TAXUS EXPRESS2 PACLITAXEL-ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE)
Device Facts
| Record ID | P030025 |
|---|---|
| Device Name | TAXUS EXPRESS2 PACLITAXEL-ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE) |
| Applicant | Boston Scientific Corp |
| Product Code | NIQ · Cardiovascular |
| Decision Date | Mar 4, 2004 |
| Decision | APWD |
| Device Class | Class 3 |
| Attributes | Therapeutic |
Intended Use
The TAXUS™ Express²™ Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions ≤ 28mm in length in native coronary arteries ≥ 2.5 to ≤ 3.75 mm in diameter.
Device Story
The TAXUS Express² Coronary Stent System is a drug-eluting stent (DES) combining a 316L stainless steel Express stent with a Translute (SIBS) polymer coating loaded with paclitaxel. It is delivered via a Monorail or Over-the-Wire catheter system. Used in cardiac catheterization labs by interventional cardiologists to treat coronary artery disease. The device is deployed via balloon inflation; the polymer coating provides a slow release of paclitaxel to the vessel wall to inhibit neointimal hyperplasia and reduce restenosis. The physician monitors the procedure via angiography. The device benefits patients by reducing the need for target vessel revascularization (TVR) compared to bare metal stents. It is a permanent implant.
Clinical Evidence
Evidence based on three randomized, double-blind clinical trials (TAXUS IV, II, and I). TAXUS IV (pivotal, N=1314) compared TAXUS Express to bare metal control; primary endpoint 9-month TVR was 4.7% vs 12.1% (p<0.0001). TAXUS II (N=267) and TAXUS I (N=61) supported safety and efficacy. Clinical data showed significant reductions in late loss, binary restenosis, and MACE compared to bare metal controls. No clinical data for long-term (beyond 5 years) or specific drug interactions.
Technological Characteristics
Stent: 316L surgical grade stainless steel (ASTM F138-00). Coating: Translute (SIBS) tri-block copolymer loaded with 1 μg/mm² paclitaxel. Delivery: Monorail or Over-the-Wire catheter, compliant balloon. Sterilization: Ethylene oxide (AAMI/ISO 11135:1994). Connectivity: None. Software: None.
Indications for Use
Indicated for patients with de novo coronary artery lesions (length ≤ 28mm, vessel diameter 2.5–3.75mm). Contraindicated in patients with hypersensitivity to paclitaxel, the polymer, or its components; patients where anti-platelet/anticoagulant therapy is contraindicated; or patients with lesions preventing complete balloon inflation or proper stent placement.
Regulatory Classification
Identification
Stent, coronary, drug-eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen. The drug coating is intended to inhibit restenosis.
Reference Devices
- Express Coronary Stent System (P020009)
- NIR Conformer uncoated control stent
- NIRx Paclitaxel-Eluting Coronary Stent System
Related Devices
- P060008 — TAXUS LIBERTE PACLITAXEL-ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE) · Boston Scientific Corp · Oct 10, 2008
- P100023 — ION PACLITAXEL- ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE SYSTEMS) · Boston Scientific Corp · Apr 22, 2011
- P210014 — SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System and DIRECT Sirolimus-Eluting Coronary Stent Rapid Ex · Advanced Bifurcation Systems, Inc. · Dec 13, 2021
- P070015 — XIENCE AND PROMUS EVEROLIMUS ELUTING CORONARY STENT SYSTEMS · Abbott Vascular, Inc. · Jul 2, 2008
- P150003 — SYNERGY EVEROLIMUS-ELUTING PLATINUM CHROMIUM CORONARY STENT SYSTEM · Boston Scientific Corporation · Oct 2, 2015
Submission Summary (Full Text)
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA
## I. GENERAL INFORMATION
Product Generic Name: Drug-Eluting Coronary Stent System (NIQ)
Product Trade Name: TAXUS™ Express²™ Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire)
Applicant's Name and Address: Boston Scientific Corporation
One Boston Scientific Place
Natick, MA 01760
Premarket Approval Application (PMA) Number: P030025
Date of Panel Recommendation: November 20, 2003
Date of Notice of Approval to Applicant: March 4, 2004
## II. INDICATIONS FOR USE
The TAXUS™ Express²™ Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions ≤ 28mm in length in native coronary arteries ≥ 2.5 to ≤ 3.75 mm in diameter.
## III. CONTRAINDICATIONS
Use of the TAXUS™ Express²™ Paclitaxel-Eluting Coronary Stent System is contraindicated in patients with:
- Known hypersensitivity to paclitaxel or structurally-related compounds.
- Known hypersensitivity to the polymer or its individual components (see details in Section V – Product Description, below)
Coronary Artery Stenting is contraindicated for use in:
- Patients in whom anti-platelet and/or anticoagulant therapy is contraindicated.
- Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device.
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## IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the TAXUS Express² Paclitaxel-Eluting Coronary Stent System labeling.
## V. PRODUCT DESCRIPTION
The TAXUS Express² Stent System is a device / drug combination product comprised of two regulated components: a device (Express² Coronary Stent System) and a drug component (a formulation of paclitaxel contained in a polymer coating). The characteristics of the TAXUS Express² Stent System are described in Table 1.
Table 1. TAXUS Express² Stent System Product Description
| | TAXUS Express² Monorail (MR) Stent Delivery System | TAXUS Express² Over-The-Wire (OTW) Stent Delivery System |
| --- | --- | --- |
| Available Stent Lengths (mm) | 8, 12, 16, 20, 24, 28, 32 | 8, 12, 16, 20, 24, 28, 32 |
| Available Stent Diameters (mm) | 2.50, 2.75, 3.00, 3.50 | 2.50, 2.75, 3.00, 3.50 |
| Stent Material | A 316L surgical grade stainless steel Express stent | |
| Drug Component | A conformal coating of a polymer carrier loaded with 1 μg/mm² paclitaxel in a slow release (SR)* formulation applied to the stent with a maximum nominal drug content of 209 μg on the largest stent (3.50x32mm). | |
| Delivery System Working Length | 140 cm | 135 cm |
| Delivery System Y-Adapter Ports | Single access port to inflation lumen. Guidewire exit port is located approximately 25 cm from tip. Designed for guidewire ≤ 0.014". | Y-Connector (Side arm for access to balloon inflation/deflation lumen. Straight arm is continuous with shaft inner lumen). Designed for guidewire ≤ 0.014". |
| Stent Delivery Balloon | A compliant balloon, nominally 0.3 mm longer than the stent, with two radiopaque markers. | |
| Balloon Inflation Pressure | Nominal Inflation Pressure: 9 ATM; Rated Burst Inflation Pressure: 18 ATM | |
| Guide Catheter Inner Diameter | ≥ 0.058" | ≥ 0.066" |
| Catheter Shaft Outer Diameter | 1.8F proximally, 2.7F distally (Ø up to 3.0mm, and 8-20 mm long stents with Ø > 3.0mm)
2.0F proximally, 2.7F distally (24-32mm long stents with Ø > 3.0mm) | 3.2F proximally, 2.7F distally |
* release rate is a function of weight/weight ratio of polymer and drug, and (SR) is the formulation that was studied clinically and is used in the marketed product
## A. Device Component Description
The device component consists of the Express™ stent pre-mounted onto a stent delivery system (SDS); either the Express²™ Over-the-Wire (OTW) delivery system, or the Express²™ Monorail (MR) delivery system. The Express² OTW and MR delivery systems were previously approved for
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deployment of the uncoated Express stent in P020009 (approved September 11, 2002).
The 2.5-3.5mm diameter 316L stainless steel stents use one design. The same stent is crimped on various size delivery catheter balloons, which are sized from 2.5 to 3.5mm. Because the identical stent component is used for the entire 2.5-3.5mm diameter range, the total drug per stent is a function of stent length, irrespective of stent diameter.
The Express² Delivery Catheters were not used in the pivotal clinical trial (TAXUS IV). The TAXUS IV trial used the Express Delivery Catheters. The only differences between the Express and the Express² versions of the delivery catheters are that: (1) the Express² catheter changed one of the shaft materials to another material that was used in other components of the original Express delivery catheter shaft; and (2) the Express² manifold was molded slightly differently to allow better retention in the packaging. This PMA requested approval of only the Express² OTW and MR delivery systems for use in delivering the TAXUS Express stent. Appropriate pre-clinical testing was provided to support the Express² stent delivery system, and acute (30 day) safety and performance data was submitted March 1, 2004 (TAXUS V trial, 1167 patients) to support the clinical safety of the TAXUS Express stent mounted on the Express² catheter design.
## B. Drug Component Description
The drug component of the TAXUS Express² Paclitaxel-eluting Coronary Stent System (referred to as the TAXUS Express Stent) consists of paclitaxel (the active ingredient) and Translute™ polymer carrier (the inactive ingredient).
## B1. Paclitaxel
The active pharmaceutical ingredient in the TAXUS Express Stent is paclitaxel. It is a white powder, isolated from a spectrum of Taxus species and hybrids. The Chemical name of paclitaxel is: Benzenepropanoic acid, β-(benzoylamino)-α-hydroxy-,6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester, [2aR-[2aα,4β,4aβ,6β,9α (αR*, βS*),11α,12α,12aα,12bα]]-.
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The chemical structure of paclitaxel is shown below.
Figure 1. The Chemical Structure of Paclitaxel
Paclitaxel is a diterpenoid with a characteristic taxane skeleton of 20 carbon atoms, a molecular weight of 853.91 g/mol and a molecular formula of C47H51NO14. It is highly lipophilic, insoluble in water, but freely soluble in methanol, ethanol, chloroform, ethyl acetate and dimethyl sulfoxide.
## B2. Inactive Ingredients
The only inactive ingredient in the TAXUS Express stent is SIBS [poly(styrene-b-isobutylene-b-styrene)], a tri-block copolymer (trade name: Translute™), that is composed of styrene and isobutylene units built on 1,3-di(2-methoxy-2-propyl)-5-tert-butylbenzene. It is an hydrophobic elastomeric copolymer with a molecular weight (Mn-number average molecular weight) of 80,000 to 130,000 g/mol and a polydispersity index of 1.0 to 2.0. The polymer is mixed with the drug paclitaxel and then applied to the stents. There is no primer or topcoat layer. The drug/polymer coating is adhered to the entire surface (i.e., luminal and abluminal) of the stent. The structural formula for the polymer is shown below.
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Figure 2. The Chemical Structure of SIBS [poly(styrene-b-isobutylene-b-styrene)]
m = repeating units of styrene
n = repeating units of isobutylene
Product Matrix and Paclitaxel Content
Table 2. TAXUS™ Express²™ Stent System Product Matrix and Paclitaxel Content
| Product Code MR | Product Code OTW | Nominal Expanded Stent Inner Diameter (mm) | Nominal Un-expanded Stent Length (mm) | Nominal Paclitaxel Content (μg) |
| --- | --- | --- | --- | --- |
| H7493897008250 | H7493896808250 | 2.50 | 8 | 50 |
| H7493897008270 | H7493896808270 | 2.75 | 8 | 50 |
| H7493897008300 | H7493896808300 | 3.00 | 8 | 50 |
| H7493897008350 | H7493896808350 | 3.50 | 8 | 50 |
| H7493897012250 | H7493896812250 | 2.50 | 12 | 79 |
| H7493897012270 | H7493896812270 | 2.75 | 12 | 79 |
| H7493897012300 | H7493896812300 | 3.00 | 12 | 79 |
| H7493897012350 | H7493896812350 | 3.50 | 12 | 79 |
| H7493897016250 | H7493896816250 | 2.50 | 16 | 108 |
| H7493897016270 | H7493896816270 | 2.75 | 16 | 108 |
| H7493897016300 | H7493896816300 | 3.00 | 16 | 108 |
| H7493897016350 | H7493896816350 | 3.50 | 16 | 108 |
| H7493897020250 | H7493896820250 | 2.50 | 20 | 137 |
| H7493897020270 | H7493896820270 | 2.75 | 20 | 137 |
| H7493897020300 | H7493896820300 | 3.00 | 20 | 137 |
| H7493897020350 | H7493896820350 | 3.50 | 20 | 137 |
| H7493897024250 | H7493896824250 | 2.50 | 24 | 151 |
| H7493897024270 | H7493896824270 | 2.75 | 24 | 151 |
| H7493897024300 | H7493896824300 | 3.00 | 24 | 151 |
| H7493897024350 | H7493896824350 | 3.50 | 24 | 151 |
| H7493897028270 | H7493896828270 | 2.75 | 28 | 180 |
| H7493897028300 | H7493896828300 | 3.00 | 28 | 180 |
| H7493897028350 | H7493896828350 | 3.50 | 28 | 180 |
| H7493897032270 | H7493896832270 | 2.75 | 32 | 209 |
| H7493897032300 | H7493896832300 | 3.00 | 32 | 209 |
| H7493897032350 | H7493896832350 | 3.50 | 32 | 209 |
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## C. Mechanism of Action
The mechanism (or mechanisms) by which a TAXUS Express Stent affects neointimal production as seen in clinical studies has not been established. Paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
## VI. ALTERNATIVE PRACTICES OR PROCEDURES
Treatment of patients with coronary artery disease may include exercise, diet, drug therapy, percutaneous coronary interventions (such as angioplasty, bare metal stents, coated stents, and other drug eluting stents), and coronary artery bypass surgery (CABG).
## VII. MARKETING HISTORY
The TAXUS Express² Paclitaxel-Eluting Coronary Stent System is commercially available in the following countries:
- Argentina
- Austria
- Belgium
- Brazil
- Chile
- China
- Columbia
- Czech Rep.
- Denmark
- Egypt
- Finland
- France
- Germany
- Greece
- Hong Kong
- Hungary
- Iceland
- India
- Ireland
- Italy
- Jordan
- Liechtenstein
- Luxemburg
- Malaysia
- Mexico
- Netherlands
- Norway
- New Zealand
- Philippines
- Poland
- Portugal
- Singapore
- South Africa
- Spain
- Sweden
- Switzerland
- Thailand
- United Kingdom
- Uruguay
As of June 1, 2003, approximately 13,000 TAXUS Express Stents have been distributed outside of the U.S. No products have been withdrawn from the market in any country for any reason.
## VIII. SUMMARY OF NON-CLINICAL STUDIES
A series of non-clinical laboratory studies were performed – those related to the stent and the stent delivery system [i.e., the stent mounted on either the Monorail (MR) or Over-the-Wire (OTW) stent delivery system (SDS)], the polymer substance [i.e., polyisobutylene styrene (SIBS)], the drug substance
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(i.e., paclitaxel), and the finished combination product (i.e., TAXUS Express² paclitaxel-eluting coronary stent).
## A. Biocompatibility Studies
A series of GLP and non-GLP biocompatibility tests and USP Physicochemical tests were conducted to demonstrate the components of the TAXUS Express² Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire) are non-toxic. Tests were conducted on ethylene oxide-sterilized bare metal stents, stent delivery systems, polymer films, and polymer-only coated stainless steel (SS) coupons. These test articles were processed in the same manner as the finished TAXUS Express² product, except that where polymers were present (i.e., films and coupons), the drug substance, paclitaxel, was not included in the polymer coating. With the exception of the inclusion of the drug substance, the surface treatment, coating processing, amount of coating per unit area, and sterilization processes were equivalent for both the stents and coupons utilized during this testing. In all of these test systems, the materials were non-reactive and produced no greater response than the negative control employed in each test system.
All biocompatibility testing was conducted in accordance with:
- Guidance for the Submission of Research and Marketing Applications for Interventional Cardiology Devices; published by the Interventional Cardiology Devices Branch, Division of Cardiovascular, Respiratory and Neurology Devices, Office of Device Evaluation in May 1995.
- ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and Testing.
The GLP and non-GLP biocompatibility studies are summarized in Table 3.
Table 3. Biocompatibility Test Summary
| Test Name | Test Description | Test Article and Results |
| --- | --- | --- |
| Cytotoxicity | ISO 10993-5: In Vitro Cytotoxicity (L929 MEM Elution) | • Stent and delivery systems: Pass (non-cytotoxic)
• Polymer-only coated 316L SS coupon: Pass (non-cytotoxic) |
| Sensitization | ISO 10993-10: Sensitization (Kligman Maximization) | • Stent and delivery systems: Pass (non-sensitizing)
• Polymer-only coated 316L SS coupon: Pass (non-sensitizing) |
| Intracutaneous Reactivity | ISO 10993-10: Irritation (Injection) | • Stent and delivery systems: Pass (non-irritant)
• Polymer-only coated 316L SS coupon: Pass (non-irritant) |
| Acute Systemic Toxicity | ISO 10993-11: Systemic Toxicity (Acute) | • Stent and delivery systems: Pass (non-toxic)
• Polymer-only coated 316L SS coupon: Pass (non-toxic) |
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| Test Name | Test Description | Test Article and Results |
| --- | --- | --- |
| Pyrogenicity | LAL | • Stent and delivery systems: Pass (non-pyrogenic) |
| | ISO 10993-11: Systemic Toxicity (Material-Mediated Rabbit) | • Polymer-only coated 316L SS coupon: Pass (non-pyrogenic) |
| Hemocompatibility | Direct Contact Hemolysis | • Stent and delivery systems: Pass (non-hemolytic)
• Polymer-only coated 316L SS coupon: Pass (non-hemolytic) |
| | Lee and White Coagulation | • Stent and delivery systems: Pass (no change in coagulation time) |
| Implantation | 14-Days (Rabbit, Intramuscular) | • Stent and delivery systems: Pass (non-toxic) |
| | 30-Days (Rabbit, Intramuscular) | • Stent and delivery systems: Pass (non-toxic) |
| | 14-Day Repeat Dose Subchronic Toxicity (Mouse, Intravenous) | • Stent and delivery systems: Pass (non-toxic) |
| | 90-Day Chronic Toxicity (Mouse, Intraperitoneal) | • Polymer-only cast film: Pass (non-toxic) |
| Genotoxicity | Bacterial Reverse Mutation Assay (Ames Test) | • Polymer-only coated 316L SS coupon: Pass (non-mutagenic) |
| | In Vitro Chromosomal Aberration (human blood lymphocytes) | • Polymer-only cast film: Pass (non-clastogenic) |
| | In Vivo Mouse Micronucleus Test | • Polymer-only cast film: Pass (non-mutagenic) |
| Volatile/Metal Extracts | USP Physicochemical Extracts | • Stent and delivery systems: Pass |
*Note: Express BMS & DES biocompatibility studies were conducted in accordance with GLPs. A rationale was provided for the non-GLP biocompatibility studies of Polymer-only coated SS/coupon and Polymer-only film studies to demonstrate that appropriate animal care procedures were followed, and data integrity was maintained.*
Since the sponsor did not conduct the traditional battery of ISO-10993 testing on the finished TAXUS Express Stent (i.e., containing the drug substance), sub-chronic toxicity, thrombogenicity, and implantation of the final TAXUS Express product, containing all components and processing, were evaluated in porcine, rabbit, and canine models of stent-mediated vascular injury. The significant animal studies are summarized separately in Section VIII F – Animal Studies (below).
The genotoxicity, carcinogenicity, and reproductive toxicity of TAXUS Express Stents have not been evaluated. However, the genotoxicity, carcinogenicity, and reproductive toxicity of paclitaxel have been investigated in bacterial and mammalian cells *in vitro* and in laboratory animals *in vivo*.
Boston Scientific provided a letter from the drug substance manufacturer, Indena S.p.A., authorizing access to a Drug Master File (DMF) in support of this application. Indena manufactures a generic form of the drug Taxol®, a Bristol-Myers Squibb drug product that is approved for injection for multiple oncologic indications. *In vivo* animal and *in vitro* pharmacology and toxicology studies as well as *in vivo* and human pharmacokinetic studies were conducted on Taxol® to provide information
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about systemic, regional and local toxicity, dose-related toxicity, distribution profiles, end-organ disposition, drug metabolism and potential drug-drug interactions.
There is no evidence to suggest that any chemical interactions occur, which would form a new intermediate or molecular entity, between paclitaxel or the polymeric carrier used in the TAXUS Express Stents.
Formal carcinogenicity testing on the final TAXUS Express Stent was not conducted. Because some paclitaxel remains on the product, and the carcinogenic potential of the SIBS polymer coating had not previously been investigated, an appropriate rationale was provided to demonstrate that the carcinogenic potential of the TAXUS Express Stent was minimal based on the types and quantities of starting materials (including any manufacturing additives).
Long term biocompatibility of the drug/polymer coating on the stent in humans is unknown.
## B. In Vivo Pharmacokinetics
### B1. TAXUS Express² Paclitaxel-Eluting Coronary Stent
In the clinical studies, TAXUS I, II, and III, no paclitaxel levels were detected after stent implantation using an analytical method with a lower limit of quantitation (LLOQ) of 10 ng/ml. These findings were confirmed in preclinical studies using multiple stents with total loaded doses above the clinically available stent system and an assay with an LLOQ of 0.03 ng/ml. Hence, in the absence of any systemically detectable levels, standard pharmacokinetic parameters were not estimated.
### B2. Drug Interactions
Formal drug interaction studies have not been conducted with the TAXUS Express Stent. Paclitaxel is metabolized in the liver via cytochrome P450 (CYP) 2C8 to 6-alpha-hydroxypaclitaxel and via CYP 3A4 to 3'-p-hydroxypaclitaxel and 6-alpha,3'-p-dihydroxypaclitaxel. Paclitaxel is a substrate of P-glycoprotein. Because metabolism appears to play an important role in the elimination of paclitaxel, agents that could compete with or inhibit the CYP2C8 and CYP3A4 isoenzymes may increase paclitaxel plasma levels. Potential drug interactions may occur with any drug that affects these isoenzymes.
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## C. In Vitro Engineering Testing
In vitro engineering testing, in accordance with the FDA “Guidance for the Submission of Research and Marketing Applications for Interventional Cardiology Devices: Intravascular Stents”, May 1995, was conducted on the uncoated, bare versions of the Express stent mounted on either the Express or Express² MR and/or OTW delivery catheters, which were approved in P020009.
Supplementary in vitro engineering tests were also performed on the TAXUS Express Stent mounted on the Express and/or Express² delivery catheters. Some testing was not repeated since there was no change to the stent substrate, and where the effect of the coating and minor changes in design of the catheter delivery system were assumed to be negligible when evaluated against measurement and manufacturing tolerances. In tests that were repeated, values for the TAXUS Express stent were compared back to the uncoated stent as well as other bare metal coronary stents. Values reported for the products tested indicated statistical equivalence.
Additional tests were conducted to support the integrity of the coating on the TAXUS Express Stent and are summarized separately in Section VIII D – Coating Characterization Testing.
The in vitro engineering studies conducted are summarized in Table 4. “Pass” denotes that the test results met product specifications and/or the recommendations in the above-referenced guidance document.
Table 4: Stent and Delivery Catheter Engineering Testing
| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Stent Material Specification Conformance Testing | | |
| Bare Stent Material Analysis | Chemical analysis was conducted on the stainless steel ingot provided by the material supplier to confirm both chemical analysis and inclusion/impurity content as provided by ASTM F138-00 “Standard Specification for Wrought 18 Chromium-14 Nickel-2.5 Molybdenum Stainless Steel Bar and Wire for Surgical Implants (UNS S31673).” | Pass |
| Surface Contamination | The fully processed (but not sterilized) TAXUS Express stents were examined via SEM at 500X and 2000X to detect evidence of surface contamination or impurities on the stent material not removed by cleaning processes. Results of SEM evaluation showed no evidence of contamination above the specified limits. | Pass |
| Mechanical Properties: Tensile Strength & Elongation | Tensile strength and elongation testing was performed on tubing sizes used to fabricate the stents. The tensile strength and elongation met the product specifications. | Pass |
| Corrosion Resistance | As part of the fatigue testing, TAXUS stents were also tested according to ASTM F2129-01 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices” to demonstrate that the finished stents exhibit corrosion and repassivation characteristics comparable to or | Pass |
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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| | better than marketed 316L bare metal coronary stents. The results indicated that the corrosion resistance met product specifications. | |
| **Stent Integrity Testing** | | |
| Metal to Artery Percentage | The metal surface coverage as a function of stent diameter was calculated by dividing the total vessel contact metal surface area of the stent structure by the surface area of the vessel at any given stent/vessel diameter. Metal to artery percentage ratios were calculated for all of the stent diameters recommended in the product labeling, with the highest surface to artery ratio (24.7%) occurring when the stent is deployed to the smallest diameter (2.5mm). | Pass |
| Length Changes Upon Expansion: Stent Foreshortening | The length of the stents were measured prior to and after expansion to the largest nominal diameter. All stents met product specifications. | Pass |
| Stent Expansion Uniformity | Testing was conducted to determine the uniformity of stent expansion along the stent length. Units were inflated to nominal diameters, deflated, and diameter measurements were taken at 3 points along the stent length. Measurements were averaged and compared to baseline measurements. All stents met the uniformity expansion specification. | Pass |
| Stent Recoil | Testing was conducted to quantify the amount of elastic recoil for the stent and correlate this parameter to the recommended sizing procedures. The system was inflated to nominal diameter and measurements were taken of the stent diameter at 3 locations along the stent. The system was then deflated and the same measurements taken. Results indicated that product specifications were met. | Pass |
| Stent Conformability Testing | Testing was conducted to determine the conformability (axial flexibility) of the stent in its expanded state by determining the pure bending moment of the stent. All diameter stents met specification. | Pass |
| Compression Resistance/Radial Hoop Strength | Testing was conducted to determine the radial resistance of the stent to external compression. All stents were expanded to nominal stent diameter, placed in a compression tester, forces were applied to compress the stent 0.5mm radially, and the forces were recorded. All stents met the compression resistance specifications. | Pass |
| Stent Expansion and Safety Margin | Testing was conducted to determine whether the deformation experienced by the stent undergoing expansion above the maximum rated diameter gives rise to stent or coating fractures. No stents exhibited any strut fractures or indications of coating integrity issues when visually examined at 32X following overexpansion. | Pass |
| Magnetic Resonance Imaging | Bench testing at field strengths of 3 Tesla (T) or less, and a maximum spatial gradient of 325 gauss/cm, showed that the stent should not migrate in this MR environment. This stent has not been evaluated to determine if it is safe in MRI systems with field strength greater than 3 T.
The following statement is also included in the instructions for use: "This product has not been evaluated for heating in the MR environment. The effect of heating in the MR environment for overlapping stents or stents with fractured struts, or on the drug or polymer coating is not known. MR imaging quality may be compromised if the area of interest is in the exact same area or relatively close to the position of the stent." | Pass |
| Stent Dimensional Verification | Testing was conducted to measure and optically inspect the stent to document that stent dimensional product specifications do not deviate from product specifications. All | Pass |
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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| | product met specifications. | |
| Finite Element Analysis | An in-depth analysis of the stent was conducted to ensure that the implant conditions to which the stent will be subjected would not result in failure due to fatigue. The FEA evaluated the structural integrity of the stent and coating when subjected to the expected loading conditions generated in coronary arteries. The analysis took into account manufacturing, delivery, implantation and clinical loading over the implant life, and predicted that fatigue failures will not occur over the 400 million cycles of loading. | n/a |
| 10 Year Accelerated Pulsatile Fatigue Testing | Accelerated In vitro testing of approximately 10 years (400 million cycles) equivalent real time was conducted to ensure that the stent, when expanded to its largest intended diameters, will not show fatigue failure during simulated 10 year life span testing. The stents were dynamically cycled over simulated vessel conditions for 400 million cycles. Following cycling, stents were visually inspected using 40X optical microscopy. No signs of strut cracking or breaking were detected. Additionally, eight stents (4 coated, and 4 with coating removed after fatigue testing) were randomly analyzed using SEM. All tested stents were free from fatigue induced surface defects, and there was no evidence of coating fatigue or corrosion. The stent met the 10 year accelerated fatigue resistance requirement of the product specification. | Pass |
| Stent Radiopacity | Testing was conducted on the bare metal stent as the addition of the coating did not add or detract from the radiopacity of the stent in clinical use. | Pass |
| Stent/Catheter Delivery System Testing | | |
| Balloon in Stent Burst, Balloon Bonds, and Inflation Lumen Integrity Testing | Stents systems with sizes representative of the available product were tested to burst, and all other sizes were also tested and required to meet rated burst pressure. All stent systems met rated burst pressure. The results demonstrate with 95% confidence that at least 99.9% of the balloons will not experience loss of integrity at or below the rated burst pressure. | Pass |
| Stent Diameter vs. Balloon Inflation Pressure (Compliance) | Testing was performed to determine how the diameter of a deployed balloon varies with applied balloon pressures. The stent sizing results verify that the stent systems meet the labeled compliance values. | Pass |
| Stent Deployment Testing | Testing was performed to determine the TAXUS Express and Express² stent deployment pressures. Samples of every TAXUS Express stent and delivery system and representative sizes of the TAXUS Express² stent and delivery system were tested and demonstrated that these product met the labeled deployment specification of ≤ 9 atm (132 psi). | Pass |
| Balloon Inflation and Deflation Testing | Express² delivery systems across the range of balloon lengths and diameters were tested for inflation/deflation times, and all stent systems met specifications. | Pass |
| Repeat Balloon Inflation | TAXUS Express² stent systems across the range of stent/balloon lengths and diameters were required to complete 20 pressurization cycles to Rated Burst Pressure (RBP). The stent/balloon burst results show statistically that, with 95% confidence, 90% of the catheters will not experience balloon, shaft, or proximal/distal seal loss of integrity at or below the maximum recommended rated balloon burst pressure. | Pass |
| Stent/Balloon Crossing Profile | Stent systems for each diameter balloon were tested to determine the deflated stent/balloon profile. All samples met the product specification. | Pass |
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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Pre- and Post-Deployment Catheter Withdrawal Forces (into a Guide Catheter) | Testing was carried out to verify that the TAXUS Express² Stent system can be safely withdrawn back into the recommended guide catheter sizes both before and after stent deployment. This testing also verified that after stent deployment, the balloon could be withdrawn from the stent. Testing indicated that all samples could be withdrawn back into the recommended guide catheter prior to and after stent delivery. All samples met the product specification. | Pass |
| Non-Coaxial Withdrawal Forces (into a Guide Catheter) | Testing was carried out to demonstrate that the TAXUS Express² stent system can be safely withdrawn into the guide catheter when the entry is non-coaxial. Testing indicated that all samples could be withdrawn back into the recommended guide catheter after tracking through a simulated tortuous model. All samples met the product specification. | Pass |
| Stent Securement - Force Testing | Testing was conducted to assess the force required to displace a crimped TAXUS stent from the Express² delivery systems (1) directly from the balloon catheter, and (2) after tracking through a simulated tortuous artery model. All stent systems met the stent securement specification. Stent securement to the specification was demonstrated with 95% confidence that 99.7% of the TAXUS Express stents will not be dislodged from the Express² delivery systems. | Pass |
| System Track Testing | Testing was conducted to demonstrate that the tracking force of the TAXUS Exress² Coronary Stent System through a simulated artery is comparable to the Express Coronary Stent System. Peak force was measured as the catheter was tracked through a simulated artery, and found to be comparable. All samples met product specification. | Pass |
| Full Unit Tensile Testing | Representative sizes of the TAXUS Express² stent delivery system were tested to determine the tensile strength of the delivery catheter. All stent systems exceeded the minimum catheter tensile strength specification. | Pass |
## D. Coating Characterization Testing
The following methods were developed to characterize and set initial specifications for the TAXUS Express stent. The coating characterization testing conducted on the TAXUS Express stent is summarized in Table 5.
Table 5: Coating Characterization Testing
| Test | Description of Test |
| --- | --- |
| Materials Analysis - Polymer | Polymer components were tested to ensure conformity to raw material specifications and incoming inspection procedures. |
| Chemical Analysis – Polymer | Assays were conducted to determine Mw, Mn, polydispersity, monomer content, presence/formation of oligomers and free monomers. |
| Chemical Analysis - Drug | Drug substance was tested to ensure conformity to incoming Certificate of Analysis. |
| Drug Content | Assay was conducted to quantitatively determine the total amount of the drug substance, paclitaxel, on the TAXUS Express stent. |
| Dose Density | Dose per unit area was calculated. |
| Drug Content along Stent Length | Testing was conducted to characterize the uniform distribution of drug along the length of the TAXUS Express stent. |
| Coating Uniformity/ Reproducibility | Testing was conducted to verify the reproducibility of coating uniformity from stent to stent and batch to batch. |
| Coating Thickness | Testing was conducted to describe the coating thickness along the length of the stent. |
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| Test | Description of Test |
| --- | --- |
| Impurities/Degradation Products | Assays were conducted to quantitatively determine the type and amount of impurities and degradation products on the TAXUS Express stent. |
| In Vitro Elution | Assay was developed to measure the in vitro release kinetics of paclitaxel off the TAXUS Express stent. |
| Particulates | Particulate levels were determined for the TAXUS Express² stent delivery system (pre- and post-deployment) to be within the USP <788> specification for small volume injections. |
## E. Chemistry Manufacturing and Controls (CMC) Testing
Where applicable, International Conference on Harmonization (ICH) Guidelines were followed for the testing routinely performed on the TAXUS Express² stent as part of CMC. This testing is summarized in Table 6. Information to support the stability of the TAXUS Express² Stent is summarized separately in Section VIII G – Stability, below.
Table 6: CMC Release Testing
| Test | Description of Test |
| --- | --- |
| Material Analysis – Polymer | The polymer was tested to ensure conformity to specifications. The polymer met specifications prior to utilization in finished goods. |
| Drug Identity | Assay was conducted to verify the identity of the drug substance, paclitaxel, on the TAXUS Express stent. The product met specifications established for finished goods release. |
| Drug Content/Impurities | Assays were conducted to quantitatively verify the amount of drug and the type and amount of impurities on the TAXUS Express stent. The product met specifications established for finished goods release. |
| Drug Content Uniformity | Multiple stents were assayed to verify the uniformity of the drug content between individual stents was within specifications established for finished goods release. |
| Residual Solvents | Assay was conducted on the TAXUS Express stent to verify that residual levels of solvents used in the manufacturing process were below acceptable limits established for finished goods release. |
| In Vitro Elution | The in vitro release profile of paclitaxel was measured on the TAXUS Express stent. Specifications were based on the elution characteristics of stents evaluated in the clinical investigation. The product met specifications established for finished goods release. |
| Particulates | Particulate levels were monitored to verify that they remain below acceptable levels as established in the product specifications. |
## F. Animal Studies
Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials, so a series of animal studies were conducted to evaluate safety, efficacy (proof of concept), and overall product performance.
Boston Scientific conducted a series of studies evaluating a variety of paclitaxel-eluting stent formulations (e.g., various drug dosages and concentrations, etc.), polymer-coated control stents and/or bare metal control stents. These studies were conducted in coronary arteries of pigs,
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or iliac arteries of rabbits. These studies served as the basis for the dose selection for the TAXUS Express stent used in the clinical studies.
The intravascular safety and biocompatibility of paclitaxel-eluting stents were evaluated in a series of animal studies in a porcine model of stent-mediated vascular injury. Some of these studies were conducted in accordance with §21CFR 58 (Good Laboratory Practices). A rationale was provided for the non-GLP animal studies to demonstrate that appropriate animal care procedures were followed, and data integrity was maintained. The results of these tests support the safety and biocompatibility of the TAXUS Express Stent. Summaries of these studies are included in Table 7.
Table 7: Summary of Major Supportive Animal Studies
| Study # | Stent Design | Type/ # of Animals | # of Stents | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| BS5P | Test Article: TAXUS Express Stent MR* (3.0x8mm, 3.5x8mm) Control: BMS GLP: no | Domestic Swine Test & Control: 36 (LAD, LCX, RCA) 2 stents/vessel Animals received both test and control | Test: 54 Control: 34 | 28, 90, & 180 days | • Histologic and histomorphometric evaluations of overlapping stents
• Evaluation of degree of re-endothelialization by SEM
• Acute delivery
• Chronic vascular response. |
| RVF 02-069 | TAXUS Express SR** (3.0x16mm, 3.5mmx16mm) Control: BMS GLP: no | Domestic Swine Test & Control: 11 (LAD, LCX, RCA) 2 stents/vessel Some animals received both test and control | Test: 16 Control: 18 | 180 days | • Histologic and histomorphometric evaluations of overlapping stents
• Evaluation of degree of re-endothelialization by SEM
• Chronic vascular response |
| A242-GX-00 | Test Article: polymer-coated NIR Conformer (no drug) [3.0x15mm, 3.5mmx15mm] Control: BMS GLP: no | Domestic Swine Test: 14 Control: 13 (LAD, LCX, RCA) 1 stent/vessel | Test: 26 Control: 22 | 28, 90, & 180 days | • Histologic and histomorphometric evaluations
• Chronic vascular response (SIBS polymer coating & BMS) |
| RVF01-049 and 050 | TAXUS Express MR (3.0x16mm, 3.5x16mm) Control: BMS GLP: Yes | Domestic Swine Test: 23 Control: 22 (LAD, LCX, RCA) 1 stent/vessel 1 or 2 stents/animal | Test: 35 Control: 35 | 28, 90, 180, & 360 days | • Histologic and histomorphometric evaluations of overlapping stents
• Evaluation of degree of re-endothelialization by SEM
• Acute Delivery
• Chronic vascular response |
| A203-GX-00 | TAXUS NIRx MR (3.0x15mm, 3.5x15mm) GLP: yes | Domestic Swine Test: 17 Control: 15 | Test: 38 Control: 30 | 28, 90, & 180 days | • Histologic and histomorphometric evaluations of overlapping stents
• Evaluation of degree of |
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| Study # | Stent Design | Type/ # of Animals | # of Stents | Follow-up Duration | Endpoints |
| --- | --- | --- | --- | --- | --- |
| | | | | | re-endothelialization by SEM
• Chronic vascular response |
*MR = Moderate Release formulation of TAXUS Express stent (not the subject of this PMA application)<br/>
**SR = Slow Release formulation of TAXUS Express stent (the subject of this PMA application)
## G. Stability
Site-specific stability studies were conducted to establish a shelf life/expiration date for the TAXUS Express² Paclitaxel-Eluting Coronary Stent System. Testing to establish package integrity and functional testing of the stent system were conducted on aged product. Testing evaluation included drug identity, assay, degradants, *in vitro* elution, particulates, sterility, drug content uniformity, residual solvents and endotoxins. Appropriate engineering tests were also repeated on aged product and compared to baseline to ensure that the TAXUS Express² Stent System performed acceptably. The data generated support a shelf life of 6 months.
A GLP polymer stability study was conducted to establish the chemical stability of the main inactive ingredient in the TAXUS Express stent. The stability of SIBS was investigated via GPC analysis of explanted cast polymer films that had been implanted for 13 weeks in a mouse model, with no change in molecular weight or polydispersity. In addition, a literature review was conducted to support that chemical degradation of this polymer is unlikely to occur in the physiologic environment.
## H. Sterilization
The TAXUS Express² Paclitaxel Eluting Stent System (Monorail and Over-The-Wire) is sterilized using ethylene oxide sterilization, and has been validated per AAMI/ISO 11135:1994 “Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization.”
Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of 10⁻⁶.
The amount of bacterial endotoxins was verified to be within the specification limit for TAXUS Express² stent delivery systems.
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# IX. OVERVIEW OF CLINICAL STUDIES
TAXUS IV was a randomized, double-blind, controlled pivotal U.S. study of the safety and performance of the 1 µg/mm² (loaded drug/stent surface area) slow rate-release formulation TAXUS™ Express™ Stent in patients with low risk, de novo coronary artery lesions. A total of 1,326 patients at 73 U.S. sites were enrolled with patients randomized 1:1 to the TAXUS Express Stent or the uncoated Express control stent. The primary endpoint for the study was the 9-month ischemia driven TVR rate. Secondary endpoints included 9-month clinical assessments for all patients and analysis of angiographic and intravascular ultrasound (IVUS) parameters in a subset of patients. After the procedure, patients were treated with aspirin indefinitely and with clopidogrel or ticlopidine for 6 months. Follow-up through 12 months is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing.
TAXUS II was a randomized, double-blind, controlled supporting study of the safety and performance of the 1 µg/mm² TAXUS NIRx™ Paclitaxel-Eluting Coronary Stent System (TAXUS NIRx Stent), in which two sequential cohorts of patients with low risk, de novo coronary artery lesions were treated. The slow rate-release (SR) formulation was studied in Cohort I and the moderate rate-release (MR) formulation in Cohort II. A total of 536 patients in 15 countries were enrolled. Patients in each cohort were randomized (1:1) to the TAXUS NIRx Stent or the NIR™ Conformer uncoated control stent. The primary endpoint for the study was mean percent in-stent net volume obstruction at 6 months as measured by IVUS. Secondary endpoints included 6-month clinical and angiographic parameters. After the procedure, patients were treated with aspirin indefinitely and with clopidogrel or ticlopidine for 6 months. Follow-up through 12 months is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing, with an additional angiographic follow-up scheduled at the 2 year time-point. For TAXUS II, results are only presented for the SR treatment group (Cohort I) and corresponding control.
TAXUS I was a randomized, double-blind, controlled feasibility study comparing the 1 µg/mm² slow rate-release formulation of the TAXUS NIRx Stent with the NIR Conformer uncoated control stent in de novo lesions. IVUS guidance during the index procedure and at 6-month follow up was required. Patients received aspirin indefinitely and clopidogrel or ticlopidine for 6 months. In brief, 61 patients were enrolled by 3 centers in Germany. Baseline demographic, lesion characteristics were similar between the 2 groups. The primary endpoint was 30-Day Major Adverse Cardiac Event (MACE). Follow-up through 24 months is currently available and follow-up for clinical parameters through 5 years is ongoing.
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Table 8. Clinical Trial Comparison
| | TAXUS IV (Pivotal) | TAXUS II (SR) (Supportive) | TAXUS I (Feasibility) |
| --- | --- | --- | --- |
| Study Type | • prospective
• multi-center randomized
• double-blind | • prospective
• multi-center randomized
• double-blind
• two sequential cohorts | • prospective
• multi-center randomized
• double-blind |
| Number of Patients | Total: 1314
TAXUS Express Stent: 662
Control: 652 | Total: 267
TAXUS NIRx Stent: 131
Control: 136 | Total: 61
TAXUS NIRx Stent: 31
Control: 30 |
| Dose Release Formulation | SR (1 μg /mm²) | SR (1 μg /mm²) | SR (1 μg /mm²) |
| Lesion Criteria | De novo lesions in native coronary artery ≥10mm and ≤28mm in length and vessel diameter ≥2.5mm to ≤3.75mm in diameter and coverable with 1 stent | De novo lesions in native coronary artery ≤12mm in length and vessel diameter ≥3.0mm to ≤3.5mm in diameter and coverable with 1 stent | De novo lesions in native coronary artery ≤12mm in length and vessel diameter ≥3.0mm to ≤3.5mm in diameter and coverable with 1 stent |
| Product Used | Express Stent on the Maverick™ Monorail Stent Delivery Balloon Catheter | NIRx Stent premounted on the Advance Monorail Stent Delivery Balloon Catheter | NIRx Stent hand-crimped on the Advance Monorail Stent Delivery Balloon Catheter |
| Antiplatelet Therapy | Aspirin indefinitely and clopidogrel or ticlopidine for 6 months | Aspirin indefinitely and clopidogrel or ticlopidine for 6 months | Aspirin indefinitely and clopidogrel or ticlopidine for 6 months |
| Follow-Up | 30 days: clinical
4 months: clinical or telephone
9 month: clinical, angiographic
1 – 5 years: telephone | 30 days: clinical
6 and 24 months: clinical, angiographic
1,3,4,5 years: telephone | 30 days: clinical
6 and 24 months: clinical, angiographic
1,3,4,5 years: telephone |
X. POTENTIAL ADVERSE EFFECTS OF THE PRODUCT ON HEALTH
A. Observed Adverse Events
Observed adverse event experience comes from three clinical studies, TAXUS IV, II and I.
Principal adverse events for these trials are shown in Table 9. Stent apposition was recorded for the TAXUS IV and TAXUS II trials and is presented in Table 9. See also Section X B - Potential Adverse Events, below.
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Table 9. Principal Adverse Events
| | TAXUS IV (SR)
to 12 months | | TAXUS II (SR)
to 12 months | | TAXUS I (SR)
to 24 Months | |
| --- | --- | --- | --- | --- | --- | --- |
| | TAXUS
Stent | Control
Stent | TAXUS
Stent | Control
Stent | TAXUS
Stent | Control
Stent |
| In-Hospital | N=662*
% (n) | N=652*
% (n) | N=131*
% (n) | N=136*
% (n) | N=31*
% (n) | N=30*
% (n) |
| MACE | 2.4% (16) | 2.1% (14) | 1.5% (2) | 4.4% (6) | 0.0% (0) | 0.0% (0) |
| Death | 0.0% (0) | 0.3% (2) | 0.0% (0) | 0.7% (1) | 0.0% (0) | 0.0% (0) |
| Myocardial Infarction | 2.4% (16) | 2.1% (14) | 1.5% (2) | 3.7% (5) | 0.0% (0) | 0.0% (0) |
| Q-wave | 0.2% (1) | 0.2% (1) | 0.0% (0) | 0.7% (1) | 0.0% (0) | 0.0% (0) |
| Non Q-wave | 2.3% (15) | 2.0% (13) | 1.5% (2) | 2.9% (4) | 0.0% (0) | 0.0% (0) |
| Target Vessel Revascularization (TVR) | 0.0% (0) | 0.2% (1) | 0.8% (1) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| Target Lesion Revascularization (TLR) | 0.0% (0) | 0.2% (1) | 0.8% (1) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| TVR, non-target lesion | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| TVR, CABG | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| CVA | 0.0% (0) | 0.2% (1) | 0.0% (0) | 0.0% (0) | - | - |
| Stent Thrombosis (acute/in-hospital) | 0.0% (0) | 0.3% (2) | 0.8% (1) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| Out-of-Hospital | N=653*
% (n) | N=644*
% (n) | N=129*
% (n) | N=131*
% (n) | N=31*
% (n) | N=30*
% (n) |
| MACE | 8.4% (55) | 18.3% (118) | 9.3% (12) | 18.3% (24) | 3.2% (1) | 10.0% (3) |
| Death | 1.4% (9) | 0.9% (6) | 0.0% (0) | 0.8% (1) | 0.0% (0) | 0.0% (0) |
| Myocardial Infarction | 1.1% (7) | 2.5% (16) | 0.8% (1) | 2.3% (3) | 0.0% (0) | 0.0% (0) |
| Q-wave | 0.6% (4) | 0.2% (1) | 0.8% (1) | 1.5% (2) | 0.0% (0) | 0.0% (0) |
| Non Q-wave | 0.5% (3) | 2.3% (15) | 0.0% (0) | 0.8% (1) | 0.0% (0) | 0.0% (0) |
| Target Vessel Revascularization (TVR) | 6.9% (45) | 16.8% (108) | 9.3% (12) | 16.0% (21) | 3.2% (1) | 10.0% (3) |
| Target Lesion Revascularization (TLR) | 4.3% (28) | 14.8% (95) | 3.9% (5) | 13.0% (17) | 0.0% (0) | 10.0% (3) |
| TVR, non-target lesion | 2.8% (18) | 3.1% (20) | 3.1% (4) | 3.1% (4) | 3.2% (1) | 0.0% (0) |
| TVR, CABG | 1.7% (11) | 4.0% (26) | 3.1% (4) | 0.8% (1) | 0.0% (0) | 3.3% (1) |
| CVA | 1.7% (11/654) | 0.6% (4) | 0.8% (1)† | 0% (0/136) | - | - |
| Stent Thrombosis (sub-acute/<30 days) | 0.3% (2) | 0.3% (2) | 0.0% (0) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
| Stent Thrombosis (late/≥31 days) | 0.3% (2) | 0.2% (1) | 0.8% (1) | 0.0% (0) | 0.0% (0) | 0.0% (0) |
Numbers are % (Count/Sample Size). * Note: sample size is defined as N at the top of each column for In-Hospital and Out-of-Hospital measures except where noted by inclusion of a denominator
MACE: Major Adverse Cardiac Events, comprised of Cardiac Death, MI and TVR.
TVR: Target Vessel Revascularization, defined as Ischemia-driven repeat percutaneous intervention of the target vessel or bypass surgery of the target vessel. A TVR will be considered as ischemia-driven if the target vessel diameter stenosis is ≥50% by QCA and any of the following are present:
- the patient had a positive functional study corresponding to the area served by the target vessel;
- ischemic ECG changes at rest in a distribution consistent with the target vessel;
- ischemic symptoms referable to the target lesion.
Primary endpoint of TAXUS IV: 9-month TVR.
For definitions of other AEs refer to tables 9-1 and 9-2
†This event was reported by site as Serious Adverse Event (SAE) (visual field defect right eye): It was subsequently adjudicated by the Clinical Event Committee as a Transient Ischemic Attack but downgraded to the non-serious adverse event.
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In the TAXUS IV trial, a pre-specified subset of patients underwent IVUS evaluation of the treated lesion immediately after treatment and as part of a scheduled angiographic evaluation at 9 months. In the TAXUS II trial, all patients underwent IVUS evaluation immediately after treatment and as part of the follow-up angiographic evaluation at 6 months. In both studies, the incomplete apposition rate post-procedure and at follow-up was comparable between patients in the TAXUS stent treatment group and the Control group. From the TAXUS IV trial, the majority of incomplete stent apposition cases that were present post-procedure had resolved, and the incidence of late acquired stent apposition was low and comparable between groups. There was no correlation of clinical adverse events or MACE events that were related to the occurrence of incomplete stent apposition. Frequencies of incomplete stent apposition are shown in Table 10 for both TAXUS IV and TAXUS II.
Table 10. Frequency of Incomplete Stent Apposition
| | TAXUS IV (SR) Trial | | TAXUS II (SR) Trial | |
| --- | --- | --- | --- | --- |
| | TAXUS Stent | Control Stent | TAXUS Stent | Control Stent |
| Incomplete Stent Apposition Rate Post-Procedure | 11.6% (13/112) | 6.4% (7/109) | 11.1% (14/126) | 9.3% (12/129) |
| Incomplete Stent Apposition Rate at Follow-up | 4.0% (4/99) | 3.0% (3/100) | 12.5% (15/120) | 7.9% (10/127) |
| | | | | |
| Resolved | 6.4% (6/94) | 5.4% (5/93) | 6.8% (8/118) | 4.9% (6/123) |
| Persistent | 3.2% (3/94) | 1.1% (1/93) | 4.2% (5/118) | 4.1% (5/123) |
| Late Acquired | 1.1% (1/94) | 2.2% (2/93) | 8.5% (10/118) | 4.1% (5/123) |
Numbers are % (Count/Sample Size).
IA = Incomplete Apposition, BL = Baseline, FU = Follow-up.
Resolved = # patients with BL IA and without FU IA + # patients evaluable at baseline and follow-up.
Persistent = # patients with BL IA and with FU IA + # patients evaluable at baseline and follow-up.
Late Acquired = # patients without BL IA and with FU IA + # patients evaluable at baseline and follow-up.
Incomplete Apposition variables are from assessment by IVUS core laboratory.
## B. Potential Adverse Events
Potential adverse events (in alphabetical order) which may be associated with the use of a coronary stent in native coronary arteries include but are not limited to:
- Abrupt stent closure
- Acute myocardial infarction
- Allergic reaction
- Aneurysm
- Angina
- Arrhythmias, including ventricular fibrillation (VF) and ventricular tachycardia (VT)
- Arteriovenous fistula
- Cardiac tamponade
- Coronary Artery Occlusion
- Cardiogenic shock
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- Death
- Dissection
- Drug reactions to antiplatelet agents / anticoagulation agents / contrast media
- Emboli, distal (air, tissue or thrombotic emboli)
- Embolization, stent
- Emergent Coronary Artery Bypass Surgery (CABG)
- Failure to deliver the stent to the intended site
- Fever
- Fistulization
- Heart failure
- Hematoma
- Hemorrhage
- Hypotension/Hypertension
- Incomplete Stent Apposition
- Infection, including infection and/or pain at the access site
- Myocardial infarction
- Myocardial ischemia
- Perforation or Rupture
- Pericardial effusion
- Prolonged angina
- Pseudoaneurysm
- Renal failure
- Respiratory Failure
- Restenosis of stented segment
- Rupture of native and bypass graft
- Shock/Pulmonary edema
- Spasm
- Stent compression
- Stent migration
- Stroke/cerebrovascular accident/TIA
- Stent thrombosis (acute, subacute, or late)/occlusion
- Ventricular fibrillation
- Vessel perforation
- Vessel spasm
- Vessel trauma requiring surgical repair or reintervention
Potential adverse events not captured above, that may be unique to the paclitaxel drug coating:
- Allergic/immunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
- Alopecia
- Anemia
- Blood product transfusion
- Gastrointestinal symptoms
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- Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
- Hepatic enzyme changes
- Histologic changes in vessel wall, including inflammation, cellular damage or necrosis
- Myalgia/Arthralgia
- Peripheral neuropathy
There may be other potential adverse events that are unforeseen at this time.
## XI. SUMMARY OF CLINICAL STUDIES
### A. TAXUS IV Pivotal Clinical Trial
**Objective:** The primary objective of this study was to demonstrate superiority of the TAXUS™ Express™ Stent as compared with a matched uncoated control stent for reduction of the target vessel revascularization rate (TVR) 9 months post index procedure.
**Conclusion:** In selected patients, the TAXUS Express Stent significantly reduced the rate of 9-month TVR (primary endpoint) as compared to control. This reduction was attributable to reduction in revascularization procedures [percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)] performed on the target lesion (TLR). Quantitative coronary angiography (QCA) and IVUS analyses confirmed a significant reduction in binary restenosis rate, minimum lumen diameter (MLD), percent diameter stenosis (%DS), late loss, and % in-stent net volume obstruction. These results were achieved without increased edge stenosis and late loss at the proximal and distal edges, which were significantly lower in the TAXUS group. In addition, lower MACE rates in the TAXUS group, along with low and comparable rates of stent thrombosis, aneurysm and incomplete apposition between groups, demonstrates the safety of the TAXUS Express Stent.
**Design:** This was a multi-center, prospective, randomized, double-blind study in patients at 73 U.S. sites. Eligible patients were those presenting for stenting of de novo lesions of a single native coronary artery [reference vessel diameter (RVD) 2.5 to 3.75 mm] with a target lesion 10 to 28 mm in length and stenosis ≥50% in diameter, using visual estimates, who were candidates for PCI or CABG, and had documented angina pectoris or functional ischemia.
A total of 1314 patients were enrolled and evaluable in this study: 662 in the TAXUS group and 652 in the Control group. Patients were randomized to receive either a TAXUS Express Stent or uncoated Express™ coronary stent (bare metal control). Study randomization was sub-stratified for medically
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treated diabetes, reference vessel diameter, and lesion length. Multiple stenting was allowed for bailout only. After the procedure, patients were treated with aspirin indefinitely and clopidogrel or ticlopidine for 6 months.
Follow-up included 1, 4, and 9-month clinical assessments. In addition, patients agreed to annual telephone follow-up for clinical parameters through 5 years post procedure (Note: 4-month follow-up was by phone or office visit). Follow-up through 12 months (+ 30 days) is currently available in 1272/1314 (96.8%) of patients.
A subset of patients were pre-assigned to have angiographic (n=732) and IVUS (n=268) follow-up at 9 months. Angiographic assessments were performed for the area of the vessel within the stent margins (in-stent) and also for the area within the stent margins, including the area immediately 5 mm proximal and distal from the stent margins (analysis segment).
**Demographics:** Patients were well matched for baseline demographics with no statistically significant differences between groups. Factors evaluated included age (mean 62 years), gender (72% male), race (89.3% Caucasian, 5.0% African American, 3.1% Hispanic, 1.6% Asian, and approximately 1.0% other), diabetes (29%), prior MI (30%), hypertension (70%), hyperlipidemia (65%), ejection fraction (mean 55%), Canadian Cardiovascular Society Classification (CSS) Angina Class (26% III or IV), IIb/IIIa inhibitor use (57%), left anterior descending (LAD) (41%), left circumflex (LCX) (28%), right coronary artery (RCA) (31%), RVD (mean 2.8 mm), MLD (mean 0.93 mm), %DS (mean 66%), and lesion length (mean 13.4 mm). Smoking history (current and previous) was slightly lower in the TAXUS™ Express™ Stent arm (63.0%) than in the control arm (66.3%), and was not found to be a significant predictor of outcome in the trial.
**Methods:** Baseline clinical and angiographic data were collected on standardized case report forms by coordinators at the clinical sites. Angiographic and IVUS outcomes were assessed in a blinded fashion by quantitative analysis at designated core laboratories. An independent Clinical Events Committee adjudicated clinical events, and the trial was monitored by an independent Data Monitoring Committee.
**Results:** In selected patients, elective TAXUS Express Stent placement in native coronary artery de novo lesions resulted in a reduction in the incidence of TVR at 9 months compared to Control (4.7% vs. 12.1%, p<0.0001). Overall MACE including cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR) were reduced in the TAXUS group at 9 months compared to control (8.5% vs. 15.2%, p=0.0002). Stent thrombosis rates were comparable between the groups (0.6% TAXUS vs 0.8% Control, p=0.7513). Clinical outcomes through 12 months were consistent with the 9 month outcomes.
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By follow-up angiography at 9 months, there was a significantly lower in-stent late loss (0.39 mm vs. 0.92 mm, p<0.0001) and analysis segment late loss (0.23 mm vs. 0.61 mm, p<0.0001) as compared to Control. Additionally, in-stent and analysis segment binary restenosis were significantly reduced (5.5% vs. 24.4%, p<0.0001, in-stent; 7.9% vs. 26.6%, p<0.0001, analysis segment). Percent diameter stenosis and late loss at the proximal (13.19% vs. 16.13%, p=0.0167; 0.15 mm vs. 0.27 mm, p=0.0016) and distal edges (7.60% vs. 11.83%, p=0.0001; 0.05 mm vs. 0.17 mm, p=0.0007) were significantly lower in the TAXUS as compared to the Control groups.
Examination by IVUS at 9 months showed that neointimal hyperplasia volume was significantly reduced in the TAXUS Express Stent arm (17.56 mm3 vs. 41.48 mm3, p<0.0001). The rate of incomplete stent apposition was low and comparable between the TAXUS and Control treatment arms at 9-months (4.0% vs. 3.0%, p=0.7209). There were no clinical events related to occurrences of incomplete stent apposition.
Forty-two (6.5 %) of the patients in the TAXUS Express Stent arm of the TAXUS IV trial received more than one stent for bailout purposes. The incidence of MACE in these patients was not different than in those patients receiving only one stent.
Table 11 summarizes principal safety and effectiveness results through 12 months and Figure 3 provides the cumulative percent of patients who are TVR-Free through 12 months.
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Table 11. TAXUS IV Principal Safety and Effectiveness Results through 12 months
| | TAXUS (N=662) | Control (N=652) | Difference [95% CI] | P |
| --- | --- | --- | --- | --- |
| Effectiveness Measures | | | | |
| Clinical Procedural Success | 97.3% (643/661) | 97.4% (635/652) | -0.1% [-1.9%, 1.6%] | 1.0000 |
| Technical Success | 97.9% (648/ 661) | 98.2% (640/ 652) | -0.3% [-1.8%, 1.2%] | 0.8436 |
| 9 Month Results | | | | |
| ²Target Vessel Revascularization | 4.7% (31/655) | 12.1% (78/ 645) | -7.4% [-10.4%, -4.4%] | <0.0001 |
| In-stent restenosis | 5.5% (16/ 291) | 24.4% (65/ 266) | -18.9% [-24.7%, -13.1%] | <0.0001 |
| Analysis segment restenosis | 7.9% (23/ 291) | 26.6% (71/ 267) | -18.7% [-24.8%, -12.5%] | <0.0001 |
| MLD (mm), In-stent | | | | |
| Post-Procedure | 2.65 +/- 0.42 (373) | 2.67 +/- 0.41 (351) | -0.01 [-0.07,0.05] | 0.6577 |
| 9-Month | 2.26 +/- 0.58 (291) | 1.75 +/- 0.65 (266) | 0.51 [ 0.41,0.61] | <0.0001 |
| MLD (mm), Analysis Segment | | | | |
| Post Procedure | 2.26 +/- 0.48 (374) | 2.29 +/- 0.50 (356) | -0.03 [-0.10,0.04] | 0.4526 |
| 9-Month | 2.03 +/- 0.55 (291) | 1.68 +/- 0.61 (267) | 0.35 [0.26, 0.45] | <0.0001 |
| % DS, In-stent | | | | |
| Post Procedure | 4.21 +/- 10.84 (373) | 5.16 +/- 11.41 (351) | -0.95 [-2.57, 0.67] | 0.2497 |
| 9-Month | 17.43 +/-17.71 (291) | 37.24 +/- 19.76 (266) | -19.82 [-22.93,16.70] | <0.0001 |
| % DS, Analysis Segment | | | | |
| Post Procedure | 19.16 +/- 9.67 (374) | 19.33 +/- 10.45 (356) | -0.17 [-1.63, 1.29] | 0.8219 |
| 9-Month | 26.29 +/- 15.45 (291) | 39.79 +/- 18.45 (267) | -13.50 [-16.31,-10.68] | <0.0001 |
| Late Loss, In-stent (mm) | 0.39 +/- 0.50 (291) | 0.92 +/- 0.58 (266) | -0.53 [-0.62, -0.44] | <0.0001 |
| Late Loss, Analysis Segment (mm) | 0.23 +/- 0.44 (291) | 0.61 +/- 0.57 (267) | -0.38 [-0.47, -0.30] | <0.0001 |
| % Net Volume Obstruction | 12.20 +/- 12.44 (81) | 29.40 +/- 14.05 (80) | -17.19 [-21.29,-13.10] | <0.0001 |
| Minimum Lumen Area | 5.14 +/- 2.19 (81) | 4.15 +/- 1.64 (80) | 0.99 [ 0.39, 1.59] | 0.0014 |
| Neointimal Volume | 17.56 +/- 18.21 (81) | 41.48 +/- 23.02 (80) | -23.92 [-30.33,-17.51] | <0.0001 |
| Clinical Endpoints to 9 months | | | | |
| †TVR-Free | 95.25% | 87.89% | 7.36% [4.35%, 10.37%] | <0.0001 |
| †TLR-Free | 96.93% | 88.51% | 8.42% [5.62%, 11.22%] | <0.0001 |
| †TVF-Free | 92.40% | 85.48% | 6.92% [3.54%, 10.30%] | 0.0001 |
| †MACE-Free | 91.51% | 84.88% | 6.63% [3.14%, 10.12%] | 0.0003 |
| Clinical Endpoints to 12 months | | | | |
| †TVR-Free | 92.87% | 82.88% | 9.99% [6.41%, 13.57%] | <0.0001 |
| †TLR-Free | 95.58% | 84.89% | 10.69% [7.46%, 13.92%] | <0.0001 |
| †TVF-Free | 90.03% | 80.57% | 9.46% [5.61%, 13.31%] | <0.0001 |
| †MACE-Free | 89.15% | 79.97% | 9.18% [5.26%, 13.10%] | <0.0001 |
| ²Safety Measures | | | | |
| In-hospital MACE | 2.4% (16/662) | 2.1% (14/ 652) | 0.3% [-1.3%, 1.9%] | 0.854 |
| MACE to 9 months | 8.5% ( 56/ 655) | 15.2% (98/ 645) | -6.6% [-10.1%, -3.1%] | 0.0002 |
| MACE to 12 months | 10.7% ( 70/ 653) | 20.0% (129/ 644) | -9.3% [-13.2%, -5.4%] | <0.0001 |
| TVR to 9 months (Primary Endpoint) | 4.7% ( 31/ 655) | 12.1% (78/ 645) | -7.4% [-10.4%, -4.4%] | <0.0001 |
| TVR to 12 months | 6.9% ( 45/ 653) | 16.9% (109/ 644) | -10.0% [-13.5%, -6.5%] | <0.0001 |
| TVF to 9-months | 7.6% (50/655) | 14.6% (94/645) | -6.9% [-10.3%, -3.5%] | 0.0001 |
| TVF to 12-months | 9.7% (64/ 653) | 19.2% (125/ 644) | -9.6% [-13.4%, -5.8%] | <0.0001 |
| Stent Thrombosis to 30 days | 0.3% (2/ 662) | 0.6% (4/ 652) | -0.3% [-1.0%, 0.4%] | 0.4487 |
| Stent Thrombosis to 9 months | 0.6% ( 4/ 655) | 0.8% (5/ 645) | -0.2% [-1.1%, 0.7%] | 0.7513 |
| Stent Thrombosis to 12 months | 0.6% ( 4/ 653) | 0.8% (5/ 644) | -0.2% [-1.1%, 0.7%] | 0.7515 |
| CVA to 12 months | 1.7% ( 11/ 654) | 0.8% (5/ 644) | 0.9% [-0.3%, 2.1%] | 0.2075 |
| Serious Bleeding Events to 12 months | 2.8% (18/654) | 1.9% (12/644) | 0.9% [-0.7%, 2.5%] | 0.3564 |
| Serious Vascular Events to 12 months | 1.8% (12/653) | 1.9% (12/644) | -0.0% [-1.5%, 1.4%] | 1.0000 |
| Platelet Disorders to 12 months | 0.6% (4/653) | 0.8% (5/644) | -0.2% [-1.1%, 0.7%] | 0.7515 |
| Hematological Dyscrasia to 12 months | 1.5% (10/654) | 0.8% (5/644) | 0.7% [-0.4%, 1.9%] | 0.2991 |
Numbers are % (Count/Sample Size) or Mean±SD (N) (Min, Max). CI = Confidence Interval.
Difference = TAXUS SR - Control.
SE of Difference: = sqrt(p₁q₁/n₁ + p₂q₂/n₂) for proportions, = sqrt[(1/n₁ + 1/n₂)[(n₁-1)s₁² + (n₂-1)s₂²]/(N-2)] for continuous variables.
95% CI of Difference = Diff±1.96-SE. 95%
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P-values are two-sided and from Student's t test for continuous variables and Fisher's exact test for discrete variables.
Undef = Undefined.
Primary endpoint is 9-month TVR.
Clinical Procedural Success: using the assigned study stent to achieve an in-target-lesion diameter stenosis <30% in the average of 2 near- orthogonal projections, as visually assessed by the physician, without the occurrence of in-hospital MACE.
Technical success: successful delivery and deployment of the study stent to the target lesion, without balloon rupture, embolization, or use of the product outside the treatment strategy.
MLD = Minimum Lumen Diameter
WHO-defined non-Q-wave MI – Elevation of post-procedure CK levels to >2 times normal with elevated CKMB in the absence of new pathological Q-waves.
Stent thrombosis:
Clinical presentation of acute coronary syndrome with angiographic evidence of stent thrombosis
Angiographic documentation of a complete occlusion (TIMI flow 0 or 1) of a previously successfully treated artery (TIMI flow 2 to 3 immediately after stent placement and DS ≤30%), and/or angiographic documentation of a flow limiting thrombus within or adjacent to a previously successfully treated lesion
Acute MI of the distribution of the treated vessel
Death within first 30 days (without other obvious cause) was considered a surrogate for stent thrombosis when angiography was not available
CVA – Sudden onset of vertigo, numbness, aphasia, or dysarthria due to vascular lesions of the brain such as hemorrhage, embolism, thrombosis, or rupturing aneurysm, that persisted >24 hours.
9-Month MACE: the proportion of patients who experience a MACE up to the 9-month follow-up. MACE includes cardiac death, myocardial infarction (MI) including WHO defined Q- and non-Q-wave MI, and target vessel revascularization (TVR).
30-Day MACE: binary MACE rate to 30 days post-procedure.
9-Month Restenosis: the proportion of patients who demonstrate ≥50% diameter stenosis of the target lesion by Quantitative Coronary Analysis (QCA) performed at the Angiographic Core Laboratory at the 9-month follow-up.
Serious Bleeding Complications included: hemorrhage (gastric ulcer, mediastinal, rectal, upper GI, and GI not specified), hematuria, hemoptysis, and hemothorax. Serious Vascular Complications included: hematoma (catheter site and not specified), hemorrhage (catheter site and retroperitoneal), arterial injury, and vascular pseudoaneurysm. Platelet disorders included thrombocytopenia. Hematologic dyscrasia included: anemia, and pancytopenia.
The following survival estimates are by Kaplan-Meier Methods with standard error estimates by Greenwood formula:
†TLR-Free – No target lesion revascularization.
†TVR-Free – No target vessel revascularization.
†TVF-Free – No cardiac death, Q-wave or WHO-defined non Q-wave MI, or target vessel revascularization.
†MACE-Free – No death, Q-wave or WHO-defined non Q-wave MI, or target vessel revascularization.
² For each parameter in the safety measures, the denominator is the number of patients randomized to each treatment arm (excluding de-registered patients) who had sufficient follow up (at least 240 days for 9 month visit and at least 330 days for 12 month visit) plus any patients who had an event prior to the milestone visit.
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Figure 3. TAXUS IV Freedom From TVR to 1 Year (Event-Free Survival ± 1.5 SE)
Time After Initial Procedure
| TAXUS | 0 | 7 | 14 | 30 | 60 | 90 | 120 | 150 | 180 | 270 | 365 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Entered | 662 | 662 | 660 | 660 | 660 | 656 | 652 | 646 | 641 | 633 | 615 |
| Censored | 0 | 2 | 0 | 0 | 1 | 1 | 1 | 4 | 3 | 4 | 330 |
| Events | 0 | 0 | 0 | 0 | 3 | 3 | 5 | 1 | 5 | 14 | 14 |
| At Risk | 662 | 661 | 660 | 660 | 659.5 | 655.5 | 651.5 | 644 | 639.5 | 631 | 450 |
| Events/Month | 0.0 | 0.0 | 0.0 | 0.0 | 3.0 | 3.0 | 5.0 | 1.0 | 5.0 | 4.7 | 4.4 |
| Event Free | 100.0% | 100.0% | 100.0% | 100.0% | 99.5% | 99.1% | 98.3% | 98.2% | 97.4% | 95.2% | 92.9% |
| Std Error | 0.00% | 0.00% | 0.00% | 0.00% | 0.26% | 0.37% | 0.50% | 0.52% | 0.62% | 0.83% | 1.04% |
| Control | 0 | 7 | 14 | 30 | 60 | 90 | 120 | 150 | 180 | 270 | 365 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Entered | 652 | 652 | 650 | 650 | 648 | 646 | 631 | 616 | 597 | 586 | 562 |
| Censored | 0 | 1 | 0 | 1 | 0 | 2 | 2 | 4 | 1 | 1 | 274 |
| Events | 0 | 1 | 0 | 1 | 2 | 13 | 13 | 15 | 10 | 23 | 31 |
| At Risk | 652 | 651.5 | 650 | 649.5 | 646 | 645 | 630 | 614 | 596.5 | 585.5 | 425 |
| Events/Month | 0.0 | 4.3 | 0.0 | 1.9 | 2.0 | 13.0 | 13.0 | 15.0 | 10.0 | 7.7 | 9.8 |
| Event Free | 100.0% | 99.8% | 99.8% | 99.7% | 99.4% | 97.4% | 95.4% | 93.0% | 91.5% | 87.9% | 82.9% |
| Std Error | 0.00% | 0.15% | 0.15% | 0.22% | 0.31% | 0.63% | 0.82% | 1.00% | 1.10% | 1.29% | 1.50% |
Tests Between Groups, To 365 Days
| Test | Chi-Square | Degrees of Freedom | p-Value |
| --- | --- | --- | --- |
| Log-Rank | 31.5258 | 1 | <0.0001 |
| Wilcoxon | 32.3772 | 1 | <0.0001 |
Patients event-free at 366 days or later are censored at 366 days.
Intervals are end inclusive, e.g. interval 90 is defined as 31-90 days, inclusive.
Event-free and standard error estimates are for interval end. Standard errors by Greenwood formula.
"at risk" is the number of patients who "entered" an interval minus (the number of patients "censored" during the interval divided by 2).
"censored" is the number of patients whose last follow-up occurred during that interval and did not have a TVR, e.g., a patient who did not have a TVR and whose last follow-up was on Day 178 would be censored in the 151-180 interval (180 column).
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## B. TAXUS II (SR) Supporting Clinical Trial
**Objective:** The primary objective of this study was to evaluate the safety and effectiveness of the TAXUS™ NIRx™ Paclitaxel-Eluting Coronary Stent System (1 μg/mm² SR formulation) compared with a matched uncoated control stent.
**Conclusion:** In selected patients, use of the SR formulation of the TAXUS NIRx (SR) Stent significantly reduced the percent of in-stent net volume obstruction as determined by IVUS at 6 months. There were significant improvements in overall MACE rates as well as reintervention procedures required in the target lesion. No substantial differences were observed as compared to the uncoated control group with respect to safety assessments.
**Design:** This was a prospective, double-blind trial conducted at 38 sites in 15 countries. Eligible patients had documented angina pectoris and a single de novo lesion in a native coronary artery measuring ≤ 12 mm in length with a visual RVD ≥ 3.0 mm and ≤ 3.5 mm.
A total of 267 patients were enrolled and evaluable in this study: 131 TAXUS group and 136 in the Control group. Patients were randomized to receive either a TAXUS NIRx™ (SR) Stent or uncoated NIR coronary stent (bare metal control). After the procedure, patients were treated with aspirin indefinitely and clopidogrel or ticlopidine for 6 months.
Follow-up included 1, 6, and 12 month clinical assessments. In addition, patients agreed to annual telephone follow-up for MACE clinical parameters through 5 years post procedure. Follow-up through 12 months (± 30 days) is currently available for 264/267 (98.8%) of patients.
All patients were required to have angiographic and IVUS follow-up at 6 and 24 months. Angiographic assessments were performed for the area of the vessel within the stent margins (in-stent) and also for the area within the stent margins, including the area immediately 5 mm proximal and distal from the stent margins (analysis segment).
**Demographics:** There were no clinically significant differences between groups with respect to baseline demographics or clinical characteristics. Factors evaluated included age (mean 61 years), gender (74.5% male), diabetes (13.5%), prior MI (38.5%), hypertension (65%), LAD (42%), LCX (19%), RCA (39%), RVD (mean 2.7 mm), MLD (mean 1.0 mm), %DS (mean ~63%), current smoking (21.4%), IIb/IIIa use (12%) and lesion length (mean 10.5 mm). Demographic data regarding hyperlipidemia, ethnicity and ejection fraction were not monitored in this study. A statistically significantly higher CCS Class was noted in the uncoated control group as compared to the TAXUS group
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(P=0.0104). This was due to a difference in CCS Class II (42.7% TAXUS vs. 27.9% Control) and CSS Class III (7.6% TAXUS vs. 19.9% Control). CCS Class I, and CCS Class IV were comparable between treatment groups. The difference in CCS class was not found to be a significant predictor of outcome in the trial.
**Methods:** Baseline clinical and angiographic data were collected on standardized case report forms by coordinators at the clinical sites. Angiographic and IVUS outcomes were assessed in a blinded fashion by quantitative analysis at designated core laboratories. An independent Clinical Events Committee adjudicated clinical events, and the trial was monitored by an independent Data Monitoring Committee.
**Results:** In selected patients, 6-month percent in-stent net volume obstruction (primary endpoint) as determined by IVUS was statistically significantly lower in the TAXUS™ NIRx™ (SR) Stent treatment group as compared with the uncoated control group (7.85% versus 23.17%, p<0.0001).
In-stent restenosis, for the TAXUS NIRx (SR) Stent treatment group was 2.3% as compared to 17.9% for the uncoated control group (p<0.0001). Analysis segment restenosis, was 5.5% for the TAXUS NIRx (SR) Stent group as compared to 20.1% for the uncoated control group (p=0.0004). At the 6-month time-point, statistically significant improvements were also observed in late loss, MLD, and %DS for the TAXUS NIRx (SR) Stent group as compared to the uncoated control group.
Lower rates for MACE were observed in the TAXUS NIRx (SR) Stent group as compared with the uncoated control group at 6-months follow-up (8.5% versus 19.5%, p=0.0125), and 12-month follow-up (10.9% versus 22.0%, p=0.0191) (Table 12). MACE-free survival was improved in the TAXUS group as compared with the uncoated control group at both 6 and 12 months.
Table 12 summarizes the principle safety and effectiveness results of the TAXUS II (SR) trial through 12 months. Figure 4 provides the cumulative percent of patients who are TVR-Free through 12 months.
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Table 12. TAXUS II (SR) Principal Safety and Effectiveness Results through 12 months
| | TAXUS II (SR) (N=131) | Control (N=136) | Difference [95% CI] | P Value |
| --- | --- | --- | --- | --- |
| Effectiveness Measures | | | | |
| Clinical Procedural Success | 95.4% (125/131) | 93.4% (127/136) | 2.0% [-3.5%, 7.5%] | 0.5976 |
| Technical Success | 97.7% (128/131) | 98.5% (134/136) | -0.8% [-4.1%, 2.4%] | 0.6794 |
| 6-Month % Net Volume Obstruction | 7.85±9.87 (118) | 23.17±18.19 (125) | -15.32 [-19.03, -11.61] | <0.0001 |
| 6-month in-stent restenosis | 2.3% (3/128) | 17.9% (24/134) | -15.6% [-22.6%, -8.6%] | <0.0001 |
| 6-month Analysis segment restenosis | 5.5% (7/128) | 20.1% (27/134) | -14.7% [-22.5%, -6.8%] | 0.0004 |
| MLD (mm), Stented Segment | | | | |
| Post-Procedure | 2.53±0.29 (128) | 2.58±0.37 (135) | -0.05 [-0.13, 0.03] | 0.2132 |
| 6-Month | 2.23±0.47 (128) | 1.79±0.54 (134) | 0.44 [0.32, 0.56] | <0.0001 |
| MLD (mm), Analysis Segment | | | | |
| Post Procedure | 2.15±0.37 (128) | 2.23±0.43 (135) | -0.08 [-0.17, 0.02] | 0.1202 |
| 6-Month | 2.01±0.46 (128) | 1.70±0.49 (134) | 0.31 [0.20, 0.43] | <0.0001 |
| % DS, Stented Segment | | | | |
| Post Procedure | 10.90±6.52 (128) | 10.20±5.94 (135) | 0.70 [-0.81, 2.20] | 0.3659 |
| 6-Month | 19.53±12.71 (128) | 31.77±17.11 (134) | -12.25 [-15.91, -8.59] | <0.0001 |
| % DS, Analysis Segment | | | | |
| Post Procedure | 23.07±9.27 (128) | 21.24±8.41 (135) | 1.83 [-0.31, 3.97] | 0.0943 |
| 6-Month | 26.79±12.78 (128) | 35.11±15.09 (134) | -8.32 [-11.71, -4.93] | <0.0001 |
| 6-Month Late Loss (mm), Stented Segment | 0.31±0.38 (127) | 0.79±…
