoint.

Results

The primary endpoint, baseline TIMI flow grade, was significantly higher in Pre-treatment Group (0.88 ± 1.14 vs 0.53 ± 0.86, P = 0.02). However in-hospital mortality, in-hospital stent thrombosis, bleeding rates and other clinical and angiographic outcomes were similar in the two groups.

Conclusions

In a real world STEMI network, pre-treatment with ticagrelor in spoke hospitals or in ambulance loading at least 1.5 h before primary PCI is safe and might improve pre-PCI coronary reperfusion, in comparison with ticagrelor administration immediately before PCI.

Highlights

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The ATLANTIC randomized study failed to demonstrate a superiority of ticagrelor pre-treatment before primary PCI, probably due to a too short interval between the drug administration and coronary angiography. Thus this treatment is not currently recommended before primary PCI.
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In many real world hub and spoke STEMI networks the time interval between ticagrelor administration and primary PCI may be much longer than those observed in the ATLANTIC study.
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In the large Italian STEMI registry RENOVAMI, ticagrelor pre-treatment at least 1.5 h before primary PCI was safe and improved pre-PCI coronary reperfusion, in comparison with ticagrelor administration at the moment of primary PCI. These data support the hypothesis that, in selected patients with a long time from first medical contact and primary PCI, pre-treatment with ticagrelor may give some clinical benefit.

1 Introduction

Dual antiplatelet therapy inhibiting both thromboxane A2-dependent platelet aggregation and P2Y12 receptors has a capital role in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) and this particular patient population needs more aggressive antiplatelet drugs to improve clinical outcomes . To maximize this benefit, an earlier administration of P2Y12-receptor inhibitors has been advocated according to theoretical pharmacological issues . However the translation into clinical practice of such theories was not so straightforward, with conflicting results in registries , randomized studies and meta-analyses . In fact an early treatment with clopidogrel before primary PCI had been previously suggested to reduce the rate of ischemic events without bleeding excess , but these benefits might be limited by a variability in the individual response to the drugs and the time needed for absorption and active metabolites production . Conversely prasugrel and ticagrelor could become active in a time range compatible with the majority of transfers for primary PCI , even if a full antiplatelet efficacy may manifest only after several hours . Recently the Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) study, a multicenter, randomized, double-blind clinical trial involving 1862 STEMI patients, compared pre-hospital (in ambulance) versus in-hospital treatment with ticagrelor . In this study pre-hospital ticagrelor administration did not improve pre-PCI coronary reperfusion, even if a trend for better ST-segment elevation resolution after primary PCI and a reduction of definite stent thrombosis at 30 days were reported. As the ATLANTIC median time from randomization to angiography was 48 min, time for ticagrelor absorption and platelet inhibition might have been insufficient in many cases to affect the primary endpoint, especially in large MIs with reduced cardiac output or after treatment with opioids , both causes of delayed intestinal absorption. Thus, at the moment, it is unknown if pre-hospital treatment with ticagrelor might improve pre-PCI reperfusion in real world STEMI patients with expected longer transport times and consequently more time for the novel antiplatelet agent to function.

2 Methods

2.1 Population

The RENOVAMI (“REgister of Myocardial Infarction Patients Treated by the NOVAra STE-MI Network“, ClinicalTrials.gov Identifier: NCT01760382 ) is a prospective, ongoing, observational, cohort study focusing on STE-ACS patient treated with primary PCI conducted in a single, tertiary, large-volume center which serves as hub center for a local primary PCI network. RENOVAMI has been organized by the Hospital Cardiology Department of the “Maggiore della Carità” Hospital of Novara and is endorsed by the Italian Council of Cardiology Practice.

We analyzed data from a cohort of consecutive acute coronary syndrome presenting with ST-segment elevation (STE-ACS) patients undergoing primary PCI in our center, treated between January 2012 (date of first availability for clinical use of ticagrelor in our network) and December 2015. We applied standard criteria for STE-ACS diagnosis, taking into account clinical presentation, electrocardiographic findings and the results of serum biochemical markers of necrosis . Patients were treated according to usual clinical practice and PCI was performed using standard techniques . We excluded patients younger than 18 years, patients presenting more than 12 h after symptoms onset, patients treated with thrombolysis, patients with failure of primary PCI to mechanically restore the patency of the culprit coronary vessel and patients unable to give informed consent.

A team of research nurses collected and entered in a dedicated database the information on patient demographic characteristics, medical history, pre-hospital and in-hospital therapy, timing of care delivery, angiographic and interventional details, laboratory tests and in-hospital patient outcomes. In particular, a detailed recording of the administered antithrombotic treatment was made. The antithrombotic strategy and the initial P2Y12 inhibitor choice, along with the subsequent confirmation or change of hospital and pre-discharge antiplatelet therapy, were done at discretion of the treating physicians. Data on in-hospital major adverse cardiovascular events (MACE) including death, myocardial infarction, definite or probable stent thrombosis, urgent revascularization, stroke, and bleeding events according to Bleeding Academic Research Consortium (BARC) criteria were prospectively collected. Outcome adjudication were performed by a local adjudicator committee formed by the Cardiology Department director, the Coronary Care Unit director and the Catheterization Laboratory director, who reviewed the respective medical records (clinical charts, coronary angiography reports, laboratory values, discharge summaries). In controversial cases divergence was resolved by consensus.

2.2 Study endpoints and statistical analysis

The primary focus of this retrospective analysis was the intention-to-treat comparison of patients pre-treated (in spoke centers or in ambulance) with a 180 mg ticagrelor load at least 1.5 h before PCI (Group 1) with a population of propensity score-matched controls treated with ticagrelor load only at the time of primary PCI in the hub hospital (Group 2). To account for the effect over reperfusion indexes of the duration of ischemia, patients were also matched according to time from symptoms onset to mechanical reperfusion.

Thrombolysis in myocardial infarction (TIMI) flow grade in the infarct related coronary artery (IRCA) immediately before primary PCI was the primary endpoint of the study.

Other secondary endpoints included the clinical and angiographic pre- and post-procedural outcomes and the rates of in-hospital major adverse cardiovascular events and definite stent thrombosis. In particular, we assessed the rate of patency of the IRCA (TIMI flow grade > 0) before primary PCI, the TIMI thrombotic burden (0–5) before primary PCI , the rates of >70% reduction from baseline of ST-segment elevation 90 min after PCI, the rates of post-procedural TIMI 3 flow grade (0–3), the rates of post-procedural TIMI perfusion grade (0–3) , the post-procedural TIMI 3–2 vs 1–0 blood flow grade, and the post-procedural corrected TIMI frame count (cTFC) . New myocardial infarction was defined according to the “universal definition of myocardial infarction” . Coronary stenosis were described according to the AHA-ACC classification and thrombus burden was graded according to the TIMI grade I-V classification as recommended . Finally TIMI coronary blood flow grade and cTFC were assessed according to current recommendations . Angiograms were analyzed on site by 2 independent experienced interventional cardiologists, discrepancies were resolved by consensus.

As in-hospital outcomes we considered the rates of in-hospital mortality, in-hospital definite stent thrombosis, in-hospital nonfatal reinfarction, in-hospital stroke and in-hospital bleedings, classified according to BARC .

Categorical data are presented as counts and percentages. Continuous data with normal and skewed distribution are presented as means ± SD and medians (interquartiles) respectively. The Kolmogorov–Smirnov test was used to examine data distribution normality. Unpaired T test was employed for comparisons of continuous variables with normal distribution, whereas Mann–Whitney U test was used for continuous variables with non-normal distribution, and Chi ²test was used for categorical clinical and angiographic characteristics and for outcome rates.

In total, 15 clinical variables with a potential influence over the baseline TIMI flow grade were used to calculate propensity scores (age, male sex, body mass index, admission from a spoke hospital, symptoms to reperfusion time, hypertension or hypotensive drugs use, type 2 diabetes or antidiabetic drugs use, dyslipidemia or lipid-lowering drugs use, tobacco use, peripheral vascular disease, impaired renal function with glomerular filtration rate ≤ 30 mL/min, ST elevation in the anterior precordial leads, baseline left ventricular ejection fraction, previous MI, PCI or coronary artery bypass graft, clopidogrel pre-procedural load). Greedy, Mahalanobis distance 1:10 within propensity score calipers (width of 0.20 of the standard deviation of the logit of the propensity score) matching was used. Standardized differences of the mean < 10% were taken to indicate good balance in the matched sample.

Variables independently correlated with pre-intervention TIMI blood flow in the infarct related artery were identified with multiple regression analysis. The covariates tested for in this model were age, diabetes, estimated glomerular filtration rate (eGFR) <30 mL/min, anterior location of the ST elevation, pre-treatment with ticagrelor 180 mg loading dose and time interval from symptoms to balloon. Covariates with an exploratory P < 0.1 were entered into a multiple regression analysis model. Potential interactions between covariates were tested; variables with a significance that was explained by multicollinearity were excluded. Finally, covariates significantly associated with the outcome of interest at a significance level of P < 0.05 were included in the final model.

In-hospital mortality, stent thrombosis, BARC 3 bleeding and net clinical effect rates were calculated and plotted according to the Kaplan–Meier method, and comparisons between groups were performed using the log-rank test. The relation of ticagrelor pre-treatment and the risk for each study endpoint was assessed with Cox proportional hazards models. The covariates tested for in this model were male sex, age, hypertension, diabetes, dyslipidemia, body mass index (BMI) > 30 kg/m ²of body surface area (BSA), estimated glomerular filtration rate (eGFR) <30 mL/min, cigarette smoking (active or quitted <2 years), previous MI and/or PCI, previous CABG, peripheral artery disease, left ventricular ejection fraction (LVEF), pre-treatment with ticagrelor 180 mg loading dose, intraprocedural use of GP2b3a inhibitors, multivessel CAD, left main, type B2/C lesion, multivessel PCI, direct stenting, high pressure post-dilation, number of implanted stents, drug eluting stents (DES) use, and total stent length (mm). Univariate associations with clinical outcomes were estimated for all clinical and procedural variables and included with a P level < 0.10. Covariates were considered independently associated with the outcome of interest at a significance level of P < 0.05 in the final model.

All tests were 2-tailed and statistical significance was considered for P < 0.05. Statistical analyses were performed using SPSS for Windows (version 16.0; SPSS, Inc., Chicago, IL), NCSS (version 8.0 NCSS, Kaysville, UT) and PASS (version 11.0, Kaysville, UT).

2.3 Ethical issues

The present study is a retrospective propensity score-matched analysis and was conducted according to the local institutional review board guidelines. All patients signed a written informed consent for personal data treatment when enrolled in the RENOVAMI registry.