Twelve-month results of a Paclitaxel R eleasing Balloon in Patients Pr esenting with In-stent Restenosis First-in-Man (PEPPER) trial

Abstract

Background

Coronary in-stent restenosis (ISR) continues to be a therapeutic challenge especially after drug eluting stent (DES) implantation. We studied patients with ISR to investigate safety and efficacy of a novel drug coated balloon (DCB) incorporating paclitaxel into a microcrystalline structure by applying the inert excipient butyryltri- n -hexyl citrate (BTHC) in a prospective First-in-Man trial.

Methods and Materials

Eighty-one patients were enrolled at 9 European sites, thereof 43 (53.1%) presenting with bare metal stent (BMS)-ISR and 38 (46.9%) with DES-ISR. The primary study endpoint was in-stent late lumen loss (LLL) independently assessed by a quantitative coronary angiography laboratory at 6 months. A secondary endpoint was major adverse cardiac events (MACE), a composite of cardiac death, non-fatal myocardial infarction, clinically driven target vessel revascularization after 6 and 12 months.

Results

At 6 months, overall LLL was 0.07±0.31 mm showing differences in BMS-ISR and DES-ISR treatment (− 0.05±0.28 mm vs. 0.19±0.29 mm, respectively, P =.001). Overall MACE rates at 6 and 12 months were 6.5% and 11.8%. At the 12-month follow-up, one myocardial infarction, and no cardiac death nor stent thrombosis had occurred.

Conclusion

Application of a novel paclitaxel coated balloon using BTHC as an excipient in patients with ISR is safe and results in very low LLL, revascularization- and MACE-rates at follow-up. (ClinicalTrials.gov:NCT00961181).

1 Introduction

The use of DES has led to a reduction of restenosis after treatment of de novo coronary artery lesions compared with BMS implantation . Nevertheless, treatment of patients with ISR continues to be a frequent therapeutic problem and treatment of patients with ISR in a drug eluting stent (DES-ISR) has become a therapeutic challenge . The use of DES in the treatment of DES-ISR is controversial since it is associated with a prolonged dual antiplatelet therapy up to 12 months with the inherent increased risk of bleeding complications.

In recent years, DCB have emerged as a valuable option to treat ISR . It has been shown that the use of DCB in treatment of ISR is superior to balloon angioplasty with sustained long-term outcomes at 5 years . Furthermore, DCB were superior to DES with respect to angiographic parameters and were associated with fewer clinical events in BMS-ISR .

We report 12 months results of a novel paclitaxel coated balloon using BTHC as an inert excipient for therapy of either BMS-ISR or DES-ISR. Preliminary 6 months outcomes of a subset of patients showed very promising early results, irrespective of whether the initially implanted stent was a DES or BMS .

2 Methods

The study design has been previously reported . Briefly, this single-arm trial was performed at nine heart centers in Europe. Completeness and quality of data was assured by 100% source data verification. Data management was performed by an independent contract research organization and offline quantitative coronary angiography (QCA) analysis was performed by an independent core laboratory (Deutsche Klinik für Diagnostik, Wiesbaden, Germany). All safety endpoint and serious adverse events were adjudicated by an independent clinical events committee and the study was conducted in accordance with the Declaration of Helsinki, ISO14155 and local regulations. The protocol was approved by independent ethical committees, and written informed consent was obtained from all patients prior to study procedures. All patients were requested to undergo repeat angiography 6 months after successful intervention. The trial was registered at Clinicaltrials.gov (NCT00961181).

Eighty-one patients presenting with coronary ISR after BMS or DES implantation were enrolled between August 2009 and April 2010. Eligible patients were older than 18 years, and presented with stable angina, unstable angina or documented silent ischemia with a percent diameter stenosis ≥ 50% and < 100%. Major exclusion criteria were acute myocardial infarction within 72 h pre-procedure, left ventricular ejection fraction of < 30%, additional coronary lesions in the target vessel which required treatment, known hypersensitivity or contraindication to required medication and conditions likely to preclude follow-up angiography.

Patients received peri- and post-procedural aspirin, clopidogrel and heparin according to standard practice at site. Dual antiplatelet therapy with aspirin and clopidogrel was recommended for 3 months post-procedure. Pre-dilatation with a shorter uncoated balloon was performed in all subjects with the exception of one.

The DCB used in this trial contains paclitaxel in a concentration of 3 μg/mm ²using butyryltri-n-hexyl citrate (BTHC) as excipient (Pantera Lux Paclitaxel coated PTCA balloon catheter; BIOTRONIK, Bülach Switzerland). BTHC incorporates paclitaxel into a micro-crystalline structure to improve drug uptake into the vessel wall compared to crystalline paclitaxel. In animal models, it proved its efficacy and had angiographic results comparable to iopromide , the most studied excipient in DCB to date . The Pantera Lux was available in length of 10 to 30 mm with diameters of 2.0 to 4.0 mm.

Angiography after intra-coronary nitroglycerin administration was performed before and after all interventions and at 6 months follow-up (184±19 days post-procedure) using identical projections. The CAAS II Research System (Pie Medical Imaging, Maastricht, The Netherlands) was used for automated contour detection and quantification. Measurements included an in-stent-analysis from shoulder to shoulder of the dilated DCB and an in-segment analysis considering the DCB treated area plus 5 mm proximal and distal. ISR was defined as recurrent diameter stenosis of at least 50% and was classified according to the Mehran classification .

Clinical follow up was performed at 6 and 12 months ( Fig. 1 ). In-stent LLL was the primary endpoint. Secondary endpoints included in-segment LLL at 6 months, in-stent and in-segment percent diameter stenosis at 6 months, and cumulative major adverse cardiac event (MACE) rate within 6 and 12 months. Thereby events up to 210 days (180+30 days time window) respective 425 days (365+60 days time window) were assigned to the 6 and 12 months follow-up interval.

MACE was defined as a composite of cardiac death, non-fatal myocardial infarction (MI) and clinically driven target vessel revascularization (TVR). Cardiac death, TVR and target lesion revascularization (TLR) were defined according to the Academic Research Consortium guidelines and MI according to the universal definitions of myocardial infarction . Device success was defined as exact deployment of the device after pre-dilatation as documented by two different projections assessed by angiography.

Analysis was based on the intention to treat population. Continuous variables were expressed as mean±S.D. Binary variables were reported as absolute and relative frequencies. For continuous data, groups were compared with a parametric Student’s t test or a nonparametric Mann–Whitney U test according to the distribution of the data. Normality was tested using the Kolmogorov–Smirnov test. Categorical variables were compared with Fisher’s exact test. P <.05 was considered statistically significant. The SPSS statistical software (version 17.0, SPSS, Chicago, IL, USA) was used for all statistical calculations.