First Human Trial of KW39 Slotted-Tube Stents for Percutaneous Coronary Intervention

Abstract

The KW39 stent is a balloon-expandable, stainless-steel, slotted-tube stent, newly designed to adjust to the shape of the coronary arteries. We evaluated the clinical efficacy and safety of KW39 stent-based percutaneous coronary interventions in human native coronary arteries. A total of 105 patients (110 lesions), with a diagnosis of stable angina, acute coronary syndrome, or asymptomatic myocardial ischemia, were included in this prospective study. The primary endpoint was the target-lesion revascularization rate at the conclusion of a 6-month follow-up period. The secondary endpoints were the rates of technical and procedural success and the rate of major adverse cardiac events (defined as cardiac death, myocardial infarction, and target-lesion revascularization) in the course of the 6 months after stent placement. The 6-month target-lesion revascularization rate was 8.6%. The KW39 stent was highly satisfactory in regard to all secondary endpoint comparisons. Binary (>50%) in-stent restenosis was observed in 22 of 110 lesions (20%). The mean diameter stenosis at 6 months after percutaneous coronary intervention was 35.1% ± 14.4%, and the mean late lumen loss was 1.06 ± 0.48 mm. Stepwise multivariate analysis showed probable causal associations between adverse local environments for stent implantation and the subsequent need for target-lesion revascularization. We conclude that KW39 stent implantation was technically feasible and clinically safe in the patient population that we studied. The results of the safety endpoints, including cardiac death and acute myocardial infarction, were acceptable.

Until 2006, drug-eluting stents (DESs), such as sirolimus-eluting and paclitaxel-eluting stents, were considered to be safe, because they could more effectively reduce the risk of restenosis than could bare-metal stents (BMSs).^1,2 However, reviews of 47 randomized control trials comprising more than 14,500 patients showed no significant differences in death, acute myocardial infarction (MI), or thrombosis between patients receiving DESs and BMSs.^3–12 Although some DESs significantly reduced the risk of target-vessel revascularization through 5 years, the DES benefit seemed to occur entirely within the 1st year; cumulative event rates in the 2nd and 3rd years were similar between DESs and BMSs.^11–17 So the high cost of DESs and the lack of evidence of their cost-effectiveness have limited their use.¹⁸

Moreover, the emergence of DESs has raised concerns regarding the occurrence of late stent thrombosis.³ New-generation DESs with novel polymers, antiproliferative drugs, and improved platforms have been approved, but late stent thrombosis remains the major pitfall of percutaneous coronary intervention (PCI).¹⁷

The KW39 stent (Kawasumi Laboratories, Inc.; Tokyo, Japan) is a balloon-expandable, stainless-steel (SUS316L), flexible slotted-tube stent, developed in Japan. The surface of the KW39 stent is pretreated with acid pickling followed by electronic polishing. The KW39 stent can be easily handled by experienced PCI operators, does not require specific training for use, and is designed to provide both higher radial force and lower bending rigidity, which are important requirements for stents (Fig. 1). For example, the 3 × 16-mm KW39 stent with S-shaped links is designed to provide the radial force of 1.34 MPa and bending rigidity of 50.3 N/mm². We conducted a prospective study of KW39-based PCI of human native coronary arteries in order to evaluate the feasibility and safety of the stent's clinical application.

Fig. 1 The KW39 stent is a stainless-steel (SUS316L), flexible, slotted-tube stent with a 0.10-mm strut thickness, a 0.12-mm cellular width, and a 0.06-mm width of the S-shaped link. Digitized images show the KW39 stent A) before and B) after expansion. C) Photograph of the KW39 stent. D) Scanning electron microscopic image of the KW39 stent.

Patients and Methods

The study population comprised patients with coronary artery diseases confirmed by angiography who were monitored from April 2003 through March 2006 at the Maizuru Kyosai Hospital, the Kurashiki Central Hospital, or the Yokohama Rosai Hospital. Their coronary artery diseases included stable angina, acute coronary syndromes including unstable angina and acute MI, and asymptomatic myocardial ischemia.

The patients' inclusion criteria were coronary arteries with more than 60% diameter stenosis (according to the modified American College of Cardiology/American Heart Association lesion classifications), age over 20 years, satisfaction of the criteria for coronary artery bypass graft surgery, and agreement to sign the informed consent. Exclusion criteria were the presence of allergies to stainless steel (SUS316L), aspirin, ticlopidine hydrochloride, contrast agents, or heparin, the urgent need to receive treatment for more than 1 coronary lesion, a left ventricular ejection fraction of less than 0.30, excessive vessel calcification, or an ischemic attack associated with acute MI within the past 7 days. All of the patients who met the inclusion criteria received angioplasty with the implantation of a KW39 stent.

Percutaneous coronary intervention was performed by using conventional equipment. The devices, including those for balloon pre- and post-dilation, were chosen at the investigators' discretion. Dimensional measurements were made using quantitative coronary angiography. Lesion lengths and reference-vessel diameters were measured in millimeters. Late lumen loss was calculated as the difference between the minimal lumen diameter measured immediately after the procedure and that measured at follow-up. Irregular arterial walls were defined as the small irregular filling defects detected in the coronary arteries by angiography. All patients received antiplatelet therapy, including aspirin (100 mg/d indefinitely), ticlopidine hydrochloride (200 mg/d for >4 wk), or (in rare cases) heparin, in order to reduce the risk of thrombotic complications.

Regular clinical examinations, including electrocardiography, were scheduled at 1- and 6-month follow-up intervals. Cardiac isoenzyme testing (for creatine kinase [CK] levels) was performed before PCI, 24 hours after PCI, and 6 months after PCI. Follow-up angiography was scheduled within 6 months of PCI. The following clinical outcomes—all occurring during the first 6 months after PCI—were evaluated: all-cause death, target-vessel revascularizations, stent thrombosis, bypass surgery, readmission for heart failure, and major adverse cardiac events (defined as cardiac death, MI, and target-lesion revascularization [TLR]).

The primary endpoint was the TLR rate during the first 6 months. The secondary endpoints were the technical and procedural success rates, major adverse cardiac events, a CK rise to more than 3 times the upper limit of normal, and narrow vessels (diameter stenosis >50%) at the 6-month angiographic follow-up.

Statistical Analysis. Continuous values were expressed as mean ± SD. The time to the primary endpoint, TLR, was evaluated by the Kaplan-Meier method. Patients were censored from the Kaplan-Meier plots when they reached the primary endpoint. The difference was tested by means of the log-rank test. Cox proportional hazard models were used to estimate adjusted hazard ratios of TLR associated with 11 clinical variables: age, eccentric stenoses, irregular arterial walls, calcified lesions, history of coronary artery disease, bifurcation lesions, smoking, hypertension, diabetes mellitus, hyperlipidemia, and family history of ischemic heart disease. Both forward and backward stepwise regressions were performed with a P value < 0.05 by using the likelihood ratio test as the criterion to remain in the model. Analyses were done with PASW version 18.0.2 software (IBM Corporation; Somers, NY).

This study was approved and executed under the supervision of local institutional review boards according to the Good Clinical Practice for Medical Devices guidelines, as well as the Pharmaceutical Affairs Act in Japan. Compliance and adherence to the study protocol were monitored by an external monitoring company.

Results

We enrolled a total of 107 patients. Two patients were excluded due to protocol violations (patient's refusal of treatment and a lesion requiring more than 1 stent). Therefore, this cohort study consisted of 105 patients (mean age, 66.4 ± 11.8 yr; 75.2% male): 19 (18.1%) patients with asymptomatic myocardial ischemia, 55 (52.4%) with stable angina, and 31 (29.5%) with acute coronary syndromes including unstable angina (n = 23, 21.9%) and acute MI (n = 8, 7.6%) (Table I). The total number of treated lesions was 110.

TABLE I. Baseline Clinical Characteristics of the 105 Patients Receiving the KW39 Stent

The mean lesion length was 16.25 ± 6.16 mm, and the mean length of the stents was 19.4 ± 5.02 mm (range, 8–29 mm). All of the patients who met the inclusion criteria completed the follow-up protocol on schedule.

The technical and procedural success rates were 100%. By improving the delivery system, we achieved optimal stent expansion, and the inflation pressure was 11.3 ± 3 atm. The 6-month TLR rate, the primary endpoint of the study, was 8.6% (n = 9). The KW39 stent was also highly satisfactory in regard to all secondary endpoint comparisons. One patient died of noncardiac causes (sepsis with multisystem failure after severe pneumonia) 39 days after the procedure. Neither cardiac death nor stent thrombosis occurred during the 6-month follow-up after PCI. As a result, the 6-month major adverse cardiac event rate and the TLR rate were the same (8.6%) (Table II). No patient experienced a procedure-related CK rise greater than 3 times the upper limit of normal, bypass surgery, or readmission due to heart failure. The mean diameter of stenosis was reduced from 60.3% ± 9.3% before the PCI to 12.7% ± 7.9% immediately after the PCI (Table III). Binary (>50%) in-stent restenosis was observed in 22 patients (21%). The mean diameter of stenosis at 6 months was 35.1% ± 14.4% and the mean late lumen loss was 1.06 ± 0.48 mm.

TABLE II. Clinical Outcomes in 105 Patients at 6 Months after Percutaneous Coronary Intervention

TABLE III. Characteristics of the 110 Lesions

The Kaplan-Meier curves showed that patients with regular arterial walls had significantly lower rates of TLR (Fig. 2; log-rank test P = 0.025). Stepwise multivariate analysis showed that 3 of 11 clinical factors analyzed were associated with higher TLR: irregular arterial walls (adjusted hazard ratio, 5.78 [95% confidence interval (CI), 1.47–22.69], P = 0.012), calcified lesion (adjusted hazard ratio, 6.59 [95% CI, 1.35–32.13], P = 0.02), and history of coronary artery disease (adjusted hazard ratio, 18.67 [95% CI, 1.82–191.59], P = 0.014) (Table IV).

Fig. 2 Kaplan-Meier estimates of cumulative incidence of target-lesion revascularization (TLR) in accordance with 105 patients' arterial wall regularity (n = 65) or irregularity (n = 40).

TABLE IV. Univariate and Multivariate Analysis Showing the Hazard Ratio That Was Associated with Target-Lesion Revascularization

Discussion

Percutaneous coronary intervention with the KW39 stent appears to be feasible and safe in clinical settings. The 6-month TLR rate of 8.6% was lower than those of other BMSs (mean, 17.2%).³ The technical and procedural success data were satisfactory, without increase in morbidity or death. Neither cardiac death nor PCI-related stent thrombosis occurred during the course of this study. The results of the secondary endpoints were acceptable, but they might have been underpowered due to the small sample size and the short follow-up duration.

The mechanical requirements of stents include radial force, flexibility, and conformability. The radial force of a stent—the force directed outward, against the coronary arterial wall—is the primary factor governing the performance of a stent, because sufficient radial force is the factor that assures complete stent apposition.¹⁹ The longitudinal flexibility of a stent—its ability to bend—enables expanded stents to conform to vascular contours. Stents with lower bending rigidity provide better conformability²⁰ to the geometry of the lumen, which can reduce the risk of vascular injury and in-stent restenosis. Complete stent apposition and conformability preserve the original shear-stress pattern of arterial flow and contribute to improved endothelialization and reduced neointimal hyperplasia.²¹ The endothelialization of stents, in particular, can prevent platelet adhesion and activation, as well as fibrinogen deposit.²²

The most evident advantage of the KW39 stent is that it optimally balances the 2 competing goals of higher radial force and lower bending rigidity. Higher radial force is achieved by using a smaller number of cell structures arranged circumferentially and stent struts with a larger cross-sectional area, which increases the 2nd moment of area (also known as the 2nd moment of inertia). Since these 2 factors—the higher radial force and the lower bending rigidity—impose interface stress on the arterial wall, especially at the edges of the stent, the KW39 stent's deformation resistance is enhanced. Increasing the number of longitudinally arranged links has improved longitudinal flexibility. For this purpose, the 3-mm-diameter KW39 stent is constructed with 7 cell structures arranged circumferentially and 8 to 10 arranged longitudinally. In comparison with the already available stents of the same diameter, the radial force of the KW39 stent (3 × 16 mm) is slightly lower than that of the NIR stent* (Boston Scientific Corporation; Natick, Mass) (3 × 16 mm) (1.34 MPa vs 1.48 MPa, respectively), but higher than that of the ACS MULTI-LINK coronary stent* (3 ×16 mm) (1.12 MPa). At least the KW39 stent maintains a high radial force. Although the major concern of most stent manufacturers is to achieve higher radial force, a recent study using a porcine model strongly suggested the existence of an optimal stent radial force that would cause minimal vascular restenosis.¹⁹ Radial forces higher than optimal would damage the vascular walls, leading to an inflammatory reaction and restenosis.

The KW39 stent has S-shaped link struts, which are easier to expand.²³ The 4-point bending test enables the measurement of bending stiffness with a constant moment of inertia and without radial deformation. The bending rigidity of the stent was 50.3 N/mm² by this test. The bending rigidity of the NIR stent is 215.6 N/mm² and that of the ACS MULTI-LINK is 69.9 N/mm². Mori and Saito²⁴ tested the bending rigidity of their 4 original stents constructed from an SUS316L tube—identical except for differing link configurations (S-, N-, W-, and modified W-shape)—and obtained the following bending rigidity values: 85.28 N/mm² for the stent with an S-shaped link; 41.67 N/mm² for the stent with an N-shaped link; 188.67 N/mm² for the stent with a W-shaped link; and 78.79 N/mm² for the stent with a modified W-shaped link. Thus, in the comparison of these stainless-steel stents, the KW39 stent, with its S-shaped links, has excellent longitudinal flexibility.

At 6 months, the stenosis diameter of 35.1% ± 14.4% and the binary in-stent restenosis rate of 20% observed after implantation of the KW39 were higher than those reported after implantation of DESs. Moreover, KW39 stents showed poorer results than did DESs in regard to mean late lumen loss (KW39, 1.06 ± 0.48 mm; sirolimus-eluting stent, 0.19 ± 0.45 mm; and paclitaxel-eluting stent, 0.32 ± 0.55 mm). These facts imply that the mechanical properties of stents are not the final answer to the improvement of this method of treatment. We observed a significant association between TLR and the local environment in which the stent was implanted, including irregular arterial walls, calcified lesions, and local ischemia, rather than an association with broader comorbidities. Poorly polished stent surfaces, with cracks and fissures, might activate a local inflammatory response that leads to restenosis. Therefore, a good surface polishing or thin-film coating might play an important role in preventing in-stent restenosis. Recently, variability in response to antiplatelet therapy has been identified as a predictor of stent thrombosis.^25,26 As a consequence, there is a heightened effort to develop stents with improved surface biocompatibility that helps to inactivate the thrombotic pathway.

In conclusion, PCI with the KW39 stent was technically feasible and safely performed in our study population. The KW39 stent offers both high radial force and very good flexibility to adjust to the shape of the arteries. However, the long-term safety and efficacy of the KW39 need to be established in large-scale studies.

Acknowledgments

We thank Drs. Yasushi Fuku, Akitoshi Hirono, and Hiroyuki Tanaka of Kurashiki Central Hospital, Dr. Norihito Usui of Maizuru Kyosai Hospital, and Drs. Kazuhiko Yumoto and Toshiaki Tamaki of Yokohama Rosai Hospital for their collection of data.