2.1

Study population

Between August 2007 and January 2009, a consecutive cohort of 54 patients with up to 2 de novo lesions located in different native coronary arteries were enrolled into the PLUS-ONE FIM Study. Vessels with a diameter between 3.0 to 3.75 mm (by visual assessment) and lesion lengths up to 20 mm were enrolled in the study. Patients presented with symptoms of angina or silent ischemia documented through non-invasive assessment.

We excluded patients with acute myocardial infarction (MI), severe left ventricular dysfunction (LVEF < 30%) visible coronary thrombus or contraindication to any protocol medication. Patients with angiographic lesions at the bifurcations, the ostia and/or the left main coronary artery were also excluded. The study protocol was approved by the local hospital Ethics Committee and written inform consent was obtained from all patients prior to study enrolment.

2.2

Device description

The Cobra-P coronary stent system is a next generation DES designed to improve performance and safety through the combination of a cobalt-chromium stent platform with a novel design (Cobra BMS), a fully bioabsorbable non-polymeric coating and paclitaxel, an antiproliferative drug of proven efficacy in controlling neointimal proliferation ( Fig. 1 ). Detailed preclinical data including pharmacokinetic and histopathological assessment of this low-dose paclitaxel-eluting stent were reported previously . Briefly, angiographic late loss was not significantly different for both conventional PES and Cobra-P system in juvenile pig coronary artery. In terms of histopathological evaluation, although the inflammatory cell infiltration and intramural thrombus scores were no different between conventional PES and Cobra-P, medial necrosis was increased for conventional PES. These pathological evaluations suggest less toxicity to the coronary artery for the Cobra-P system.

Components of the Cobra-P stent. The Cobra-P DES system is a balloon-expandable stent that consists of a thin cobalt super alloy with a stent strut of 71 μm, silica matrix coating without polymer (Synergy™) which is a bioabsorbable coating designed to elute 100% of the drug within 6 months, and low-dose paclitaxel (3.7 μg/18 mm stent: 0.03 μg/mm ² and 8 μg/18 mm stent: 0.06 μg/mm ² ).

2.3

Stent platform

The Cobra BMS is a balloon-expandable stent composed of a cobalt-chromium super alloy chosen for improved strength and radiopacity compared to stainless steel. Each stent is laser cut from a thin-walled cobalt-chromium superalloy tube and electrolytically polished to achieve proper surface finish and corrosion resistance. The design consists of sinusoidal elements that have an optimized crown width and nominal strut thickness of 71 μm that allows for ease of deployment without loss of radiopacity. Replacing standard crowns with more rounded, sweeping “bulbs” is anticipated to decrease vessel trauma. It has wide struts and crowns that enhance radiopacity. Crossovers and crowns are reinforced to provide support and minimize recoil (2%) and the rounded atraumatic crowns and struts may minimize vessel impact. The crossing profile is 0.88 mm and the metal/artery ratio is 16.1% for the 3.0 mm diameter stent.

2.4

Coating

The Synergy ^TM bioabsorbable silica matrix is a polymer-free biocompatible coating that is non-thrombogenic and non-inflammatory. The silica matrix is a uniform coating of ≤ 2 μm thickness allowing for a controlled release of the drug for approximately 50 days, and is fully bioabsorbable so that it hydrates and completely erodes through dissolution in body fluids within 6 months. This compound is extensively used in different medical applications, such as immunoassays, artificial organs, implantable intraocular lenses, and drug delivery systems.

2.5

Pharmacological agent and drug kinetics

Paclitaxel is a microtubule-stabilizing drug that blunts different cellular pathways thought to be involved in the restenotic process and has proven efficacy in inhibiting neointimal proliferation . The Cobra-P stent releases 90% of the paclitaxel in 50 days and 100% within 180 days. This compares to the Taxus Liberté (Boston Scientific Corporation, Natick, MA) stent that releases 10% in 30 days and 90% in years. This allows the Cobra-P to have elution kinetics similar to the Taxus slow-release stents while having less than 10% of the total drug load on the Cobra-P stent when compared to the Taxus slow-release stent. In the PLUS-ONE study, 2 different low doses of paclitaxel were evaluated: 3.7 μg/18 mm stent (0.03 μg/mm ² ) and 8 μg/18 mm stent (0.06 μg/mm ² ).

2.6

Procedure

Patients eligible for DES placement were considered for enrollment into the PLUS-ONE study. Upon verification that patients met all the inclusion criteria and none of the exclusion criteria and had signed the informed consent, all interventions were performed according to current standard guidelines. After elective pre-dilatation, stents were deployed, and post-dilated as needed at high pressure guided by intravascular ultrasound. For the study, the Cobra-P stent was available in 2 diameters: 3.0 and 3.5 mm and 3 different lengths: 12, 18 and 24 mm. Lesion success was defined as final residual in-stent diameter stenosis less than 30%, and procedural success was defined as lesion success in the absence of any in-hospital MACE events.

Dual antiplatelet therapy including a loading dose of aspirin (100 mg) and clopidogrel (300 mg) was given before the procedure. Patients were discharged on aspirin 100 mg/day indefinitely and clopidogrel 75 mg/day for a minimum of 12 months.

Patients were clinically evaluated by medical appointment at 1, 4 and 12 months. Clinical evaluation is intended to continue up to 5 years. Angiography follow-up was performed 4 months after stent implantation.

2.7

Quantitative coronary angiography

Following intracoronary administration of nitrate, coronary angiograms with multiple views were obtained before and after stent deployment, and at 4 months follow-up in a standard fashion. These images were independently analyzed at the core laboratory of Stanford University Medical Center (Cardiovascular Core Analysis Laboratory, Stanford, CA), blinded to patient characteristics. All images were reviewed by 2 independent observers, and adjudication of option was based on consensus of these observers. Conventional angiograms were assessed using an off-line quantitative coronary angiography system (Quant32, Sanders Data Systems, Palo Alto, CA). Quantitative coronary angiography (QCA) was performed in the in-stent as well as in-lesion segment, including the 5 mm both proximal and distal to the in-stent segment .

2.8

Study endpoints

The primary endpoint of the study was the cumulative rate of major adverse cardiac events (MACE) at the 4-month follow-up. MACE was defined as death, non-fatal myocardial infarction (Q and non Q wave) and need for target lesion revascularization (TLR). Myocardial infarction was defined by an increase in the CK-MB twice the upper normal limit with or without new Q waves on the ECG.

Secondary endpoints included acute success (angiographic and procedure), MACE at hospital discharge, 30 days, and annually up to 5 years by the protocol. Additional secondary endpoints included diameter stenosis (%), in-stent and in-segment late loss (mm) and binary restenosis rate (%) as measured by QCA at the 4-month follow-up.

2.9

Statistical analysis

All analyses were performed using the SPSS 11.0 statistical analysis program (SPSS Chicago, IL). Categorical variables were compared by chi-square test or Fisher exact test. For continuous variables with normal distributions, comparisons between the group A and B were performed with a 2-tailed, unpaired t test, and comparisons between baseline and follow-up were done by 2-tailed, paired t test. Mann–Whitney test was used for comparison when continuous variables were not normal distributions. Statistical significance was defined as P < .05.

2.1

Study population

Between August 2007 and January 2009, a consecutive cohort of 54 patients with up to 2 de novo lesions located in different native coronary arteries were enrolled into the PLUS-ONE FIM Study. Vessels with a diameter between 3.0 to 3.75 mm (by visual assessment) and lesion lengths up to 20 mm were enrolled in the study. Patients presented with symptoms of angina or silent ischemia documented through non-invasive assessment.

We excluded patients with acute myocardial infarction (MI), severe left ventricular dysfunction (LVEF < 30%) visible coronary thrombus or contraindication to any protocol medication. Patients with angiographic lesions at the bifurcations, the ostia and/or the left main coronary artery were also excluded. The study protocol was approved by the local hospital Ethics Committee and written inform consent was obtained from all patients prior to study enrolment.

2.2

Device description

The Cobra-P coronary stent system is a next generation DES designed to improve performance and safety through the combination of a cobalt-chromium stent platform with a novel design (Cobra BMS), a fully bioabsorbable non-polymeric coating and paclitaxel, an antiproliferative drug of proven efficacy in controlling neointimal proliferation ( Fig. 1 ). Detailed preclinical data including pharmacokinetic and histopathological assessment of this low-dose paclitaxel-eluting stent were reported previously . Briefly, angiographic late loss was not significantly different for both conventional PES and Cobra-P system in juvenile pig coronary artery. In terms of histopathological evaluation, although the inflammatory cell infiltration and intramural thrombus scores were no different between conventional PES and Cobra-P, medial necrosis was increased for conventional PES. These pathological evaluations suggest less toxicity to the coronary artery for the Cobra-P system.

Components of the Cobra-P stent. The Cobra-P DES system is a balloon-expandable stent that consists of a thin cobalt super alloy with a stent strut of 71 μm, silica matrix coating without polymer (Synergy™) which is a bioabsorbable coating designed to elute 100% of the drug within 6 months, and low-dose paclitaxel (3.7 μg/18 mm stent: 0.03 μg/mm ² and 8 μg/18 mm stent: 0.06 μg/mm ² ).

2.3

Stent platform

The Cobra BMS is a balloon-expandable stent composed of a cobalt-chromium super alloy chosen for improved strength and radiopacity compared to stainless steel. Each stent is laser cut from a thin-walled cobalt-chromium superalloy tube and electrolytically polished to achieve proper surface finish and corrosion resistance. The design consists of sinusoidal elements that have an optimized crown width and nominal strut thickness of 71 μm that allows for ease of deployment without loss of radiopacity. Replacing standard crowns with more rounded, sweeping “bulbs” is anticipated to decrease vessel trauma. It has wide struts and crowns that enhance radiopacity. Crossovers and crowns are reinforced to provide support and minimize recoil (2%) and the rounded atraumatic crowns and struts may minimize vessel impact. The crossing profile is 0.88 mm and the metal/artery ratio is 16.1% for the 3.0 mm diameter stent.

2.4

Coating

The Synergy ^TM bioabsorbable silica matrix is a polymer-free biocompatible coating that is non-thrombogenic and non-inflammatory. The silica matrix is a uniform coating of ≤ 2 μm thickness allowing for a controlled release of the drug for approximately 50 days, and is fully bioabsorbable so that it hydrates and completely erodes through dissolution in body fluids within 6 months. This compound is extensively used in different medical applications, such as immunoassays, artificial organs, implantable intraocular lenses, and drug delivery systems.

2.5

Pharmacological agent and drug kinetics

Paclitaxel is a microtubule-stabilizing drug that blunts different cellular pathways thought to be involved in the restenotic process and has proven efficacy in inhibiting neointimal proliferation . The Cobra-P stent releases 90% of the paclitaxel in 50 days and 100% within 180 days. This compares to the Taxus Liberté (Boston Scientific Corporation, Natick, MA) stent that releases 10% in 30 days and 90% in years. This allows the Cobra-P to have elution kinetics similar to the Taxus slow-release stents while having less than 10% of the total drug load on the Cobra-P stent when compared to the Taxus slow-release stent. In the PLUS-ONE study, 2 different low doses of paclitaxel were evaluated: 3.7 μg/18 mm stent (0.03 μg/mm ² ) and 8 μg/18 mm stent (0.06 μg/mm ² ).

2.6

Procedure

Patients eligible for DES placement were considered for enrollment into the PLUS-ONE study. Upon verification that patients met all the inclusion criteria and none of the exclusion criteria and had signed the informed consent, all interventions were performed according to current standard guidelines. After elective pre-dilatation, stents were deployed, and post-dilated as needed at high pressure guided by intravascular ultrasound. For the study, the Cobra-P stent was available in 2 diameters: 3.0 and 3.5 mm and 3 different lengths: 12, 18 and 24 mm. Lesion success was defined as final residual in-stent diameter stenosis less than 30%, and procedural success was defined as lesion success in the absence of any in-hospital MACE events.

Dual antiplatelet therapy including a loading dose of aspirin (100 mg) and clopidogrel (300 mg) was given before the procedure. Patients were discharged on aspirin 100 mg/day indefinitely and clopidogrel 75 mg/day for a minimum of 12 months.

Patients were clinically evaluated by medical appointment at 1, 4 and 12 months. Clinical evaluation is intended to continue up to 5 years. Angiography follow-up was performed 4 months after stent implantation.

2.7

Quantitative coronary angiography

Following intracoronary administration of nitrate, coronary angiograms with multiple views were obtained before and after stent deployment, and at 4 months follow-up in a standard fashion. These images were independently analyzed at the core laboratory of Stanford University Medical Center (Cardiovascular Core Analysis Laboratory, Stanford, CA), blinded to patient characteristics. All images were reviewed by 2 independent observers, and adjudication of option was based on consensus of these observers. Conventional angiograms were assessed using an off-line quantitative coronary angiography system (Quant32, Sanders Data Systems, Palo Alto, CA). Quantitative coronary angiography (QCA) was performed in the in-stent as well as in-lesion segment, including the 5 mm both proximal and distal to the in-stent segment .

2.8

Study endpoints

The primary endpoint of the study was the cumulative rate of major adverse cardiac events (MACE) at the 4-month follow-up. MACE was defined as death, non-fatal myocardial infarction (Q and non Q wave) and need for target lesion revascularization (TLR). Myocardial infarction was defined by an increase in the CK-MB twice the upper normal limit with or without new Q waves on the ECG.

Secondary endpoints included acute success (angiographic and procedure), MACE at hospital discharge, 30 days, and annually up to 5 years by the protocol. Additional secondary endpoints included diameter stenosis (%), in-stent and in-segment late loss (mm) and binary restenosis rate (%) as measured by QCA at the 4-month follow-up.

2.9

Statistical analysis

All analyses were performed using the SPSS 11.0 statistical analysis program (SPSS Chicago, IL). Categorical variables were compared by chi-square test or Fisher exact test. For continuous variables with normal distributions, comparisons between the group A and B were performed with a 2-tailed, unpaired t test, and comparisons between baseline and follow-up were done by 2-tailed, paired t test. Mann–Whitney test was used for comparison when continuous variables were not normal distributions. Statistical significance was defined as P < .05.