SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System and DIRECT Sirolimus-Eluting Coronary Stent Rapid Ex

P210014 · Advanced Bifurcation Systems, Inc. · NIQ · Dec 13, 2021 · Cardiovascular

Device Facts

Record IDP210014
Device NameSLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System and DIRECT Sirolimus-Eluting Coronary Stent Rapid Ex
ApplicantAdvanced Bifurcation Systems, Inc.
Product CodeNIQ · Cardiovascular
Decision DateDec 13, 2021
DecisionAPWD
Device ClassClass 3
AttributesTherapeutic

Intended Use

The Svelte SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System (Svelte SLENDER IDS) is indicated for improving coronary artery luminal diameter in patients with symptomatic heart disease due to atherosclerotic lesions ≤ 24 mm in length in native coronary arteries with ≥ 2.25 mm to ≤ 4.00 mm reference vessel diameters, using direct stenting or pre-dilatation interventional techniques. The Svelte DIRECT Sirolimus-Eluting Coronary Stent Rapid Exchange Delivery System (Svelte DIRECT RX) is indicated for improving coronary artery luminal diameter in patients with symptomatic heart disease due to atherosclerotic lesions ≤ 34 mm in length in native coronary arteries with ≥ 2.25 mm to ≤ 4.00 mm reference vessel diameters, using direct stenting or pre-dilatation interventional techniques.

Device Story

Svelte DES is a combination product comprising a cobalt-chromium stent coated with a bioresorbable polyesteramide (PEA) polymer containing sirolimus. Two delivery systems: SLENDER IDS (fixed-wire) and DIRECT RX (rapid exchange). Used in cardiac catheterization labs by interventional cardiologists to treat coronary artery disease. Stent is delivered to the lesion site via balloon catheter; balloon inflation deploys the stent, which provides mechanical scaffolding to maintain luminal diameter. Sirolimus is released from the polymer coating to inhibit smooth muscle cell proliferation and reduce restenosis. Output is the physical stent placement; healthcare providers monitor success via angiography. Benefits include improved coronary blood flow and reduced need for revascularization.

Clinical Evidence

Pivotal OPTIMIZE study (N=1639) compared Svelte DES to XIENCE/Promus DES. Primary endpoint (12-month TLF) was 10.30% (Svelte) vs 9.49% (Control). Non-inferiority not met (upper CI 3.78% > 3.58% margin). High TVMI rates (9.4% vs 8.2%) were attributed to sensitive troponin biomarker use and low-threshold MI definitions. Post-hoc analyses using relative margins, troponin-adjusted margins, or SCAI/4th Universal MI definitions demonstrated non-inferiority. Supplemental data from DIRECT I, II, and III studies (N=600+) support safety and effectiveness.

Technological Characteristics

Stent: L605 cobalt-chromium alloy (ASTM F90). Coating: Bioresorbable polyesteramide (PEA) polymer with 213 μg/cm² sirolimus. Delivery: Fixed-wire (IDS) or rapid exchange (RX) balloon catheter. Dimensions: 2.25-4.00 mm diameter, 8-38 mm length. Sterilization: Ethylene oxide (EtO) per EN ISO 11135:2014. Connectivity: None (mechanical/drug-eluting).

Indications for Use

Indicated for patients ≥ 18 years with symptomatic heart disease due to atherosclerotic lesions (≤ 24 mm for SLENDER IDS; ≤ 34 mm for DIRECT RX) in native coronary arteries (2.25-4.00 mm RVD). Contraindicated in patients unable to receive anti-platelet/anti-coagulant therapy, those with hypersensitivity to sirolimus, PEA, cobalt, chromium, nickel, tungsten, or contrast media, and those 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

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Drug-Eluting Coronary Stent System Device Trade Name: Svelte SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System (SLENDER IDS®) Svelte DIRECT Sirolimus-Eluting Coronary Stent Rapid Exchange Delivery System (DIRECT RX®) Device Procode: NIQ Applicant's Name and Address: Svelte Medical Systems, Inc. 675 Central Avenue, Suite 2 New Providence, New Jersey 07974 USA Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P210014 Date of FDA Notice of Approval: December 13, 2021 II. INDICATIONS FOR USE The Svelte SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System (Svelte SLENDER IDS) is indicated for improving coronary artery luminal diameter in patients with symptomatic heart disease due to atherosclerotic lesions ≤ 24 mm in length in native coronary arteries with ≥ 2.25 mm to ≤ 4.00 mm reference vessel diameters, using direct stenting or pre-dilatation interventional techniques. The Svelte DIRECT Sirolimus-Eluting Coronary Stent Rapid Exchange Delivery System (Svelte DIRECT RX) is indicated for improving coronary artery luminal diameter in patients with symptomatic heart disease due to atherosclerotic lesions ≤ 34 mm in length in native coronary arteries with ≥ 2.25 mm to ≤ 4.00 mm reference vessel diameters, using direct stenting or pre-dilatation interventional techniques. III. CONTRAINDICATIONS The Svelte SLENDER IDS and the Svelte DIRECT RX (collectively, Svelte DES) are contraindicated for use in patients: - Unable to receive anti-platelet and/or anti-coagulant therapy. PMA P210014: FDA Summary of Safety and Effectiveness Data {1} - With known hypersensitivity to sirolimus, PEA III Ac Bz, cobalt, chromium, nickel, tungsten or contrast media. - Judged to have lesions preventing complete inflation of an angioplasty balloon or proper placement of a coronary stent or delivery system, including chronic total occlusions. # IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Svelte DES labeling. # V. DEVICE DESCRIPTION The Svelte DES is a combination product consisting of (1) a cobalt chromium (CoCr) alloy stent coated with a bioresorbable polymeric drug carrier containing the anti-proliferative drug sirolimus and (2) the delivery system, either fixed-wire (SLENDER IDS) or rapid exchange (DIRECT RX). The characteristics of the Svelte DES are described in Table 1. Table 1. Svelte DES Product Characteristics | Characteristic | Svelte DES SLENDER IDS | Svelte DES DIRECT RX | | --- | --- | --- | | Stent Pattern | 3-cell (2.25, 2.50, 2.75, 3.00 mm diameter) 4-cell (3.50, 4.00 mm diameter) | | | Stent Lengths (mm) | 8, 13, 18, 23, 28 | 8, 13, 18, 23, 28, 33, 38 | | Stent Diameters (mm) | 2.25, 2.50, 2.75, 3.00, 3.50, 4.00 | | | Stent Strut Thickness (mm) | 2.25 – 3.00 mm diameters: 0.081 mm 3.50 – 4.00 mm diameters: 0.084 mm | | | Stent Material | A medical grade L605 CoCr alloy | | | Drug Component | A conformal (all surfaces of the stent) coating of a bioresorbable polymer loaded with 213 μg/cm² of sirolimus | | | Delivery System Working Length | 145 cm | 139 cm | | Delivery System Design | 0.014” fixed-wire catheter with integrated torquer and single access port to inflation lumen | Rapid exchange with a single access port to inflation lumen. Designed for guide wires ≤ 0.014” | | Stent Delivery System Balloon | Compliant balloon with two radiopaque markers to designate the stent placement on the balloon | | | Guiding Catheter Compatibility | ≥5 F (min. guide catheter ID of 0.056”/1.42 mm) | | | Balloon Inflation Pressure | Nominal: 12 atm (1216 kPa) Rated Burst Pressure: 18 atm (1824 kPa) | | | Catheter Shaft Outer Diameter | Distal: 0.029 in (2.2 F, 0.73 mm) Proximal: 0.025 in | Distal: 0.035 in (2.7 F, 0.89 mm) Proximal: 0.026 in | PMA P210014: FDA Summary of Safety and Effectiveness Data Page 2 of 55 {2} | Characteristic | Svelte DES SLENDER IDS | Svelte DES DIRECT RX | | --- | --- | --- | | | (1.9 F, 0.63 mm) | (2.0 F, 0.67 mm) | ## A. Device Component Description The Svelte DES stent is made of CoCr. The stent has two designs that are differentiated by the number of cells and the number of links. The 3-cell design with three links around the circumference is used for 2.25-3.00 mm diameter stents and the 4-cell design with four links around the circumference is used for 3.50-4.00 mm diameter stents. Each stent length configuration has end units that make up the end columns and repeating inner units that make up the internal columns. In order to create various stent lengths, the number of repeating inner columns is varied. Figure 1 illustrates a 3-cell (top) and 4-cell (bottom) Svelte DES stent. ![img-0.jpeg](img-0.jpeg) Figure 1: 3-Cell (top) and 4-Cell (bottom) Stent Configurations The stent is crimped onto the balloon of one of the two available delivery systems: SLENDER IDS or DIRECT RX. SLENDER IDS is a novel fixed-wire delivery system consisting of a shapeable, radiopaque wire tip, low-compliant delivery balloon and proximal shaft. SLENDER IDS contains two proximal shaft markers (90 cm and 100 cm) indicating the position of SLENDER IDS relative to the end of a brachial or femoral catheter. An integrated torquing device located on the proximal end of the catheter shaft facilitates navigation. The Slender IDS has a very low profile and integrated design that is particularly suited for use with a direct PCI strategy. Figure 2 provides a pictorial representation of the SLENDER IDS. PMA P210014: FDA Summary of Safety and Effectiveness Data Page 3 of 55 {3} ![img-1.jpeg](img-1.jpeg) Figure 2: SLENDER IDS Delivery System DIRECT RX is a rapid exchange delivery system with a low-compliant delivery balloon. Figure 3 provides a pictorial representation of the DIRECT RX. ![img-2.jpeg](img-2.jpeg) Figure 3: DIRECT RX Delivery System # B. Drug Component Description The Svelte DES stent is conformally coated with a bioresorbable drug coating. The drug matrix is composed of sirolimus (the active ingredient) and bioresorbable polyesteramide (PEA; inactive ingredient). # 1. Sirolimus Sirolimus (also known as rapamycin) is the active pharmaceutical ingredient in the Svelte family of stents. The sirolimus chemical name is: [3S[3R*[S*(1R*,3S*,4S*)),6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*,23R*,2 6S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone. The molecular structure of sirolimus is $\mathrm{C_{51}H_{79}NO_{13}}$ and its molecular weight is 914.19 Da. The chemical structure is provided in Figure 4. PMA P210014: FDA Summary of Safety and Effectiveness Data {4} ![img-3.jpeg](img-3.jpeg) Figure 4: Chemical Structure of Sirolimus The Svelte DES product matrix and nominal total loaded dose of sirolimus per nominal stent length/diameter is shown in Table 2. Table 2. Svelte DES Product Matrix and Drug Content | Stent Design | Stent Diameters (mm) | Stent Length (mm) | Sirolimus Dose (μg/stent) | | | --- | --- | --- | --- | --- | | | | | SLENDER IDS | DIRECT RX | | 3-cell | 2.25 2.50 2.75 3.00 | 8 | 58 | 58 | | | | 13 | 87 | 87 | | | | 18 | 126 | 126 | | | | 23 | 156 | 156 | | | | 28 | 195 | 195 | | | | 33 | | 224 | | | | 38 | | 263 | | 4-cell | 3.50 4.00 | 8 | 79 | 79 | | | | 13 | 119 | 119 | | | | 18 | 173 | 173 | | | | 23 | 213 | 213 | | | | 28 | 266 | 266 | | | | 33 | | 306 | | | | 38 | | 360 | 2. Inactive Ingredient: polyesteramide (PEA) The bioresorbable PEA carrier is a synthetic amorphous elastomeric random copolymer consisting of amino acid units (L-leucine and L-lysine benzyl ester) separated by hydrocarbon diacid (decanedioic acid) and diol (1,6-hexanediol and 1,4-dianhydrosorbitol) spacers. The structural formula of the PEA carrier is shown in Figure 5. PMA P210014: FDA Summary of Safety and Effectiveness Data {5} ![img-4.jpeg](img-4.jpeg) Figure 5: Chemical Structure of PEA Carrier ## 3. Mechanism of Action of Sirolimus Sirolimus inhibits T-lymphocyte activation, smooth muscle and endothelial cell proliferation in response to cytokine and growth factor stimulation. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12). The sirolimus-FKBP-12 complex binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), leading to inhibition of cell cycle progression from the G₁ to S phase. The sirolimus drug coated on the Svelte DES has an ancillary function as an anti-proliferative and anti-restenotic agent due to its ability to interrupt smooth muscle cell migration and proliferation. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of coronary artery disease. These may include exercise, diet, smoking cessation, drug therapy, percutaneous coronary interventions (such as angioplasty and placement of other coronary stents), and coronary artery bypass graft surgery (CABG). Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The Svelte DES have been market released (CE Mark certified) outside the United States since 2016 and have been in commercial use in the Netherlands, Belgium, Czech Republic and United Kingdom. No Svelte devices have been withdrawn from distribution in any country for any reason related to product safety or effectiveness. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Adverse events (in alphabetical order) that may be associated with the use of a stent in native coronary arteries include but are not limited to: - Access site complications (incl. arteriovenous fistula, hematoma, infection, nerve injury, pain, peripheral ischemia, phlebitis, pseudoaneurysm) PMA P210014: FDA Summary of Safety and Effectiveness Data {6} - Acute myocardial infarction - Acute pulmonary edema - Allergic reaction or hypersensitivity to contrast media, antiplatelets, anticoagulants, L-605 cobalt chromium alloy, PEA, sirolimus or sirolimus derivatives - Aneurysm formation - Angina pectoris (stable or unstable) - Atrial fibrillation - Bradycardia - Bleeding complications that may require transfusions or surgical repair - Cardiac arrhythmias, including ventricular fibrillation and ventricular tachycardia - Cardiac perforation - Cardiac tamponade - Cardiogenic shock - Congestive heart failure - Coronary artery complications (incl. abrupt closure, dissection, embolism, injury, perforation, plaque rupture/shift, restenosis, rupture, spasm, thrombosis, total occlusion) - Death - Delayed endothelialization - Distal emboli - Endocarditis - Emergency cardiac surgery - Fever or pyrogenic reactions - Hypotension/hypertension - Infections - Myocardial ischemia - Nausea and vomiting - Palpitations - Perforation of the heart or great vessels - Pericardial effusion - Respiratory insufficiency or failure - Renal failure - Retroperitoneal hematoma - Stent collapse - Stent dislodgement from the delivery system - Stent embolization - Stent thrombosis or occlusion - Stroke/cerebrovascular accident/transient ischemic attack - Vasovagal reaction - Vasospasm - Volume overload Potential adverse events related to the oral administration of sirolimus include, but are not limited to: PMA P210014: FDA Summary of Safety and Effectiveness Data Page 7 of 55 {7} - Abnormal liver function tests - Anemia - Arthralgia - Diarrhea - Hypercholesterolemia - Hypersensitivity (including anaphylactic/anaphylactoid type reactions) - Hypertriglyceridemia - Hypokalemia - Infections - Interstitial lung disease - Leukopenia - Lymphoma and other malignancies - Thrombocytopenia There may be other potential adverse events that are unforeseen at this time. For the specific adverse events that occurred in clinical studies, please see Section X below. ## IX. SUMMARY OF NONCLINICAL STUDIES A series of non-clinical laboratory studies and pharmacokinetic studies related to the product were performed. Studies included those performed on the bare metal stent alone, the coated stent alone, the polymer-only coated stent alone, the delivery systems, and the finished combination product. ## A. Laboratory Studies ### 1. In Vitro Engineering Testing In vitro engineering testing was conducted on test samples representative of the Svelte DES in accordance with the following FDA guidance documents: - FDA Guidance Document issued on April 18, 2010, Non-Clinical Engineering Tests and Recommended Labelling for Intravascular Stents and Associated Delivery Systems - FDA Guidance Document issued on August 18, 2015, Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems - FDA Guidance Document issued on May 20, 2021, Testing and Labeling Medical Devices for Safety in the Magnetic Resonance (MR) Environment Specific in vitro engineering tests were performed on the representative uncoated, bare metal version of the Svelte DES and the delivery systems. Table 3 summarizes this testing. "Pass" denotes that the test results met product specifications and/or the recommendations in the above referenced guidance documents. PMA P210014: FDA Summary of Safety and Effectiveness Data Page 8 of 55 {8} Table 3. Summary of Engineering Testing | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Material Characterization | | | | | Material Composition | To identify and list all components and their respective materials used in the construction of the stent and delivery systems. | The stent is fabricated from L605 CoCr alloy tubing, to which ASTM F90 applies. The incoming raw materials conform to specifications. | Pass | | Stent Mechanical Properties | To test the mechanical properties for the stent tubing. | The stent tubing tensile, yield strength, and elongation must meet specification. | Pass | | Stent Corrosion Resistance | To determine the stent resistance to fretting, pitting, and crevice corrosion. | Per ASTM F2129 | Pass | | Stent Dimensional and Functional Attributes | | | | | Dimensional Verification (Unexpanded Stent Dimensions) | To inspect and measure the stent dimensions. | Stent dimensions must meet specifications. | Pass | | Dimensional Verification (Uniformity of Stent Expansion) | To measure the diameter of the expanded stent per ASTM F2081. | The uniformity of stent expansion must meet specifications. | Pass | | Percent Surface Area | To determine the surface coverage of the stent in the vessel. | Percent contact surface area must be 6-15%. The percent surface area of the stent must meet specifications. | Pass | PMA P210014: FDA Summary of Safety and Effectiveness Data {9} | Test | Purpose | Acceptance Criteria | | | | Results | | --- | --- | --- | --- | --- | --- | --- | | Foreshortening | To ensure the foreshortening of the stent falls within acceptable limits. | Dia. | Length | Maximum Foreshortening % | | Pass | | | | | | IDS | RX | | | | | 2.25 - 2.75 mm | 8 - 13 mm | ≤20% | ≤20% | | | | | 18 - 28 mm | ≤12% | ≤12% | | | | | | 3.00 mm | 8* - 13 mm | ≤20%* | ≤20%* | | | | | 18 - 28 mm | ≤12% | ≤12% | | | | | | 3.50 mm | 8 - 13 mm | ≤20% | ≤20% | | | | | 18 - 28 mm | ≤12% | ≤12% | | | | | | 4.00 mm | 8* - 13 mm | ≤20%* | ≤20%* | | | | | 18 - 28 mm | ≤15% | ≤15% | | | | *Stent sizes 3.00x8 and 4.00x8mm did not meet the acceptance criteria, with reported maximum foreshortenings of up to 21.2% and 27.4%, respectively. This was deemed acceptable based on robust scientific and clinical rationales. Accurate foreshortening percentages are in the product labeling. | | | | | | | | Recoil | To measure the elastic recoil of stent from its expanded diameter while still on the delivery balloon to its relaxed diameter after deflating the balloon per ASTM F2079. | Stent recoil ≤8% at nominal pressure and rated burst pressure | | | | Pass | | Stent Integrity | To examine the deployed stent for defects. | Stent will have no significant surface defects such as cracks or scratches when examined under microscope. | | | | Pass | | Radial Stiffness and Radial Strength | To characterize the ability of the stent to resist collapse under external loads. | Radial Stiffness: Characterization onlyRadial Strength: Diameter decreases to 15% of starting diameter at ≥5 psi | | | | Pass | PMA P210014: FDA Summary of Safety and Effectiveness Data {10} PMA P210014: FDA Summary of Safety and Effectiveness Data Page 11 of 55 | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Stress/Strain and Fatigue Analysis | To identify the critical locations of stress or strain on the stent using FEA. | Goodman and Maximum Equivalent Strain Damage (MESD) analysis must demonstrate acceptable safety factors (>1). | Pass | | Accelerated Durability | To determine the long-term integrity of the stent under cyclical loading conditions in an overlapping and bent configuration. | Per ASTM F2477. No stent fractures that would adversely affect stent performance after 400 million cycles (10 year equivalent) | Pass | | Magnetic Resonance Imaging (MRI) Safety and Compatibility | To determine the effect of MR on the position and temperature of the stent, and to determine the extent of image artifact during MRI. | See product labeling for safe MRI use conditions | Pass | | Radiopacity | To determine stent visibility using angiographic imaging to assure proper stent placement. | Stent is visible under fluoroscopy. | Pass | | **Delivery System Dimensional and Functional Attributes** | | | | | Dimensional Verification | To inspect and measure the dimensional properties of the stent delivery systems. | The stent delivery systems must meet dimensional specifications (e.g., length, inner and outer diameter, and crossing profile). | Pass | | Delivery, Deployment, and Retraction | To evaluate the performance of the stent delivery systems to safely and reliably deliver the stent to the intended location. | The stent delivery systems can safely and reliably deliver the stent to the intended location according to the instructions for use, without damage to the stent. | Pass | {11} PMA P210014: FDA Summary of Safety and Effectiveness Data Page 12 of 55 | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Balloon Rated Burst Pressure | To determine the rated burst pressure (RBP) of the balloon with the mounted stent. | RBP ≥18 atm The RBP label claim is the pressure at which 99.9% of the balloons can survive with 95% confidence. | Pass | | Balloon Fatigue | To determine the ability of the balloon to withstand repeated inflation/deflation cycles. | The balloon catheter must demonstrate that 90% of the balloons will survive 10 inflations to RBP, with 95% confidence and maintain pressure per specification. | Pass | | Balloon Compliance (Stent Diameter vs. Balloon Pressure) | To determine the relationship between the stent diameter and the balloon inflation pressure. | To generate a compliance chart in the labeling that relates stent diameter to balloon pressure. | Pass | | Balloon Inflation and Deflation Time | To determine the amount of time required to inflate or deflate the balloon delivery systems. | Inflation Time: Characterization of time to inflate the balloon to targeted label RBP. Deflation Time: IDS: Upper STI of Deflation Time ≤20 seconds from RBP RX: Upper STI of Deflation Time ≤30 seconds from RBP | Pass | | Catheter Bond Strength and Tip Pull Test | To determine the bond strengths of the delivery systems and their tips | Catheter bond strengths must meet specifications. | Pass | | Flexibility and Kink Test | To demonstrate the smallest radius that the delivery systems can conform to prior to kinking. | The stent delivery systems will not kink or exhibit a diameter reduction affecting the performance while traversing vessels with a bend radius of 0.50 in (12.7 mm). | Pass | | Catheter Torque Strength | To demonstrate that the delivery systems can withstand torsional forces that are typical of clinical use. | IDS & RX: Withstand 15 full rotations without failure. IDS Only: Hold pressure to targeted label RBP for 30 seconds after 3 full rotations. | Pass | {12} | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Coating Integrity | To demonstrate minimal degradation of the coating on the stent delivery systems during acute clinical performance. | Characterization only | Pass | | Stent Securement | To measure the force that will dislodge the stent prior to deployment. | Stent dislodgement by forward motion and reverse motion: Lower STI ≥0.5N | Pass | # 2. Coating Characterization Testing The coating characterization testing conducted on the Svelte DES is summarized in Table 4. Table 4. Coating Characterization Testing | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Acute Particulate Evaluation – Baseline unconstrained expansion to RBP | To measure the particulate matter generated by the stent during unconstrained expansion to RBP without tracking. | Characterization only | Pass | | Acute Particulate Evaluation – Simulated use | To measure the particulate matter generated during simulated use of the delivery system through an in vitro model to maximum dilatation limit in an overlapping configuration in a mock vessel with 15mm bend radius. | Characterization only | Pass | | Acute Coating Integrity | To assess the drug coating integrity of the stent as manufactured (e.g. prior to tracking and expansion). | Characterization only | Pass | | Acute Coating Durability | To assess the durability of the coating when subjected to simulated clinical use conditions. | Characterization only | Pass | PMA P210014: FDA Summary of Safety and Effectiveness Data {13} | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Chronic Coating Integrity, including Particulate Evaluation | Particulate evaluation and coating integrity assessment of stents in bent overlapped configuration after exposure to pulsatile stresses and strains. | Characterization only | Pass | | Coating Thickness and Uniformity | To measure the coating thickness along the length of the expanded stent post deployment to RBP for both the abluminal and luminal stent surfaces. To analyze the coating uniformity along the length and circumference of the stent via assaying individual stent segments for sirolimus. | Characterization only | Pass | | Coating Characterization – Adhesion of the coating to the stent substrate | To measure the coating adhesion (delamination strength) of the expanded stent post deployment to RBP. | Characterization only | Pass | # 3. Chemistry, Manufacturing &amp; Controls (CMC) Release Testing Each batch of finished devices undergoes testing prior to release and distribution. Where applicable, the test methods follow International Conference on Harmonization (ICH) guidelines. This testing is summarized in Table 5. Table 5. CMC Release Testing | Test | Purpose | | --- | --- | | Drug Identity | To verify the identity of the drug substance in the finished stent. | | Drug Content | To verify that the total amount of the drug on the stent is within the specifications established for the finished product. | | Content Uniformity | To verify the uniformity of the drug content between individual stents is within the specifications established for the finished stent. | | Related Substances | Testing is conducted to verify that the amount of impurities are within the specifications established for the finished product. | PMA P210014: FDA Summary of Safety and Effectiveness Data {14} | Test | Purpose | | --- | --- | | Drug Release | To verify that the in vitro release of the drug substance is within the specifications established for the finished product. | | BHT Content | Testing is conducted to verify that the amount of BHT is within the specifications established for the finished product. | | Particulate Matter | To verify that particle counts are below acceptable levels for the finished product. | | Molecular Weight | Testing is conducted to verify that the molecular weight of the polymer in the drug coating is within the specifications established for the finished product. | | Bacterial Endotoxins | To verify that endotoxin levels are within specifications established for the finished product. | | Sterility | To verify the sterility of the finished product. | 4. Stability and Shelf Life Stability/shelf-life studies were conducted to establish a shelf life for the Svelte DES. The stability testing included a combination of real time and accelerated aging stability studies for drug properties, particulate matter, packaging integrity and sterility, polymer coating properties, and relevant engineering attributes of the stent and delivery system. The data generated supports a product shelf life of 2 years. 5. Packaging and Sterilization Packaging verification testing was performed to demonstrate that the design of the Svelte DES packaging can withstand the hazards of the distribution environment and that the sterility of the product is maintained throughout the labeled shelf life. The Svelte DES are sterilized with ethylene oxide (EtO) gas to a sterility assurance level (SAL) of $1 \times 10^{-6}$. The quantity of bacterial endotoxins was verified to be within the specification limits. The sterilization processes are in compliance with EN ISO 11135:2014. 6. Biocompatibility A series of Good Laboratory Practice (GLP) biocompatibility tests and USP Physicochemical tests were conducted to demonstrate that the components of the Svelte DES are non-toxic and biocompatible. Tests were conducted on final, ethylene oxide sterilized coated stents, polymer only coated stents, uncoated stents, stent delivery systems and the insertion tool accessory device. These test articles were processed in the same manner as the finished Svelte DES. The results of the biocompatibility studies indicated that the Svelte DES was biologically safe and acceptable for clinical use: PMA P210014: FDA Summary of Safety and Effectiveness Data Page 15 of 55 {15} All biocompatibility testing was conducted in accordance with one or more of the following general regulations, standards and guidance documents: Good Laboratory Practices Regulations (21 CFR § 58) - ISO 10993-1:2018, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process - AAMI / ANSI / ISO 10993-1:2009, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process - FDA Use of International Standard ISO 10993-1, "Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process", Guidance for Industry and Food and Drug Administration Staff, June 16, 2016 - USP "Physicochemical Test – Containers Plastics" &lt;661&gt; Table 6 provides a summary of the biocompatibility testing conducted to support the Svelte DES. Table 6. Summary of Biocompatibility Testing | Test Name | Test Description | Test Article | Result | | --- | --- | --- | --- | | Chemical Characterization | ISO 10993-18: Chemical Characterization of Materials Extraction of Chemical Compounds | • Coated (drug and polymer blend) stent | Extractables/leachables not of toxicological concern for applicable endpoints | | Cytotoxicity | ISO 10993-5: In vitro Cytotoxicity (L929 MEM Elution) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Uncoated stent • IDS Delivery System • RX Delivery System • Insertion Tool | Pass (non-cytotoxic) | | | ISO 10993-5: In vitro Cytotoxicity (Neutral Red Uptake) | • Coated (drug and polymer blend) stent • Polymer only coated stent | | | Sensitization | ISO 10993-10: Sensitization Kligman Maximization (Guinea Pig) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-sensitizer) | | Intracutaneous Reactivity | ISO 10993-10: Intracutaneous Injection (Rabbit) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-irritant) | PMA P210014: FDA Summary of Safety and Effectiveness Data Page 16 of 55 {16} PMA P210014: FDA Summary of Safety and Effectiveness Data Page 17 of 55 | Test Name | Test Description | Test Article | Result | | --- | --- | --- | --- | | Pyrogenicity | ISO 10993-11: Material Mediated Pyrogenicity (Rabbit) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-pyrogenic) | | Systemic Toxicity (Acute) | ISO 10993-11: Systemic Injection (Mouse) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-toxic) | | Systemic Toxicity (Subchronic) | ISO 10993-6 and ISO 10993-11: 90 Day Subcutaneous Implantation (Rabbit) | • Coated (drug and polymer blend) stent | Pass (non-toxic) | | | ISO 10993-6 and ISO 10993-11: 90 Day Intramuscular Implantation (Rat) | • Uncoated stent | | | Systemic Toxicity (Chronic) | ISO 10993-6 and ISO 10993-11: 26 Week Subcutaneous Implantation (Rat) | • Coated (drug and polymer blend) stent | Pass (non-toxic) | | Implantation | ISO 10993-6: 7 Day Intramuscular (Rabbit) | • Coated (drug and polymer blend) stent | Pass (non-toxic, non-irritant) | | | ISO 10993-6: 4 Week Intramuscular (Rabbit) | | | | Hemocompatibility | ISO 10993-4: Thrombogenicity (Dog) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System | Pass (non-thrombogenic) | | | ISO 10993-4: Thrombogenicity (Swine) | • RX Delivery System | | | | ASTM F756: In vitro Hemolysis (Rabbit Blood - Direct & Indirect Contact) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-hemolytic) | | | ISO 10993-4: In vitro Hemocompatibility (Human Blood - Direct Contact) | • Coated (drug and polymer blend) stent • Uncoated stent | Pass (no effect on hematology) | | | ISO 10993-4: In vitro Hemocompatibility (Human Blood - Indirect Contact) | • Coated (drug and polymer blend) stent | | | | ISO 10993-4: In vitro UPTT (Human Plasma - Direct Contact) | • Coated (drug and polymer blend) stent • Uncoated stent | Pass (no effect on clotting time) | | | ISO 10993-4: In vitro Complement Activation-C3a and SC5b-9 (Human Plasma - Direct Contact) | • Coated (drug and polymer blend) stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (no activation of complement) | {17} | Test Name | Test Description | Test Article | Result | | --- | --- | --- | --- | | Genotoxicity | ISO 10993-3: Salmonella Typhimurium and Escherichia Coli Reverse Mutation Assay (Ames) | • Polymer only coated stent • Uncoated stent • IDS Delivery System • RX Delivery System | Pass (non-mutagenic) | | | ISO 10993-3: Mouse Lymphoma Forward Mutagenesis Assay | • Polymer only coated stent • Uncoated stent | Pass (non-mutagenic) | | | ISO 10993-3: Mouse Peripheral Blood Micronucleus Study | • Polymer only coated stent | Pass (non-mutagenic) | | | ISO 10993-3: Rodent Bone Marrow Micronucleus Study | • Uncoated stent | Pass (non-mutagenic) | | | Chemical Characterization: Extractable/Leachable Chemical Compounds and Toxicological Risk Assessment | • Coated (drug and polymer blend) stent | Pass based on toxicological risk assessment | | Carcinogenicity | Chemical Characterization: In vitro Polymer Intermediate Degradation Products and Toxicological Risk Assessment | • Coated (drug and polymer blend) stent | Pass based on toxicological risk assessment | | Reproductive Toxicity | | | | | Degradation | Chemical Characterization: In vitro Polymer Intermediate Degradation Products and Toxicological Risk Assessment | • Coated (drug and polymer blend) stent | Pass based on toxicological risk assessment | | Physiochemical | USP 39/ NF 34 Supplement 2, <661.2> - Absorbance | • Insertion Tool | Pass | | | USP 39/ NF 34 Supplement 2, <661.2> - Alkalinity or Acidity | | Pass | | | USP 39/ NF 34 Supplement 2, <661.2> - Total Organic Carbon | | Pass | Genotoxicity, carcinogenicity and reproductive toxicity testing on the finished drug and polymer coated Svelte DES were not conducted based on a chemical characterization and toxicological assessment along with the negative results of genotoxicity testing of the uncoated and polymer only coated stents, which showed no toxicological concern for these endpoints. A toxicological risk assessment was conducted on the degradants from the PEA in the stent coating and was found to be acceptable. Based on the known molecular structures and properties and in vitro analytical and stability testing results, there is no evidence to suggest that any chemical interactions occur between the PEA carrier and the sirolimus drug under the established processing and storage conditions that would lead to the formation of covalent bonds or that would alter the structure of the drug in any way to form a new intermediate or molecular entity. ## B. Animal Studies A series of animal studies were conducted to evaluate safety, efficacy, and overall product performance. PMA P210014: FDA Summary of Safety and Effectiveness Data Page 18 of 55 {18} To assess the safety, acute performance and certain biocompatibility endpoints of the Svelte DES, SLENDER IDS and DIRECT RX delivery systems, animal studies were conducted to evaluate the inflammation, neointimal proliferation, endothelialization, necrosis, thrombogenicity, embolism, pharmacokinetics, polymer degradation kinetics, device deliverability and radiopacity. The animal studies also included high dose and overlapping DES evaluations. Quantitative angiography, gross evaluation, quantitative histomorphometry and histopathology were performed for stents implanted in the coronary arteries as well as downstream myocardial assessments. All Svelte stents that were successfully implanted remained structurally intact for the duration of implantation. All animal studies were performed using healthy pigs in accordance with the Good Laboratory Practice (GLP) for Non-clinical Laboratory Studies requirements outlined in 21 CFR Part 58, unless otherwise noted below. The results of these studies support the safety and biocompatibility of the Svelte DES. A summary of the major animal studies performed to support product safety are shown in Table 7 below. Table 7. Summary of Major Supportive Animal Studies | Study Type | Test Article Size Treatment PEA/API ratio Dosage/stent Dose Density | Type: Number of Animals | Number of Stents | Evaluation Time Points | Testing Objectives Major Endpoints | | --- | --- | --- | --- | --- | --- | | Chronic Tissue Response Safety Study (GLP) | Svelte DES-IDS 3.00x18mm single & overlapped 70/30 API: 126μg 213 μg/cm2 | Yucatan miniswine: 69 | Test: 88 Controls BMS: 34 XIENCE DES: 60 | 3, 30, 90, 180 and 390 days | Acute performance (preparation, delivery, deployment, thrombogenicity) Angiographic analysis Clinical Pathology Radiography Histopathology Morphometric analysis SEM analysis Myocardial assessment | | High Dose Tissue Response Safety Study (GLP) | Svelte HD-DES 3.00x18mm 100% overlapped 70/30 API: 278μg 469 μg/cm2 2.2x coating | Yucatan miniswine: 12 | Test: 48 Control BMS: 24 | 30 and 90 days | Angiographic analysis Clinical Pathology Radiography Histopathology Morphometric analysis Myocardial assessment | | Pharmacokinetic, Carrier Degradation Kinetics Study | Svelte DES-IDS 3.00x18mm single 70/30 API: 124μg 213 μg/cm2 | Yucatan miniswine: 15 | Test: 45 | 30, 60, 90, 120, 180, 270, 360 days | Angiographic analysis Stent PEA carrier content at explant | | | | | | 0, 1, 5, 15, 30, 60 mins 2, 4, 6, 8, 24 hrs 2, 3, 4, 8, 12, 14 days | Drug concentration - blood | PMA P210014: FDA Summary of Safety and Effectiveness Data {19} | Study Type | Test Article Size Treatment PEA/API ratio Dosage/stent Dose Density | Type: Number of Animals | Number of Stents | Evaluation Time Points | Testing Objectives Major Endpoints | | --- | --- | --- | --- | --- | --- | | Pharmacokinetic Study | Svelte DES-IDS 3.00x18mm single 70/30 API: 124μg 213 μg/cm² | Yorkshire swine: 6 | Test: 36 | 1, 3, 8, 14, 30 and 60 days | Angiographic analysis Stent drug content at explant Drug concentration - arterial tissue at explant | | Chronic Carrier Only Tissue Response Safety Feasibility Study | Svelte DES-IDS 3.00x18mm 70/30 single API: 124μg 213 μg/cm² | Yucatan miniswine: 27 | Test: 24 Controls PEAS: 20 BMS: 26 XIENCE: 8 | 30, 90 and 390 days | Acute performance (preparation, delivery, deployment, thrombogenicity) Angiographic analysis Clinical Pathology Radiography Histopathology Morphometric analysis SEM analysis Myocardial assessment | | RX Acute Performance and Thrombogenicity Assessment Study (GLP) | Svelte DES-RX 2.50x18mm 3.00x18mm single 70/30 API: 126μg 213 μg/cm² | Yorkshire swine: 3 | Test: 10 | 0 and 3 days | Acute performance (preparation, delivery, deployment, thrombogenicity) Angiographic analysis Clinical Pathology Histopathology Histomorphology Myocardial assessment Non-cardiac organ assessment | | IDS Acute Performance Assessment Study (non-GLP) | Svelte BMS-IDS 2.50x13mm Single | Yucatan swine: 1 | Test: 4 | 0 days | Acute performance (preparation, delivery) | | IDS Acute Performance Assessment Study (GLP) | Svelte BMS-IDS 4.00x28mm Single | Yorkshire swine: 3 | Test: BMS: 5 IDS: 8 Control Vision Stent: 5 SDS: 8 | 0 days | Acute performance (preparation, delivery, deployment, thrombogenicity) Angiographic analysis Heart necropsy | ## C. Additional Studies ### 1. In Vivo Pharmacokinetics A prospective, open, non-randomized human pharmacokinetic (PK) study was conducted in the United States. A total of eight patients with symptomatic ischemic PMA P210014: FDA Summary of Safety and Effectiveness Data {20} heart disease were consented and treated from December 2018 through April 2019. At least $38\%$ (3 patients) received a sufficiently large stent so that the total implanted stent dose was $&gt;1.7$ times the sirolimus dose of the workhorse Svelte DES $(3.0 \times 18 \mathrm{~mm})$ . Blood samples were drawn to evaluate the systemic PK parameters of sirolimus release from the implanted Svelte DES. For each patient, peripheral blood samples were collected at 10 and 30 minutes, at 1, 2, 4, 6, 12, 24, 48, and 72 hours, and at 7, 14, and 30 days post-stent implantation with continued follow-up for 2 years. Whole blood concentration of sirolimus was determined using a validated high performance liquid chromatography mass spectrometry (HPLC-MS) method. PK parameters were calculated and summarized in Table 8. Terms and definitions of PK parameters are shown in Table 9. Table 8. Individual and Mean PK Parameters for Sirolimus | Subject | λz1/hr | Thalf hr | Tmax hr | Cmax ng/mL | AUClast hr*ng/mL | AUCINF hr*ng/mL | Vz/F L | CL/F L/hr | CL/F Normalized L/hr/kg | Vz/F Normalized L/kg | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | 1 | 0.00277 | 251 | 4.32 | 0.436 | 68.0 | 105 | 434 | 1.20 | 12.8 | 4.62 | | 2 | 0.00182 | 382 | 1.93 | 0.754 | 179 | 243 | 596 | 1.08 | 12.0 | 6.64 | | 3 | 0.00165 | 419 | 2.15 | 0.713 | 174 | 249 | 378 | 0.63 | 6.96 | 4.21 | | 4 | 0.00364 | 191 | 1.98 | 0.457 | 69.9 | 94.9 | 502 | 1.82 | 15.9 | 4.37 | | 5 | 0.00206 | 336 | 3.95 | 1.56 | 409 | 528 | 330 | 0.68 | 7.59 | 3.68 | | 6 | 0.00331 | 209 | 0.450 | 0.539 | 75.5 | 116 | 553 | 1.83 | 11.7 | 3.52 | | 7 | 0.00266 | 260 | 1.15 | 0.500 | 138 | 161 | 278 | 0.74 | 8.33 | 3.13 | | 8 | 0.00199 | 348 | 1.02 | 0.564 | 165 | 219 | 357 | 0.71 | 7.76 | 3.90 | | N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | | Mean | 0.00249 | 299 | 2.12 | 0.690 | 160 | 215 | 429 | 1.09 | 10.4 | 4.26 | | STD | 0.00073 | 83.5 | 1.37 | 0.369 | 111 | 141 | 113 | 0.500 | 3.19 | 1.08 | | Min | 0.00165 | 191 | 0.450 | 0.436 | 68.0 | 94.9 | 278 | 0.625 | 6.96 | 3.13 | | Median | 0.00236 | 298 | 1.96 | 0.552 | 151 | 190 | 406 | 0.911 | 10.0 | 4.06 | | Max | 0.00364 | 419 | 4.32 | 1.56 | 409 | 528 | 596 | 1.83 | 15.9 | 6.64 | | CV% | 29.2 | 27.9 | 64.8 | 53.5 | 69.7 | 65.7 | 26.3 | 46.0 | 30.7 | 25.2 | | Geometric Mean | N/A | N/A | N/A | 0.632 | 134 | 184 | N/A | N/A | N/A | N/A | | Geometric CV | N/A | N/A | N/A | 43.2 | 67.9 | 62.3 | N/A | N/A | N/A | N/A | $\mathrm{N / A} =$ Not Applicable Table 9. Terms and Definitions of PK Parameters | Term | Definition | | --- | --- | | AUCinf | Area under the curve to infinite time (AUC0-inf) | | AUClast | Area under the curve to the last measured concentration (AUC0-t) | | CL/F | Clearance of drug | | Cmax | Peak drug concentration | | Thalf | Drug elimination half-life | | Tmax | Time to peak drug concentration | | Vz/F | Volume of drug distribution | | Δz | Apparent terminal first-order elimination rate constant | Results obtained from the PK study: PMA P210014: FDA Summary of Safety and Effectiveness Data {21} - Stent nominal sirolimus dose ranged from 119 to 360 µg/stent (DES implants from 3.50×13mm to 4.00×38mm). - Whole blood Cmax values increased with increasing dose and ranged from 0.436 to 1.56 ng/mL. - AUClast and AUCinf values ranged from 68.0 to 409 hr*ng/mL and 94.9 to 528 hr*ng/mL, respectively. - The drug elimination half-life of sirolimus ranged from 191 to 419 hrs across all dose levels. - The systemic clearance of sirolimus ranged from 6.96 to 15.9 L/hr/kg across all dose levels. - A dose-proportional linear trend was observed for Cmax, AUClast, and AUCinf over a 3-fold range of both total stent sirolimus dose and normalized patient dose. ## X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study, OPTIMIZE, to establish a reasonable assurance of safety and effectiveness of the Svelte DES for improving coronary artery luminal diameter in patients with symptomatic heart disease due to atherosclerotic lesions ≤24 mm in length in native coronary arteries with ≥2.25 mm to ≤4.00 mm reference vessel diameters, using direct stenting or pre-dilatation interventional techniques in the United States, Japan and the Netherlands under IDE # G160227. Data from this clinical study were the basis for the PMA approval decision. Data from the previous DIRECT I-III studies conducted outside of the US were provided as supplemental, non-primary clinical data; these studies are described in Section XI. A summary of the pivotal OPTIMIZE study is presented below. ## A. Study Design Patients were treated between January 2, 2018 and June 4, 2019. The database for this PMA reflected data collected through June 25, 2020 and included 1639 patients. There were 74 investigational sites. The study was a prospective, single-blind, randomized (1:1), active-control, multi-center clinical study to compare the safety and effectiveness of the Svelte DES to coronary drug-eluting stents (DES) (Abbott Vascular XIENCE or Boston Scientific Promus). The control treatments were legally marketed alternatives with similar indications for use. Patients were randomized 1:1 to the Svelte DES (SLENDER IDS or DIRECT RX at investigator discretion), or the XIENCE DES or Promus DES (control DES pooled group). For each treatment group, the number and percentage of patients with 12-month TLF were summarized. The risk difference and the two-sided 95% confidence interval of the risk difference between two treatment groups were calculated based on the Farrington-Manning test. The null hypothesis was also tested using the Farrington-Manning test, as PMA P210014: FDA Summary of Safety and Effectiveness Data Page 22 of 55 {22} was an assessment of the poolability of the Control DES (XIENCE or Promus DES) to confirm consistency of results. OPTIMIZE utilized an independent angiographic core laboratory and independent clinical events committee (CEC) to evaluate and adjudicate study primary and secondary endpoint data. The core laboratories and CEC were composed of experts in their field. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the OPTIMIZE study was limited to patients who met the following inclusion criteria: General Inclusion Criteria: 1. Subject is ≥ 18 years old; 2. Subject understands the study requirements, the treatment procedures and provides written informed consent before any study-specific tests or procedures are performed; 3. Subject is an eligible candidate for PCI; 4. Subject has symptomatic coronary artery disease with objective evidence of ischemia or silent ischemia; 5. Subject has clinical symptoms or ECG changes consistent with non-ST elevation MI (NSTEMI), is clinically and hemodynamically stable and has cardiac enzymes documented to be decreasing prior to the study procedure (CK-MB is preferred, but if troponin is assessed, enzymes decreasing, stable or elevated up to 20% over the prior assessment are acceptable); 6. Subject is an acceptable candidate for CABG; 7. Subject agrees to comply with specified follow-up evaluations. Angiographic Inclusion Criteria (visual estimate): 1. Subject has ≤3 de novo target lesions in ≤2 native coronary artery vessels, with ≤2 lesions in a single vessel, each meeting the angiographic criteria and none of the exclusion criteria. 2. Target lesion(s) must be located in a native coronary artery with RVD ≥2.25 mm and ≤4.00 mm; 3. Target lesion(s) length must be ≤34 mm in length (the intention should be to cover the whole lesion with one stent of adequate length); 4. Target lesion(s) must have visually estimated stenosis ≥50% and &lt;100% with Thrombolysis in Myocardial Infarction (TIMI) flow &gt;1. For lesions with visually estimated stenosis ≥50% and ≤70%, additional confirmation by ACC/AHA guideline compliant physiologic assessment is required; 5. Coronary anatomy is likely to allow delivery of a study device(s) to the target lesion(s). Patients were not permitted to enroll in the OPTIMIZE study if they met any of the following exclusion criteria: General Exclusion Criteria: PMA P210014: FDA Summary of Safety and Effectiveness Data Page 23 of 55 {23} 1. Subject has clinical symptoms or electrocardiogram (ECG) changes consistent with acute ST elevation MI (STEMI). Subject may be included if primary PCI for STEMI was successfully completed and subject is clinically and hemodynamically stable with cardiac enzymes documented to be decreasing ≥72 hours prior to the study procedure; 2. Subject has cardiogenic shock, hemodynamic instability requiring inotropic or mechanical circulatory support, intractable ventricular arrhythmia, or ongoing intractable angina; 3. Subject has received an organ transplant or is on a waiting list for an organ transplant; 4. Subject is receiving or scheduled to receive chemotherapy 30 days before or after the index procedure; 5. Subject requires a planned PCI (including staged procedures), CABG or surgical or catheter-based valvular intervention within 12 months of the index procedure; 6. Subject was previously treated at any time with intravascular brachytherapy; 7. Subject has a known allergy to contrast (that cannot be adequately premedicated) and/or the study stent systems or protocol-required concomitant medications (e.g., platinum, platinum-chromium alloy, stainless steel, sirolimus, everolimus or structurally related compounds, polymer or individual components, all P2Y12 inhibitors or aspirin); 8. Subject has one of the following (as assessed prior to the index procedure): a. Other serious medical illness (e.g., cancer, congestive heart failure) with estimated life expectancy of &lt;24 months; b. Current problems with substance abuse (e.g., alcohol, cocaine, heroin, etc.); c. Planned procedure that may cause non-compliance with the protocol or confound data interpretation; 9. Subject is receiving chronic (≥72 hours) anticoagulation therapy (e.g., heparin, coumadin) for indications other than acute coronary syndrome (ACS); 10. Subject has a platelet count &lt;100,000 cells/mm³ or &gt;700,000 cells/mm³; 11. Subject has a white blood cell (WBC) count &lt;3,000 cells/mm³; 12. Subject has documented significant liver disease, including laboratory evidence of hepatitis; 13. Subject is on dialysis or has a baseline serum creatinine level &gt;2.0 mg/dL (177 μmol/L); 14. Subject has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions; 15. Subject has a history of cerebrovascular accident (CVA) or transient ischemic attack (TIA) within the past 6 months; 16. Subject has an active peptic ulcer or active gastrointestinal (GI) bleeding; 17. Subject has severe symptomatic heart failure (i.e., NYHA class IV); 18. Subject intends to participate in another investigational drug or device clinical study within 12 months after the index procedure; 19. Subject has a known intention to procreate within 12 months after the index procedure (a woman of child-bearing potential who is sexually active must agree to use a reliable method of contraception from the time of screening through 12 months after the index procedure); PMA P210014: FDA Summary of Safety and Effectiveness Data Page 24 of 55 {24} 20. Subject is pregnant or nursing (subject must have a negative pregnancy test within 14 days prior to the index procedure if a woman of child-bearing potential); 21. Subject is participating in another investigational drug or device clinical study; 22. Planned use of cutting balloon or atherectomy (rotational, orbital, laser or other) or any other form of treatment of the target lesion(s) during the index procedure other than plain balloon angioplasty and the randomized stent. ## Angiographic Exclusion Criteria (visual estimate): 1. Subject has a planned treatment of &gt;3 lesions; 2. Subject has a planned treatment of &gt;2 major epicardial vessels; 3. Subject has a planned treatment of a single lesion with &gt;1 stent; 4. Subject has 2 target lesions in the same vessel that are separated by &lt;15 mm; 5. Subject’s target lesion(s) is located in the left main coronary artery; 6. Subject’s target lesion(s) is located within 3 mm of the origin of the left anterior descending (LAD) coronary artery or left circumflex (LCX) coronary artery; 7. Subject’s target lesion(s) is located within a saphenous vein graft (SVG) or an arterial graft; 8. The subject’s target lesion(s) will be accessed via SVG or arterial graft; 9. Subject has a target lesion(s) with TIMI flow 0 (total occlusion) or TIMI flow 1 prior to guide wire crossing; 10. Subject’s target lesion(s) involves a complex bifurcation (e.g., bifurcation lesion requiring treatment with more than one stent); 11. Subject’s target lesion is located within 10 mm of a previously implanted stent or involves in-stent restenosis; 12. Subject has unprotected left main coronary artery disease (&gt;50% diameter stenosis); 13. Subject has been treated with any type of PCI (i.e., balloon angioplasty, stent, cutting balloon, or atherectomy) within 24 hours of the index procedure 14. Subject has thrombus or possible thrombus present in the target vessel. ## 2. Follow-up Schedule All patients were scheduled to return for follow-up examinations at 12 months post-procedure. Telephone assessments were scheduled for 1 month, 6 months, 2 years, and annually through 5 years. Due to the COVID-19 global pandemic, some 12-month assessments were conducted via telephone. The first 150 patients enrolled were assigned to receive angiographic evaluation at the index procedure and at 12-month follow up. The first 60 patients were also assigned to have IVUS performed at the index procedure and 12-month follow up. Preoperatively, patients received physical examinations, angina status was recorded, routine laboratory tests including cardiac enzyme assessments were conducted, and 12-lead electrocardiograms were performed. Postoperatively, prior to discharge, patients received another physical examination, angina status was recorded, cardiac enzymes were drawn (4 – 2 hours post-procedure and again 12 – 20 hours post-procedure or at discharge), another ECG was performed, and all adverse events were recorded. At follow-up visits and calls, angina assessment, cardiovascular and other important medication intake, and any adverse events were recorded. PMA P210014: FDA Summary of Safety and Effectiveness Data Page 25 of 55 {25} The key timepoints are shown below in the tables summarizing safety and effectiveness. ## 3. Clinical Endpoints The primary endpoint was a composite of outcomes related to both safety and effectiveness: target lesion failure (TLF) at 12 months, defined as cardiac death, target vessel myocardial infarction (TVMI) (Q-wave or non-Q-wave; MI defined below), or clinically-indicated target lesion revascularization (TLR). With regards to safety, secondary clinical outcomes evaluated at all study timepoints included the following: - Death (all cause) - Cardiac death - TVMI - Stent thrombosis according to Academic Research Consortium (ARC) criteria With regards to effectiveness, the primary endpoint of the angiographic substudy was 12-month in-stent late lumen loss (LLL). Post-procedural secondary endpoints included the following: - Device Success: Attainment of &lt;30% final residual stenosis of the target lesion using only the randomized stent; - Lesion Success: Attainment of &lt;30% final residual stenosis of the target lesion using any stent, with or without other interventional devices; - Procedure Success: Lesion success and no in-hospital major adverse cardiac events (MACE); - Direct Stent Strategy Success: Attainment of &lt;30% final residual stenosis of the target lesion without pre-dilatation if the operator had originally chosen to proceed using a direct stent approach. Clinical effectiveness endpoints included clinically-driven TLR and clinically-driven target vessel revascularization (TVR) at all study timepoints. With regards to success/failure criteria, non-inferiority testing of the primary endpoint was planned. Assuming a 12-month TLF rate of 6.5% and an absolute non-inferiority margin of 3.58% with a one-sided alpha of 0.025, a total of 1,548 patients had 80% power to demonstrate non-inferiority of TLF at 12 months follow up. To account for loss to follow-up (expected to be approximately 5%), a total of 1,630 patients were required to be randomized. The assumption of the 12-month TLF rate of 6.5% was based on the rate of 12-month TLF observed for Promus in the EVOLVE II study, which used the same patient selection criteria. The non-inferiority null and alternative hypotheses were: - H₀: πSV - πC ≥ 0.0358 - H₁: πSV - πC &lt; 0.0358 PMA P210014: FDA Summary of Safety and Effectiveness Data Page 26 of 55 {26} where $\pi_{\mathrm{SV}}$ and $\pi_{\mathrm{C}}$ are the true 12-month TLF rate for Svelte DES and the combined control group of XIENCE or Promus DES, respectively, and 0.0358 is the non-inferiority margin. The one-sided significance level was 0.025. For each treatment group (Svelte DES vs. combined control DES), the number and percentage of patients with 12-month TLF were presented, as was the risk difference and the two-sided $95\%$ confidence interval of the risk difference, calculated using the Farrington-Manning test. The primary endpoint was evaluated on an intent-to-treat (ITT) basis. The angiographic substudy’s non-inferiority null and alternative hypotheses were: - $\mathrm{H}_0: \mu_{\mathrm{SV}} - \mu_{\mathrm{C}} \geq 0.20$ - $\mathrm{H}_{1}: \mu_{\mathrm{SV}} - \mu_{\mathrm{C}} &lt; 0.20$ where $\mu_{\mathrm{SV}}$ and $\mu_{\mathrm{C}}$ were the true mean 12-month in-stent LLL for Svelte DES and the control DES, respectively, and 0.20 was the non-inferiority margin. The one-sided significance level was 0.05. For each treatment group (Svelte DES vs. control DES), descriptive statistics (sample size, mean, median, standard deviation, minimum and maximum) of in-stent 12-month in-stent LLL were presented, as was the difference between means and the one-sided $95\%$ confidence interval of the difference between means. The null hypothesis was tested using a two-sample t-test. **Protocol Definition of MI:** All MI was assumed target vessel (a component of the primary endpoint) unless objective evidence presented otherwise. The protocol definition of MI was identical to that used in the EVOLVE II study, which was itself a modification of the first Academic Research Consortium (ARC) definition (2006) and the 2007 Global Task Force Universal definition of peri-procedural MI [1] [2] [3]. The OPTIMIZE MI definition was as follows: **Spontaneous MI:** Detection of rise and/or fall of cardiac biomarkers (CK-MB or troponin) with at least one value above the $99^{\text{th}}$ percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following: 1. Symptoms of ischemia; 2. ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch block [LBBB]); 3. Development of pathological Q waves in the ECG; 4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. **Percutaneous Coronary Intervention-Related MI:** Peri-procedural PCI MI was defined by any of the following criteria. Symptoms of cardiac ischemia were not required. 1. Biomarker elevations within 48 hours of PCI: - CK-MB &gt; 3X URL or - CK-MB not measured and CK &gt; 2X URL or - Neither CK-MB nor CK measured and troponin &gt; 3X URL AND PMA P210014: FDA Summary of Safety and Effectiveness Data Page 27 of 55 {27} No evidence that cardiac biomarkers were elevated prior to the procedure OR both of the following must have been true: - $\geq 50\%$ increase in cardiac biomarker result - Evidence that cardiac biomarker values were decreasing (e.g., two samples 3-hours apart) prior to the suspected MI 2. New pathological Q waves 3. Autopsy evidence of acute MI # B. Accountability of PMA Cohort At the time of database lock, of 1639 patients enrolled in the PMA study, $95.3\%$ (1563) are available for analysis at the completion of the study, the 12-month post-index procedure visit. The disposition of the patients is summarized in Table 10. Table 10. Patient Disposition | Patient Disposition | Svelte DES | Control DES | Total | | --- | --- | --- | --- | | Signed Informed Consent | N/A | N/A | 6184 | | Screen Failures | N/A | N/A | 4542 | | Number of Patients Randomized (ITT Population) | 827 | 812 | 1639 | | Deaths Prior to 12-Month Visit | 0.7% (6/827) | 1.1% (9/812) | 0.9% (15/1639) | | Withdrew Consent/Lost to Follow-up/Other | 1.7% (14/827) | 1.8% (15/812) | 1.8% (29/1639) | | Missed 12-Month Visit | 2.2% (18/827) | 1.7% (14/812) | 1.9% (32/1639) | | Completed 12 Month Visit | 95.4% (789/827) | 95.3% (774/812) | 95.4% (1563/1639) | | Primary Endpoint Evaluable Patients | 96.2% (796/827) | 96.0% (780/812) | 96.2% (1576/1639) | The intention-to-treat (ITT) population consisted of all 1639 patients randomized in the study. Patients exiting the study early for reasons marked as "other" include those where the investigative site discontinued intent-to-treat follow-up in error due to not receiving a study stent, being randomized in error and no study procedure occurring. "Primary-Endpoint Evaluable Patients" are defined as patients 1) experiencing a TLF event within 12 months of the study procedure, or 2) completing clinical follow-up $\geq 330$ days after the study procedure. # C. Study Population Demographics and Baseline Parameters The demographics of the study population are relatively typical for a coronary stent study performed in the US. Table 11 presents demographics for the OPTIMIZE study ITT population. The mean age of the study patients was 65.4 years and $28.25\%$ were female. Patients were predominantly white $(81.9\%)$ and overweight (mean body mass index (BMI) $29.4~\mathrm{kg / m^2}$ ). Table 11. OPTIMIZE Study Baseline Demographics PMA P210014: FDA Summary of Safety and Effectiveness Data {28} | Patient Characteristics | Svelte DES (N=827 Patients) | XIENCE/Promus DES (N=812 Patients) | | --- | --- | --- | | Age (years) | | | | Mean±SD (N) | 65.09±10.02 (827) | 65.79±10.33 (812) | | Range (min, max) | (25.00,89.00) | (36.00,90.00) | | Sex | | | | Male | 72.67% (601/827) | 70.81% (575/812) | | Female | 27.33% (226/827) | 29.19% (237/812) | | Race | | | | American Indian or Alaska Native | 0.24% (2/827) | 0.25% (2/812) | | Asian | 10.88% (90/827) | 10.96% (89/812) | | Black or African American | 3.87% (32/827) | 3.33% (27/812) | | Native Hawaiian or Pacific Islander | 0.24% (2/827) | 0.00% (0/812) | | White | 81.38% (673/827) | 82.39% (669/812) | | Other | 0.85% (7/827) | 0.62% (5/812) | | Ethnicity | | | | Hispanic or Latino | 2.78% (23/827) | 2.83% (23/812) | | BMI (kg/m2) | 29.08±5.69 (826) | 29.20±5.92 (811) | Error! Not a valid bookmark self-reference. shows the baseline clinical characteristics and medical history of the ITT population. Groups were evenly matched, with the majority of patients reporting prior or current smoking, hypertension and hyperlipidemia. Approximately $30\%$ of patients were diabetic, consistent with previously reported and recent prospective studies. Table 12: Baseline Clinical Characteristics | Parameter | Svelte DES (N=827 Patients) | XIENCE/Promus DES (N=812 Patients) | | --- | --- | --- | | Smoking Status | | | | Never Smoked | 36.28% (300/827) | 38.67% (314/812) | | Previous Smoker | 47.52% (393/827) | 44.09% (358/812) | | Current Smoker | 16.20% (134/827) | 17.24% (140/812) | | History of MI | 31.44% (260/827) | 32.76% (266/812) | | Previous Revascularization | 36.88% (305/827) | 34.48% (280/812) | | Previous PCI | 93.77% (286/305) | 93.93% (263/280) | | Previous CABG | 11.80% (36/305) | 11.07% (31/280) | | History of Stroke | 3.51% (29/827) | 5.30% (43/812) | | History of Transient Ischemic Attack | 3.99% (33/827) | 4.31% (35/812) | | Congestive Heart Failure | 6.89% (57/827) | 5.91% (48/812) | | Diabetes | 28.54% (236/827) | 30.67% (249/812) | | Insulin-Dependent | 30.51% (72/236) | 27.31% (68/249) | | Non Insulin-Dependent | 69.49% (164/236) | 72.69% (181/249) | | Hypertension | 74.49% (616/827) | 74.63% (606/812) | | Hypercholesterolemia | 33.25% (275/827) | 35.84% (291/812) | | Hyperlipidemia | 54.90% (454/827) | 54.06% (439/812) | | Chronic Obstructive Pulmonary Disease | 9.67% (80/827) | 10.71% (87/812) | | Kidney Disease w/dialysis | 0.12% (1/827) | 0.00% (0/812) | | Kidney Disease w/o dialysis | 10.76% (89/827) | 11.95% (97/812) | | Renal Insufficiency | 0.48% (4/827) | 0.37% (3/812) | | Peripheral Artery Disease | 5.68% (47/827) | 6.90% (56/812) | | Arrhythmia | 11.97% (99/827) | 13.67% (111/812) | | Atrial Fibrillation/Flutter | 3.39% (28/827) | 3.20% (26/812) | | History of Cancer | 14.15% (117/827) | 15.02% (122/812) | PMA P210014: FDA Summary of Safety and Effectiveness Data {29} Baseline ischemic status was similar between the treatment and control groups with no significant differences in distribution of ischemic symptoms as presented in Table 13. Table 13. Ischemic Status at Baseline | Ischemic Status | Svelte DES (N=827 Patients) | XIENCE/Promus DES (N=812 Patients) | | --- | --- | --- | | Angina Status | | | | Asymptomatic/Free of Symptoms | 21.31% (176/826) | 20.57% (167/812) | | Silent Ischemia | 3.63% (30/826) | 4.56% (37/812) | | Stable Angina | 49.52% (409/826) | 49.88% (405/812) | | Unstable Angina | 25.54% (211/826) | 25.00% (203/812) | | CCS classification | | | | I | 18.09% (74/409) | 18.77% (76/405) | | II | 45.23% (185/409) | 47.16% (191/405) | | III | 31.78% (130/409) | 30.37% (123/405) | | IV | 4.89% (20/409) | 3.70% (15/405) | | Braunwald classification | | | | IA | 8.70% (18/207) | 4.95% (10/202) | | IIA | 5.31% (11/207) | 2.97% (6/202) | | IIIA | 8.70% (18/207) | 7.92% (16/202) | | IB | 19.81% (41/207) | 21.78% (44/202) | | IIB | 21.74% (45/207) | 20.30% (41/202) | | IIIB | 28.02% (58/207) | 32.67% (66/202) | | IC | 2.42% (5/207) | 3.47% (7/202) | | IIC | 1.93% (4/207) | 3.96% (8/202) | | IIIC | 3.38% (7/207) | 1.98% (4/202) | # Key Baseline Lesion Characteristics: Table 14 presents baseline lesion characteristics as interpreted by an independent core lab using quantitative coronary analysis (QCA). In OPTIMIZE patients, mean reference vessel diameter was $2.78 \pm 0.50 \mathrm{~mm}$ , mean lesion length was $14.57 \pm 7.28 \mathrm{~mm}$ , and mean percent diameter stenosis was $83\%$ . The target lesion location distribution is generally reflective of patients presenting for PCI with $44\%$ in the LAD, $27\%$ in the LCX, and $28\%$ in the RCA. Approximately $74\%$ of lesions were classified as complex (B2/C). Table 14. Baseline Lesion Characteristics | Baseline Lesion Characteristics | Svelte DES (N=827 Patients N=1018 Lesions) | XIENCE/Promus DES (N=812 Patients N=970 Lesions) | | --- | --- | --- | | Number of Target Lesions (Mean±SD (n)) | 1.27 ± 0.52 (822) | 1.22 ± 0.45 (809) | | Vessel Location | | | | LAD | 42.93% (437/1018) | 45.82% (444/969) | | LCX | 27.31% (278/1018) | 26.52% (257/969) | | RCA | 29.57% (301/1018) | 27.66% (268/969) | | LM | 0.20% (2/1018) | 0.00% (0/969) | | Lesion Location | | | | Proximal | 37.43% (381/1018) | 39.32% (381/969) | | Mid | 36.54% (372/1018) | 35.50% (344/969) | | Distal | 22.00% (224/1018) | 19.71% (191/969) | | Ostial | 4.03% (41/1018) | 5.47% (53/969) | | ACC/AHA Lesion Class | | | | A | 5.70% (58/1018) | 5.88% (57/969) | | B1 | 18.96% (193/1018) | 22.08% (214/969) | | B2 | 32.22% (328/1018) | 31.06% (301/969) | | C | 43.12% (439/1018) | 40.97% (397/969) | PMA P210014: FDA Summary of Safety and Effectiveness Data {30} | Baseline Lesion Characteristics | Svelte DES (N=827 Patients N=1018 Lesions) | XIENCE/Promus DES (N=812 Patients N=970 Lesions) | | --- | --- | --- | | Calcification | | | | None/Mild | 65.13% (663/1018) | 63.26% (613/969) | | Moderate | 24.66% (251/1018) | 25.90% (251/969) | | Severe | 10.22% (104/1018) | 10.84% (105/969) | | Bifurcation | 22.79% (232/1018) | 22.39% (217/969) | | Lesion Length (mm) | | | | Mean±SD (N) | 14.88±7.04 (1018) | 14.25±7.52 (969) | | Reference Vessel Diameter (mm) | | | | Mean±SD (N) | 2.78±0.51 (1018) | 2.77±0.50 (969) | | Minimal Lumen Diameter (mm) | | | | Mean±SD (N) | 1.00±0.41 (1018) | 1.00±0.40 (969) | # D. Safety and Effectiveness Results The primary endpoint was a composite that combined measures of both safety and effectiveness. Primary Endpoint: The primary endpoint was not met (Table 15). Non-inferiority of the primary endpoint of target lesion failure (TLF; cardiac death, target vessel MI, or clinically-driven TLR) 12 months following Svelte DES implantation compared to the Control DES group was not demonstrated. The 12-month TLF rate was $10.30\%$ in the Svelte DES group compared to $9.49\%$ in the Control DES group. The difference in rates was $0.81\%$ with a two-sided $95\%$ confidence interval (CI) of $-2.15\%$ to $3.78\%$ . Because the upper bound of this CI is higher than the pre-specified non-inferiority delta of $3.58\%$ , non-inferiority of the Svelte DES to the Control DES with regard to 12-month TLF was not met. Table 15. Analysis of Primary Endpoint and Components at 12-Months | | Svelte DES (N=827 Patients) | XIENCE/Promus DES (N=812 Patients) | All Patients (N=1639 Patients) | Difference [95% Confidence Interval]1 | Non-Inferiority P-Value1 | | --- | --- | --- | --- | --- | --- | | TLF | 10.30% (82/796) | 9.49% (74/780) | 9.90% (156/1576) | 0.81% [-2.15%,3.78%] | 0.034 | | Cardiac Death | 0.25% (2/791) | 0.26% (2/777) | 0.26% (4/1568) | -0.00% [-1.35%,1.34%] | | | Protocol-defined TVMI | 9.43% (75/795) | 8.22% (64/779) | 8.83% (139/1574) | 1.22% [-1.60%,4.04%] | | | Clinically-driven TLR | 1.52% (12/789) | 1.93% (15/777) | 1.72% (27/1566) | -0.41% [-2.06%,1.24%] | | 1 Two-sided $95\%$ confidence interval and non-inferiority p-value for $\pi_{EF} - \pi_C \geq 0.0358$ were calculated from Farrington-Manning test where $\pi_{EF}$ and $\pi_C$ are the true 12-month TLF rates for Svelte DES and the combined control group of XIENCE and Promus DESs, respectively. Cumulative incidence curves for TLF (Kaplan-Meier) from index procedure to 12 months are presented in Figure 6 below. PMA P210014: FDA Summary of Safety and Effectiveness Data {31} ![img-5.jpeg](img-5.jpeg) Figure 6: Cumulative Incidence of TLF to 12 Months (Kaplan-Meier) Examination of Primary Endpoint: The primary endpoint was not met. Additional information is presented below to examine the factors that may have influenced this outcome. ## Poolability of the Control DES data: The two stents comprising the control group (XIENCE and Promus) are considered to have similar performance characteristics and were assumed to be interchangeable during the design of the OPTIMIZE study. To test this assumption, the consistency of results of the primary endpoint across the two control stents was assessed using a prespecified analysis of the primary endpoint separately for Svelte DES vs. each of the control DES. When comparing Svelte DES patients with XIENCE DES patients only, the rate of 12-month TLF was 6.57% in the XIENCE DES group (N=563). The difference in rates was 3.79% with two-sided 95% CI of 0.82% to 6.75%. When comparing Svelte DES patients with Promus DES patients only (N=190), the rate of 12-month TLF was 17.89% in the Promus DES group and the difference in rates was -7.54% with two-sided 95% CI of 12.33% to 2.75%. Additional prespecified consistency analyses using a logistic regression model and Cox proportional hazards regression model identified the type of control DES to be a statistically significant predictor of 12-month TLF, indicating the primary endpoint rates were not homogenous between the two control DES groups. As discussed below, this unexpected difference between the control stents is explained by an imbalance in the biomarkers used to adjudicate TVMI and does not reflect a true difference in performance. ## Potential Role of Biomarkers While cardiac death and TLR were similar and at the low end of the expected range across randomized treatment groups, rates of TVMI were higher than the expected rate of 5% (9.4% Svelte DES vs 8.2% control DES), with 90% of all TVMI occurring peri-procedurally. TVMI varied widely by biomarker used for detection but was similar across treatment groups, although the Promus DES group unexpectedly displayed far higher rates of TVMI than the XIENCE DES group (16.9% vs 5.3%). Per protocol definition, TVMI was preferentially assessed using CK-MB, then total CK, with troponin allowed when CK-MB or total CK was not available. Because troponin is known to be a more PMA P210014: FDA Summary of Safety and Effectiveness Data Page 32 of 55 {32} sensitive marker, the percentage of patients evaluated using each biomarker was assessed as follows: - CK-MB was used in 837 patients (53%); 25 (3.0%) met criteria for MI (&gt;3X ULN); - Total CK was used in 331 patients (21%); 3 (0.9%) met criteria for MI (&gt;2X ULN); - Troponin I was used in 335 patients (21%); 104 (31%) met criteria for MI (&gt;3X ULN); - Troponin T was used in 63 patients (4%); 6 (9.5%) met criteria for MI (&gt;3X ULN). Troponin I or troponin T was used to diagnose TVMI in 25% of all study patients; this group contributed 80% of all protocol-defined TVMI observed. The rates of MI in EVOLVE II were used to set the expected MI rates for OPTIMIZE. However, although both studies preferentially assessed MI using CK-MB, troponin use in OPTIMIZE was far higher – 25% vs 1% – reflecting the increased use of troponin in clinical practice since the EVOLVE II study was conducted. The incidence of TVMI within the control DES group varied by DES (XIENCE, 5.3% vs. Promus, 17.2%). Retrospective analysis revealed that this difference was driven by biomarker type used to identify MI. Specifically, a high enrolling study site only used troponin assays and Promus DES as the control device and had a 12-month protocol-defined TVMI rate of 44.9% (40.9% Svelte DES vs. 48.9% control DES [Promus]) for the study. This one site resulted in the diagnosis of 22 of the 59 peri-procedural MIs in the control DES group and is also responsible for the statistical heterogeneity observed between the two control stents. **Post-hoc Exploratory Analyses:** Unexpectedly high rates of TVMI in both treatment groups appeared driven by the increased use of troponin compared to EVOLVE II, coupled with a low threshold MI study definition, effectively underpowering the study. Rates of TLF in both treatment groups exceeded the estimates used to power the study and the analysis for non-inferiority did not reach the required pre-specified level of statistical significance (p=0.025). The fixed non-inferiority margin (NIM) of 3.58% that was chosen based on the TLF estimate of 6.5% resulted in loss of statistical power. For this reason, the applicant conducted additional post-hoc analyses to assess non-inferiority of the Svelte DES to the control DES. Please note that these statistics should be interpreted with caution as these analyses were not pre-specified. They are presented here to add additional context to the approval decision. **Relative Risk Analysis** The OPTIMIZE study statistical analysis plan specified an absolute/fixed non-inferiority margin of 3.58%. Because TLF rates in both arms were higher than estimated, many more patients would have needed to be enrolled in the study for adequate statistical power to demonstrate non-inferiority. To examine whether using a relative margin would have changed the study outcome, a relative risk (RR) assessment was conducted. This PMA P210014: FDA Summary of Safety and Effectiveness Data Page 33 of 55 {33} analysis compared the maximum RR estimate established during study design (TLF estimate + NIM/TLF estimate [(6.5+3.58)/6.5=1.55]) with that observed in the OPTIMIZE study (RR=1.09, 95% CI [0.81-1.46]). Had the OPTIMIZE study been designed with a relative margin, non-inferiority of the Svelte DES compared with the control DES for 12-month TLF would have been demonstrated (P_NI=0.009). ## Increased Troponin Assumption Analysis When the OPTIMIZE study was designed, the assumed TLF rate was based on data where CK-MB or total CK was used to assess 99% of patients; however, during the actual trial 25% of patients were assessed using the more sensitive troponin marker. To examine whether an assumed TLF rate based on contemporary biomarker use would have changed the study outcome, a new assumed literature-derived TVMI rate was estimated based on diagnostic assessment using CK-MB or total CK in 75% and troponin in 25% of study patients. MI diagnosis based on CK-MB &gt;3X ULN was therefore estimated at 4-7% and MI diagnosis based on troponin &gt;3X ULN was estimated at 15-20%. In this analysis, the assumed TLF rate was 10.5% (95% CI 8.75%-12.25%) with an updated absolute NIM of 4.37% chosen to maintain 80% statistical power. This analysis demonstrated that had the OPTIMIZE success criteria accounted for increased troponin use, non-inferiority of the Svelte DES compared with the control DES for 12-month TLF would have been demonstrated (P_NI=0.010). ## Alternative MI Definitions Analyses The MI definition used in the OPTIMIZE study was relatively sensitive compared to other contemporary definitions. To examine whether alternative definitions of MI would have changed the study outcome, analyses for non-inferiority of 12-month TLF using the SCAI and 4th Universal definitions of MI, which take into account and accommodate troponin levels used in the assessment of peri-procedural MI, were performed. An independent CEC separately adjudicated all biomarker values through 12 months under the SCAI and 4th Universal definitions of MI. Applying the SCAI definition of MI, 12-month TLF was 3.66% and 3.33% for the Svelte DES and Control DES groups, respectively. Applying the 4th Universal definition of MI, 12-month TLF was 4.04% and 2.95% for the Svelte DES and Control DES groups, respectively. Assuming the CEC was able to make accurate post-hoc adjudications, if the OPTIMIZE trial had used either the SCAI or 4th Universal definitions of MI, non-inferiority of the Svelte DES compared with the Control DES would have been demonstrated. All post-hoc analyses are summarized in Table 16. Table 16. Post-hoc Assessments of Non-Inferiority of 12-Month TLF | OPTIMIZE Study Endpoint Analysis | Svelte DES (N=827 Patients) | Control DES (N=812 Patients) | Non-Inferiority | Difference or Relative Risk [95% Confidence Interval] 1 | Non-Inferiority P value1 | | --- | --- | --- | --- | --- | --- | | TLF: MI per protocol definition | 10.30% (82/796) | 9.49% (74/780) | Absolute Margin 3.58% | 0.81% [-2.15%, 3.78%] | 0.034 | | 1) TLF: Protocol-defined MI with relative NIM | 10.30% (82/796) | 9.49% (74/780) | Relative Margin 1.55% | 1.09% [0.81%, 1.46%] | 0.009 | PMA P210014: FDA Summary of Safety and Effectiveness Data Page 34 of 55 {34} PMA P210014: FDA Summary of Safety and Effectiveness Data Page 35 of 55 | 2) | TLF: Protocol-defined MI with troponin-adjusted absolute NIM | 10.30% (82/796) | 9.49% (74/780) | Absolute Margin 4.37% | 0.81% [-2.17%, 3.79%] | 0.010 | | --- | --- | --- | --- | --- | --- | --- | | 3) | TLF: MI per SCAI definition | 3.66% (29/793) | 3.33% (26/780) | Absolute Margin 3.58% | 0.32% [-1.64%, 2.29%] | <0.001 | | 4) | TLF: MI per 4^{th} Universal definition | 4.04% (32/793) | 2.95% (23/779) | Absolute Margin 3.58% | 1.08% [-0.85%, 3.01%] | 0.006 | Two-sided 95% confidence interval and non-inferiority p-value were calculated from Farrington-Manning test. # 1. Safety Results The analysis of safety was based on the ITT cohort of 1639 patients available for the 12-month evaluation. Key safety outcomes are presented in Table 17. Adverse events are reported in Tables 18 and 19. Safety endpoint rates were very similar across treatment groups. ARC definite/probable stent thrombosis was very low, occurring in 3 patients in both treatment groups. The only endpoint that numerically favored the control group was TVMI; this difference is relatively slight. Table 17. Summary of Safety Endpoints | Event | Svelte DES (n=827) | XIENCE/Promus DES (n=812) | | --- | --- | --- | | IN-HOSPITAL EVENTS | | | | Death | 0.00% (0/822) | 0.00% (0/809) | | Target Vessel MI | 7.91% (65/822) | 7.42% (60/809) | | 12-MONTH EVENTS | | | | Death | 0.75% (6/795) | 1.15% (9/783) | | Cardiac death | 0.25% (2/791) | 0.26% (2/777) | | Non-cardiac death | 0.50% (4/793) | 0.90% (7/781) | | Target Vessel MI | 9.43% (75/795) | 8.22% (64/779) | | STENT THROMBOSIS (ARC DEFINITE/PROBABLE) | | | | Any, all timepoints | 0.38% (3/791) | 0.39% (3/776) | | Acute (≤24 hours) | 0.12% (1/822) | 0.12% (1/809) |…
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