1

Introduction

Stenting has become the dominant percutaneous coronary intervention. Thereby, the underlying stent platform remains a key determinant of clinical outcomes .

An important issue in stent design is the thickness of stent struts which has been associated with improved stent deliverability, improved procedural outcome and lower rates of subsequent restenosis . Cobalt–chromium stents emerged as this material is stronger than 316 stainless steel, hence allowing for construction of stents with thinner struts without compromising radial strength. Furthermore, the presence of W-atoms with a high ordinal number in the alloy gives cobalt–chromium sufficient radiopacity even with thinner struts.

An additional factor influencing clinical outcomes, especially in-stent restenosis (ISR), is coating of bare metal stents, hereby coating with an amorphous silicon carbide layer has demonstrated to positively influence restenosis rates . Passive coating acts as a diffusion barrier, sealing the bare metal surface and preventing corrosion, which is responsible for cell toxicity, the stimulation of fibroblast growth and for protein and platelet adhesion. In vitro-data have shown a reduction in the proliferation of smooth muscle cells on silicon carbide coated stents by up to 52% when compared to stainless steel stents .

The purpose of this study was to evaluate the safety and efficacy of the PRO-Kinetik coronary stent system ( Fig. 1 ) in single de novo lesions. This stent system includes both features, a cobalt–chromium alloy and silicon carbide coating, and its stent design served as a basis for newer generations such as the PRO-Kinetik Energy bare metal stent, and the Orsiro stent, a hybrid drug eluting stent with a bioabsorbable polymer combined with a limus drug, which long term leaves the patient with only the silicon carbide coated stent.

Unexpanded PRO-Kinetic stent (above) and expanded PRO-Kinetic stent (below). With permission from Biotronik AG, Buelach, Switzerland.

2

Methods

The MULTIBENE study is a multi-center, prospective, consecutive, non-randomized study in patients with single de novo lesions using the PRO-Kinetik coronary stent system (Biotronik AG, Buelach, Switzerland). Telephone followup was performed at 30 days, 6 and 12 months post intervention. In a subset of 100 patients at pre-selected sites, an additional angiogram was scheduled at 6 months. Quantitative coronary angiography (QCA) was performed by an independent core laboratory (Cardiovascular Research Institute, Washington Hospital Center, USA).

Monitoring included a 100% review of all in- and exclusion criteria, informed consents, demographic data, safety events and all endpoints. 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.

Patients with a minimum age of 18 years and a single de novo coronary lesion, documented stable or unstable angina pectoris or silent ischemia and left ventricular ejection fraction (LVEF) of at least 30% were considered for this study. Furthermore total target lesion length below 20 mm, stenosis between 50% and 100%, and a reference vessel diameter (RVD) between 2.0 and 5.0 mm were required for participation. Main exclusion criteria were planned treatment with any other PCI (percutaneous coronary intervention) device in target vessel except the pre-dilatation balloon, myocardial infarction (MI) within 72 h prior to the index procedure, cardiogenic shock, and contraindication to antiplatelet therapy. Angiographic exclusion criteria were left main coronary artery disease with a stenosis above 50%, atherosclerotic disease with a stenosis above 50% proximal or distal to the target lesion, ostial or severely calcified lesion or a lesion which involves a bifurcation and requires intervention, and presence of probable or definite thrombus.

The PRO-Kinetik stent ( Fig. 1 ) was available in lengths of 8, 10, 13, 15, 18, 20, 22 mm with diameters of 2.0, 2.25, 2.5, 2.75, 3.0, 3.5, 4.0, 4.5 and 5.0 mm. Strut thickness was 0.065 mm, 0.08 mm and 0.120 mm for small, medium and large stents. Stent implantation was performed according to standard techniques. Pre-dilatation was left to the discretion of the investigators, while direct stenting was recommended.

Prior to procedure, patients received 75–100 mg aspirin and a loading dose of 300 mg clopidogrel or, in case of allergy to clopidogrel, ticlopidine 250 mg twice daily. Intravenous heparin was administered after insertion of the arterial sheath to maintain ACT > 250 s or 200–250 s if glycoprotein IIb/IIIa was used. Intracoronary nitroglycerin was administered prior to the baseline and at the post-procedure angiography. GP-IIB/IIIa administration was left to the discretion of the investigators. Follow up antiplatelet regime consisted of 75–100 mg aspirin once daily for the duration of the study and clopidogrel 75 mg once daily respective ticlopidine 250 mg twice daily for at least one month.

The primary endpoint, target vessel failure (TVF) at 6 months, was defined as a composite of cardiac death, MI and target vessel revascularization (TVR). Secondary endpoints were TVR at 6 months and major adverse cardiac events (MACE) at 30 days and 6 months. Thereby MACE events were counted hierarchically and events up to 190 days were attributed to the respective 6 months visit interval. MACE was defined as a composite of cardiac death, MI, target lesion revascularization (TLR) and coronary artery bypass graft (CABG). TVR was defined as any repeat percutaneous intervention of the target vessel. The target vessel is the entire major coronary vessel proximal or distal to the target lesion, including branches and the target lesion itself. Q-wave MI was defined as development of new, pathological Q-waves in 2 or more continuous leads with post-procedure CK or CK-MB levels elevated above normal. Non Q-wave MI was defined as elevation of post-procedure CK-MB above 3 × ULN (Upper Limit of Normal) in the absence of pathological Q waves; if no assay for CK-MB was performed, elevation of CK levels to 2 × ULN without new Q waves is also considered a non Q wave MI.

In the angiography subgroup acute gain, late lumen loss, diameter stenosis and binary restenosis were evaluated for both in-stent and in-segment. Acute gain was defined as difference between minimal lumen diameter post-procedure and minimal lumen diameter pre-procedure. Late lumen loss was defined as the difference between minimal luminal diameter after procedure and at 6 months. Diameter stenosis was defined as the difference between reference vessel diameter and minimal lumen diameter divided by reference vessel diameter × 100%. Binary restenosis was defined as diameter stenosis > 50%. In-stent was defined as within the boundaries of the stent and in-segment was defined as in-stent plus 5 mm proximal and distal to the stent edges.

Data analysis was performed on all patients who met the eligibility requirements (per protocol analysis). Discrete variables are presented as counts and percentage of the total. Continuous variables are presented as mean ± standard deviation. Data were analyzed using SAS® for Windows ^TM version 9.1.3.

2

Methods

The MULTIBENE study is a multi-center, prospective, consecutive, non-randomized study in patients with single de novo lesions using the PRO-Kinetik coronary stent system (Biotronik AG, Buelach, Switzerland). Telephone followup was performed at 30 days, 6 and 12 months post intervention. In a subset of 100 patients at pre-selected sites, an additional angiogram was scheduled at 6 months. Quantitative coronary angiography (QCA) was performed by an independent core laboratory (Cardiovascular Research Institute, Washington Hospital Center, USA).

Monitoring included a 100% review of all in- and exclusion criteria, informed consents, demographic data, safety events and all endpoints. 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.

Patients with a minimum age of 18 years and a single de novo coronary lesion, documented stable or unstable angina pectoris or silent ischemia and left ventricular ejection fraction (LVEF) of at least 30% were considered for this study. Furthermore total target lesion length below 20 mm, stenosis between 50% and 100%, and a reference vessel diameter (RVD) between 2.0 and 5.0 mm were required for participation. Main exclusion criteria were planned treatment with any other PCI (percutaneous coronary intervention) device in target vessel except the pre-dilatation balloon, myocardial infarction (MI) within 72 h prior to the index procedure, cardiogenic shock, and contraindication to antiplatelet therapy. Angiographic exclusion criteria were left main coronary artery disease with a stenosis above 50%, atherosclerotic disease with a stenosis above 50% proximal or distal to the target lesion, ostial or severely calcified lesion or a lesion which involves a bifurcation and requires intervention, and presence of probable or definite thrombus.

The PRO-Kinetik stent ( Fig. 1 ) was available in lengths of 8, 10, 13, 15, 18, 20, 22 mm with diameters of 2.0, 2.25, 2.5, 2.75, 3.0, 3.5, 4.0, 4.5 and 5.0 mm. Strut thickness was 0.065 mm, 0.08 mm and 0.120 mm for small, medium and large stents. Stent implantation was performed according to standard techniques. Pre-dilatation was left to the discretion of the investigators, while direct stenting was recommended.

Prior to procedure, patients received 75–100 mg aspirin and a loading dose of 300 mg clopidogrel or, in case of allergy to clopidogrel, ticlopidine 250 mg twice daily. Intravenous heparin was administered after insertion of the arterial sheath to maintain ACT > 250 s or 200–250 s if glycoprotein IIb/IIIa was used. Intracoronary nitroglycerin was administered prior to the baseline and at the post-procedure angiography. GP-IIB/IIIa administration was left to the discretion of the investigators. Follow up antiplatelet regime consisted of 75–100 mg aspirin once daily for the duration of the study and clopidogrel 75 mg once daily respective ticlopidine 250 mg twice daily for at least one month.

The primary endpoint, target vessel failure (TVF) at 6 months, was defined as a composite of cardiac death, MI and target vessel revascularization (TVR). Secondary endpoints were TVR at 6 months and major adverse cardiac events (MACE) at 30 days and 6 months. Thereby MACE events were counted hierarchically and events up to 190 days were attributed to the respective 6 months visit interval. MACE was defined as a composite of cardiac death, MI, target lesion revascularization (TLR) and coronary artery bypass graft (CABG). TVR was defined as any repeat percutaneous intervention of the target vessel. The target vessel is the entire major coronary vessel proximal or distal to the target lesion, including branches and the target lesion itself. Q-wave MI was defined as development of new, pathological Q-waves in 2 or more continuous leads with post-procedure CK or CK-MB levels elevated above normal. Non Q-wave MI was defined as elevation of post-procedure CK-MB above 3 × ULN (Upper Limit of Normal) in the absence of pathological Q waves; if no assay for CK-MB was performed, elevation of CK levels to 2 × ULN without new Q waves is also considered a non Q wave MI.

In the angiography subgroup acute gain, late lumen loss, diameter stenosis and binary restenosis were evaluated for both in-stent and in-segment. Acute gain was defined as difference between minimal lumen diameter post-procedure and minimal lumen diameter pre-procedure. Late lumen loss was defined as the difference between minimal luminal diameter after procedure and at 6 months. Diameter stenosis was defined as the difference between reference vessel diameter and minimal lumen diameter divided by reference vessel diameter × 100%. Binary restenosis was defined as diameter stenosis > 50%. In-stent was defined as within the boundaries of the stent and in-segment was defined as in-stent plus 5 mm proximal and distal to the stent edges.

Data analysis was performed on all patients who met the eligibility requirements (per protocol analysis). Discrete variables are presented as counts and percentage of the total. Continuous variables are presented as mean ± standard deviation. Data were analyzed using SAS® for Windows ^TM version 9.1.3.

3

Results

From February 2007 until April 2008, 202 patients in 10 centers in Belgium (6), The Netherlands (2) and Germany (2) have been implanted with the PRO-Kinetik coronary stent system. 197 patients could be included in the “per protocol” analyses group ( Fig. 2 ) as five of the initially included patients did not meet the in- and exclusion criteria. Specifically, two patients were excluded due to a totally occluded lesion (one of them received a CABG on day 189 post-procedure), one patient due to stenosis above 50% next to the target lesion, one patient due to MI within 72 h prior to procedure, and one patient due to a totally occluded lesion, cardiogenic shock, MI within 72 h and presence of thrombus (this patient received a CABG on day 98).

Patient clinical and angiographic flow chart. pt(s) = patient(s).

Baseline characteristics of the 197 “per protocol” patients are provided in Table 1 . Parameters were as expected for that indication, with a mean patient age of 64.2 years, 28.4% of the patients were woman. Nearly one quarter of the patients (22.8%) had a history of myocardial infarction and more than one third of the patients had a previous coronary intervention, thereof 30.7% experienced a prior PTCA (percutaneous transluminal coronary angioplasty) and 5.6% a prior CABG.

Table 1

Baseline Characteristics and indication for planned intervention in 197 patients.

	Mean ± SD or n (%)
Age (yrs)	64.2 ± 11.0
Male	141 (71.6)
Body mass index	27.3 ± 4.0
Diabetes mellitus	20 (10.2)
– insulin-dependent	9 (45.0)
Hypertension	122 (61.9)
Hyperlipidemia	125 (61.9)
Prior stoke or transient ischemic attack	5 (2.5)
Prior myocardial infarction	45 (22.8)
Prior congestive heart failure	15 (7.6)
Prior PTCA	62 (30.7)
Prior CABG	11 (5.6)
Stable angina	146 (73.3)
– CCS class III or IV	48 (32.9)
Unstable angina	35 (17.8)
Silent ischemia	82 (41.6)

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