Platelet glycoprotein IIb/IIIa inhibitor tirofiban in clopidogrel-naïve patients undergoing elective percutaneous coronary intervention

This was a retrospective cohort study with participants from Zuyderland Medical Centre in Heerlen, the Netherlands. The study population consisted of patients undergoing elective or ad-hoc PCI from 22 September 2014 to 1 October 2021. Eligible patients were ≥ 18 years of age who had AP or angina-equivalent symptoms and were admitted to the Cardiology Outpatient Department. Patients with ACS in the previous year and those with chronic total occlusion were excluded. All patients undergoing PCI at the Zuyderland Medical Centre are prospectively registered in a database.

The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the Committee on Research Ethics of the Zuyderland Medical Centre.

The study population was divided into 2 groups. Group 1 consisted of clopidogrel-naïve patients underwent ad-hoc PCI who received high-dose bolus of tirofiban intravenously in the cardiac catheterisation room, i.e. immediately after ICA but before the start of the PCI procedure, followed by a 600-mg loading dose of clopidogrel immediately after the intervention (group 1). Group 2 comprised patients who received clopidogrel 75 mg daily in the outpatient setting ≥ 1 day before elective PCI (group 2).

The primary outcome comprised major adverse cardiovascular events (MACE) at 30 days after adjustment for baseline differences. MACE was defined as the composite of death, myocardial infarction (MI), transient ischaemic attack (TIA), cerebrovascular accident (CVA), target-lesion revascularisation and bleeding. MI was defined as a significant troponin rise and/or fall in the clinical blood assessment [7]. Bleeding was defined according to the definition of the Bleeding Academic Research Consortium (BARC) criteria from type 3 onwards. Type 3a is defined as bleeding resulting in a haemoglobin drop of 3 to < 5 g/dl, type 3b as bleeding plus a haemoglobin drop ≥ 5 g/dl and type 3c as intracranial haemorrhage [8].

Secondary outcomes consisted of MACE at 7 days and the individual components of the primary outcome at 7 days and after 30 days. All outcomes were evaluated using electronic patient records.

Baseline characteristics were analysed for normal distribution using the Skewness and Kurtosis test. Differences in baseline characteristics between the 2 groups were compared using the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Data are presented as mean ± standard deviation for continuous variables and as median (interquartile range) or frequency and percentage for categorical variables.

Based on the PRAGUE-8 trial, we concluded that a combined endpoint of death, MI, cerebral infarction and re-intervention within 1 week is 1.3% in patients who received a loading dose of clopidogrel ≥ 6 h before CAG and PCI. Few data are available on the combination of ad-hoc bolus GPI in the elective setting with subsequent clopidogrel loading. Marian et al. conducted an RCT comparing a bolus GPI with powdered ticagrelor in patients with IAP. None of the patients who received ad-hoc bolus GPI and a 600-mg clopidogrel loading dose after PCI, had the primary outcome measure [4, 10]. Based on the studies mentioned, it could be expected that in the clopidogrel group in our study approximately 1.3% of the patients will reach the primary endpoint after 1 week. For the ad-hoc GPI group, this would be between 99 and 99.9%. With a two-sided significance level of 2.5%, a power of 80% and a non-inferiority limit of 1%, a sample size of 432 patients per treatment group and 864 patients in total was calculated.

During the study period, 1404 patients met the in- and exclusion criteria and were included in this analysis: 432 (31%) in group 1 and 972 (69%) in group 2. Their baseline characteristics are presented in Tab. 1. The mean age was 69 ± 9 years, 396 patients (28%) were female, and 406 (29%) had diabetes mellitus. Significant differences between the groups were observed for age, number of patients with hypercholesterolaemia, medical history (coronary artery bypass grafting, TIA, CVA), estimated glomerular filtration rate, creatinine level and PCI access site.

At 7 days of follow-up, the primary composite outcome (MACE) had occurred in 6 patients (1.4%) in group 1 and 30 patients (3.0%) in group 2 (p = 0.08). At 30-day follow-up, MACE were observed in 8 patients (1.9%) in group 1 compared with 41 (4.2%) in group 2 (p = 0.03) (Tab. 2). Acute stent thrombosis occurred in 3 patients (0.3%) in group 2 and none in group 1. After adjusting for baseline differences, there was no significant difference in the primary outcome (HR: 1.8; 95% CI: 0.8–3.9) (Tab. 3).

Secondary outcomes were comparable between the groups (Tab. 2). Kaplan-Meier survival curves are shown in Fig. 2.

Since this was a retrospective study, missing data could not be traced. Nonetheless, the study had enough power according to the calculated sample size. Furthermore, not all baseline characteristics were well balanced. Patients in group 2 were older, had a higher risk profile and had undergone more transfemoral procedures. Transfemoral access for performing coronary angiography may have a higher risk for bleeding complications [11]. In our study, we evaluated bleeding BARC ≥ 3; however, assessment of bleeding BARC 2 may at times also be important. Another limitation of our study is that we did not investigate the angiographic characteristics of the lesions.

Nevertheless, to reduce confounding bias, we performed Cox regression analysis. All patients who underwent elective invasive catheterisation were screened. The study sample can be considered representative of the population of patients undergoing PCI in daily practice. Performing ad-hoc PCI was at the discretion of the operator, while elective PCI was previously scheduled and usually discussed by the Heart Team. This may also have affected our findings. However, Cox regression analysis was performed to correct for important differences.

In the current study, clopidogrel-naïve patients were treated with a GPI bolus to bridge the duration action of clopidogrel. However, further research is needed to investigate the optimal pretreatment option for clopidogrel-naïve patients undergoing ad-hoc PCI, especially to analyse the safety of ad-hoc PCI in clopidogrel-naïve patients without GPI pretreatment or administration of a clopidogrel loading dose in the catheterisation laboratory immediately before or after the PCI.

This study may give an indication of the safety of GPI usage in the ad-hoc PCI setting in clopidogrel-naïve patients. Further study is necessary to determine the optimal antithrombotic therapy for ad-hoc PCI in clopidogrel-naïve patients.