XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary

Q: Who is the manufacturer of XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary?

Abbott Vascular filed the PMA application for XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary (P110019S115).

Q: What is the FDA product code for XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary?

NIQ. as a Class 3 device in the Cardiovascular panel.

Q: Who can help prepare an FDA PMA submission like XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA PMA submissions. See https://innolitics.com/services/regulatory/ or contact https://innolitics.com/contact.

P110019S115 · Abbott Vascular · NIQ · Jun 25, 2021 · Cardiovascular

Device Facts

Record ID	P110019S115
Device Name	XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary
Applicant	Abbott Vascular
Product Code	NIQ · Cardiovascular
Decision Date	Jun 25, 2021
Decision	APPR
Device Class	Class 3
Attributes	Therapeutic, Real-World Evidence

Real-World Evidence

Submission	Device	Sponsor	RWD Sources	RWE Use Summary	Key Tags
P110019S115 · Jun 25, 2021	XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary	Abbott Vascular	XIENCE V USA post-approval study (real-world clinical cohort)	The XIENCE V USA historical control cohort, representing real-world clinical practice, was used as a comparator for propensity-score-adjusted analyses of safety and effectiveness endpoints in the XIENCE 90 and XIENCE 28 trials.	Historical control; Propensity score adjustment; Real-world setting; Post-approval study

Clinical Evidence

Study Design	Population	Comparator	Key Endpoints
XIENCE V USA historical control; Retrospective analysis of a post-approval study cohort; Follow-up/Duration: Up to 12 months; Study Period: Historical (study completed in 2012)	Non-complex high bleeding risk (HBR) subjects treated with DAPT duration of up to 12 months; Sample Size: 1280 (3-month clear subjects)	XIENCE 90 trial arm	All death/all MI, BARC 2-5 bleeding
XIENCE V USA historical control; Retrospective analysis of a post-approval study cohort; Follow-up/Duration: Up to 6 months; Study Period: Historical (study completed in 2012)	Non-complex high bleeding risk (HBR) subjects treated with DAPT duration of up to 12 months; Sample Size: 1411 (1-month clear subjects)	XIENCE 28 trial arm	All death/all MI, BARC 2-5 bleeding

Indications for Use

The XIENCE [Alpine / Sierra / Skypoint] stent system is indicated for improving coronary artery luminal diameter in patients, including those at high risk for bleeding and those with diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm. In addition, the XIENCE [Alpine / Sierra / Skypoint] stent system is indicated for treating de novo chronic total coronary occlusions.

Device Story

Drug-eluting coronary stent system; consists of balloon-expandable L-605 cobalt-chromium stent coated with everolimus in non-erodible polymer (PBMA/PVDF-HFP). Delivered via rapid-exchange (RX) or over-the-wire (OTW) catheter. Used in cardiac catheterization labs by interventional cardiologists to treat coronary artery disease. Stent expands to improve luminal diameter; everolimus inhibits cell proliferation to reduce restenosis. Output is physical vessel support and localized drug delivery. Clinical benefit includes reduced angina and improved quality of life for patients with symptomatic coronary lesions, including those at high bleeding risk requiring shorter dual antiplatelet therapy (DAPT) durations.

Clinical Evidence

Prospective, single-arm, multi-center trials (XIENCE 90, N=2047; XIENCE 28, N=1605). Primary endpoint: composite of all death or all MI (modified ARC). XIENCE 90 (3-month DAPT) met non-inferiority vs. historical control (5.4% vs 5.4%, p=0.0063). XIENCE 28 (1-month DAPT) met non-inferiority vs. historical control (3.5% vs 4.3%, p=0.0005). Stent thrombosis rates were low (0.2%-0.3%).

Technological Characteristics

Stent: L-605 cobalt-chromium alloy. Coating: Everolimus (100 µg/cm²) in non-erodible PBMA and PVDF-HFP polymer. Delivery system: Balloon-expandable, RX or OTW configurations. Rated burst pressure 16-18 atm. Shelf life 24-36 months. Sterilization: Not specified.

Indications for Use

Indicated for patients, including those at high bleeding risk and with diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) and reference vessel diameters 2.25-4.25 mm, including de novo chronic total coronary occlusions.

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

XIENCE V EECSS (P070015)
XIENCE Alpine EECSS (P110019/S070)
XIENCE Sierra EECSS (P110019/S094)
XIENCE Skypoint (P110019/S113)

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: | XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS) XIENCE Sierra Everolimus Eluting Coronary Stent Systems (XIENCE Sierra EECSS) XIENCE Skypoint Everolimus Eluting Coronary Stent Systems (XIENCE Skypoint EECSS) | | Device Procode: | NIQ | | Applicant's Name and Address: | Abbott Vascular 3200 Lakeside Drive Santa Clara, California 95054 | | Date of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P110019/S115 | | Date of FDA Notice of Approval: | 6/25/2021 | The first XIENCE Everolimus Eluting Coronary Stent System PMAs (P070015 and P110019) were originally approved on July 2, 2008 and November 1, 2011. The XIENCE [Alpine / Sierra / Skypoint] stent system is indicated for improving coronary artery luminal diameter in patients, including those with diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm. Additionally, the XIENCE [Alpine / Sierra / Skypoint] system is indicated for treating de novo chronic total coronary occlusions. The SSED documents to support the indications are available on the following FDA websites and are incorporated by reference herein: - P110019: https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110019b.pdf - P110019/S066: https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110019S066B.pdf - P110019/S075: https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110019S075B.pdf PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 1 {1} The current supplement was submitted to expand the indication for the XIENCE Alpine, XIENCE Sierra, and XIENCE Skypoint Everolimus Eluting Coronary Stent Systems to include patients at high bleeding risk (HBR). Hereafter, the XIENCE Alpine, XIENCE Sierra, and XIENCE Skypoint Everolimus Eluting Coronary Stent Systems are referred to as the XIENCE family of stents. ## II. INDICATIONS FOR USE The XIENCE [Alpine / Sierra / Skypoint] stent system is indicated for improving coronary artery luminal diameter in patients, including those at high risk for bleeding and those with diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm. In addition, the XIENCE [Alpine / Sierra / Skypoint] stent system is indicated for treating de novo chronic total coronary occlusions. ### III. CONTRAINDICATIONS The XIENCE [Alpine / Sierra / Skypoint] stent system is contraindicated for use in: - Patients who cannot tolerate, including allergy or hypersensitivity to, procedural anticoagulation or the post-procedural antiplatelet regimen - Patients with hypersensitivity or contraindication to everolimus or structurally related compounds, or known hypersensitivity to stent components (cobalt, chromium, nickel, tungsten, methacrylic polymer, and fluoropolymer), or with contrast hypersensitivity. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in XIENCE [Alpine / Sierra / Skypoint] respective labeling. ### V. DEVICE DESCRIPTION The XIENCE family of stents are device/drug combination products consisting of a drug-coated stent and a balloon expandable delivery system. The stent is coated with a formulation containing everolimus, the active ingredient, embedded in a non-erodible polymer. The XIENCE family of stents are balloon-expandable stents made of L-605 cobalt chromium (CoCr) with a poly(n-butyl methacrylate) (PBMA) and copolymer vinylidene fluoride and hexafluoropropylene (PVDF-HFP)/everolimus coating. The XIENCE Alpine delivery catheter is available in two configurations, a rapid-exchange (RX) and an over-the-wire (OTW) co-axial design with the balloon and stent at the distal end of the catheter. The XIENCE Sierra and XIENCE Skypoint delivery catheters are available in a rapid-exchange (RX) design. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 2 {2} The characteristics of the XIENCE family of stents are described in **Table 1**. **Table 1. XIENCE Family of Stents Product Description** | | XIENCE Alpine | XIENCE Sierra | XIENCE Skypoint | | --- | --- | --- | --- | | Available Stent Lengths (mm) | 8, 12, 15, 18, 23, 28, 33, 38 | | | | Available Stent Diameters (mm) | 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 4.0 | | | | Stent Material | A medical grade L-605 cobalt chromium (CoCr) alloy | | | | Drug Component | A conformal (all surfaces of the stent) coating of a non-erodible polymer loaded with 100 µg/cm^{2} of everolimus with a maximum nominal drug content of 232 µg on the large stent (4.0 x 38 mm) | A conformal coating of a non-erodible polymer loaded with 100 µg/cm^{2} of everolimus with a maximum nominal drug content of 236 µg on the large stent (4.0 x 38 mm) | | | **Delivery System** | | | | | Delivery System Working Length | 145 cm | | | | Delivery System Design | RX: Single access port to inflation lumen; guide wire exit notch is located 25.5 cm from tip; designed for guide wires ≤ 0.014'. OTW: Sidearm adaptor provides access to balloon inflation / deflation lumen and guide wire lumen; designed for guide wires ≤ 0.014'. | RX: Single access port to inflation lumen; guide wire exit notch is located 25.5 cm from tip; designed for guide wires ≤ 0.014'. | | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 3 {3} | | XIENCE Alpine | | XIENCE Sierra | | XIENCE Skypoint | | | --- | --- | --- | --- | --- | --- | --- | | Stent Delivery System Balloon | A compliant, tapered balloon, with two radiopaque markers located on the catheter shaft to indicate balloon positioning and expanded stent length | | | | | | | Balloon Inflation Pressure | Rated Burst Pressure (RBP): 18 atm (1824 kPa) | | Rated Burst Pressure (RBP): 16 atm (1621 kPa) | | | | | | **Stent Diameter (mm)** | **In vitro Stent Nominal Pressure (atm)** | **Stent Diameter (mm)** | **In vitro Stent Nominal Pressure (atm)** | **Stent Diameter (mm)** | **In vitro Stent Nominal Pressure (atm)** | | | 2.25 | 10 | 2.25 | 9 | 2.25 | 9 | | | 2.5 | 10 | 2.5 | 9 | 2.5 | 9 | | | 2.75 | 10 | 2.75 | 12 | 2.75 | 12 | | | 3.0 | 10 | 3.0 | 12 | 3.0 | 12 | | | 3.25 | 10 | 3.25 | 12 | 3.25 | 12 | | | 3.5 | 10 | 3.5 | 12 | 3.5 | 12 | | | 4.0 | 10 | 4.0 | 12 | 4.0 | 12 | | Minimum Guiding Catheter Inner Diameter | 2.25 – 3.5 mm Stent Diameters 5 F (0.056” / 1.42 mm ID) 4.0 Stent Diameter, 8 – 33 mm lengths 5 F (0.056” / 1.42 mm ID) 4.0 Stent Diameter, 38 mm length 6 F (0.066” / 1.68 mm ID) | | 2.25 – 4.0 mm Stent Diameters 5 F (0.056” / 1.42 mm ID) | | | | | Catheter Shaft Outer Diameter | Distal: 0.034” (0.86 mm) Proximal (RX): 0.029” (0.74 mm) Proximal (OTW): 0.045” (1.14 mm) | | Distal: 0.037” (0.94 mm) Proximal (RX): 0.029” (0.74 mm) | | Mid Shaft: 0.039” (0.99 mm) Proximal Shaft (RX): 0.029” (0.74 mm) | | | Shelf Life | 36 months | | 24 months | | | | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 4 {4} # A. Device Component Description The XIENCE family of stents are fabricated from a single piece of medical grade L-605 CoCr alloy tubing. The stents include two designs – small and medium. The small and medium designs of the XIENCE family of stents all have 3 links connecting adjacent rings. Each link has an undulating portion called a “non-linear link” which provides flexibility to the stent in the longitudinal direction. In order to allow for different expansion ranges, each design varies the number of short and long crests per ring. - Small stent design: 2.25 mm, 2.50 mm, 2.75 mm, 3.00 mm and 3.25 mm - Medium stent design: 3.50 mm and 4.00 mm The commercial matrix is shown in Table 2 below. Table 2. U.S. Commercial Matrix for XIENCE Alpine, Sierra, and Skypoint | Stent Design | Product Diameter (mm) | Maximum Post Dilatation Expansion Diameter (mm) | Product Length (mm) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | 08 | 12 | 15 | 18 | 23 | 28 | 33 | 38 | | Small | 2.25 | 3.25^{2} 3.75 | √ | √ | √ | √ | √ | √ | √^{1} | √^{1} | | | 2.50 | | √ | √ | √ | √ | √ | √ | √ | √ | | | 2.75 | | √ | √ | √ | √ | √ | √ | √ | √ | | | 3.00 | | √ | √ | √ | √ | √ | √ | √ | √ | | | 3.25 | | √ | √ | √ | √ | √ | √ | √ | √ | | Medium | 3.50 | 4.50 (XIENCE Alpine) | √ | √ | √ | √ | √ | √ | √ | √ | | | 4.00 | 5.50 (XIENCE Sierra) 5.75 (XIENCE Skypoint) | √ | √ | √ | √ | √ | √ | √ | √ | $^{1}$ XIENCE Alpine stent diameter 2.25 mm is not available in 33 mm and 38 mm length $^{2}$ 3.25 mm maximum post dilatation expansion diameter is for XIENCE Alpine 2.25 mm and 2.5 mm diameter only # B. Drug Component Description The XIENCE family of stents are coated with everolimus (active ingredient) embedded in a non-erodible polymer (inactive ingredient). # 1. Everolimus Everolimus is the active pharmaceutical ingredient in the XIENCE family of stents. The everolimus chemical name is 40-O-(2-hydroxyethyl)-rapamycin and the chemical structure is shown in Figure 1. The nominal everolimus content per nominal stent length/diameter is shown in Table 3. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 5 {5} ![img-0.jpeg](img-0.jpeg) Figure 1. Everolimus Chemical Structure Table 3. Nominal Everolimus Content (μg) per Nominal Stent Length and Diameter | Stent Design | Diameters (mm) | Stent Length (mm) | XIENCE Alpine Nominal Drug Amount (μg) | XIENCE Sierra Nominal Drug Amount (μg) | XIENCE Skypoint Nominal Drug Amount (μg) | | --- | --- | --- | --- | --- | --- | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 8 | 40 | 39 | 39 | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 12 | 60 | 58 | 58 | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 15 | 74 | 72 | 72 | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 18 | 88 | 85 | 85 | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 23 | 109 | 111 | 111 | | Small | 2.25, 2.5, 2.75, 3.0, 3.25 | 28 | 137 | 131 | 131 | | Small | 2.25*, 2.5, 2.75, 3.0, 3.25 | 33 | 157 | 157 | 157 | | Small | 2.25*, 2.5, 2.75, 3.0, 3.25 | 38 | 185 | 177 | 177 | | Medium | 3.5, 4.0 | 8 | 50 | 53 | 53 | | Medium | 3.5, 4.0 | 12 | 75 | 72 | 72 | | Medium | 3.5, 4.0 | 15 | 91 | 99 | 99 | | Medium | 3.5, 4.0 | 18 | 116 | 117 | 117 | | Medium | 3.5, 4.0 | 23 | 141 | 145 | 145 | | Medium | 3.5, 4.0 | 28 | 174 | 181 | 181 | | Medium | 3.5, 4.0 | 33 | 199 | 209 | 209 | | Medium | 3.5, 4.0 | 38 | 232 | 236 | 236 | *XIENCE Alpine stent diameter 2.0 mm and 2.25 mm are not available in 33 mm and 38 mm length ## 2. Inactive Ingredients The XIENCE family of stents contain inactive ingredients, including poly n-butyl methacrylate (PBMA), a polymer that adheres to the stent and drug coating, and PVDF- PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 6 {6} HFP, which is comprised of vinylidene fluoride and hexafluoropropylene monomers as the drug matrix layer containing everolimus. PBMA is a homopolymer with a molecular weight (MW) of 264,000 to 376,000 daltons. PVDF-HFP is a non-erodible semicrystalline random copolymer with a molecular weight (MW) of 254,000 to 293,000 daltons. The drug matrix copolymer is mixed with everolimus (83%/17% w/w polymer/everolimus ratio) and applied to the entire PBMA-coated stent surface. The drug load is 100 μg/cm² for all product sizes. No topcoat layer is used. The polymer chemical structures are shown in Figure 2 below. PBMA ![img-1.jpeg](img-1.jpeg) PVDF-HFP ![img-2.jpeg](img-2.jpeg) Figure 2. Non-erodible Polymer Chemical Structures # 3. Mechanism of Action of Everolimus On a cellular level, everolimus inhibits, in a reversible manner, growth factor-stimulated cell proliferation. On a molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, the growth factor-stimulated phosphorylation of p70 S6 kinase and 4E-BP1 is inhibited. The latter proteins are key proteins involved in the initiation of protein synthesis. Since phosphorylation of both p70 S6 kinase and 4E-BP1 is under the control of FRAP (FKBP-12-rapamycin associated protein, also called mTOR, mammalian target of rapamycin) this finding suggests that the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein that governs cell metabolism, growth, and proliferation. Disabling FRAP function explains the cell cycle arrest at the late G1 stage caused by everolimus. # 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 bare metal stents, coated stents, and other drug eluting 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. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 7 {7} ## VII. MARKETING HISTORY ### US Marketing History XIENCE Alpine Everolimus Eluting Coronary Stent System (EECSS) received PMA approval on September 3, 2014 under P110019/S070. XIENCE Sierra EECSS received PMA approval on May 22, 2018 under P110019/S094. XIENCE Skypoint received PMA approval on May 13, 2021 under P110019/S113. ### International Marketing/Outside the US (OUS) History XIENCE Alpine EECSS was commercially available in OUS markets as of October 2014. XIENCE Sierra EECSS was commercially available OUS as of October 2017. XIENCE Skypoint was approved in Japan on October 6, 2020. **Table 4** lists countries where the XIENCE Alpine and Sierra are currently commercially available. XIENCE Skypoint is currently only available in the U.S. and Japan. The XIENCE family of stents have not been withdrawn from either U.S. or international marketing for any reason related to its safety or effectiveness. **Table 4. Countries with XIENCE Alpine and Sierra Commercial Availability** | Argentina | Albania* | Algeria* | Amer.Virgin Is. | | --- | --- | --- | --- | | Armenia | Aruba | Australia | Austria | | Bahrain | Bangladesh* | Barbados | Belarus* | | Belgium | Brazil | Brunei Darussalam* | Bulgaria | | Canada | Chile | China | Colombia* | | Costa Rica | Croatia | Cyprus* | Czech Republic | | Denmark | Dominican Rep. | Ecuador* | Egypt | | Estonia | Finland | France | French Polynesia | | French Guiana | Georgia | Germany | Greece | | Guadeloupe | Guam | Guatemala* | Hong Kong | | Hungary | Indonesia | Iran | Iraq* | | Ireland | Israel* | Italy | Jamaica | | Japan | Jordan | Kazakhstan* | Kosovo* | | Kuwait | Latvia | Lebanon | Libya* | | Lithuania | Luxembourg | Macedonia | Malaysia | | Malta* | Martinique | Mauritius | Mexico | | Mongolia* | Morocco* | Nepal* | Netherlands | | New Caledonia | New Zealand | Norway | Oman | | Pakistan* | Palestine* | Panama | Peru* | | Philippines** | Poland | Portugal | Qatar | | Reunion | Romania | Russian Federation | Saudi Arabia | | Serbia* | Singapore | Slovakia** | Slovenia | | South Africa | South Korea | Spain | Sri Lanka* | | Sweden | Switzerland | Taiwan | Thailand | | Trinidad & Tobago | Tunisia* | Turkey | Turkmenistan | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 8 {8} | Ukraine* | United Kingdom | Uruguay | United Arab Emir. | | --- | --- | --- | --- | | Venezuela* | Vietnam | Yemen* | | * Countries that have XIENCE Alpine or its rebrands commercialized only ** Countries that have XIENCE Sierra commercialized only ### **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH** Adverse events that may be associated with the use of a stent in native coronary arteries include but are not limited to: - Allergic reaction or hypersensitivity to latex, contrast agent, anesthesia, device materials (cobalt, chromium, nickel, tungsten, methacrylic polymer, and fluoropolymers), and drug reactions to everolimus, anticoagulation, or antiplatelet drugs - Vascular access complications which may require transfusion or vessel repair, including: - Catheter site reactions - Bleeding (ecchymosis, oozing, hematoma, hemorrhage, retroperitoneal hemorrhage) - Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection, perforation/rupture - Embolism (air, tissue, plaque, thrombotic material or device) - Peripheral nerve injury - Peripheral ischemia - Coronary artery complications which may require additional intervention, including: - Total occlusion or abrupt closure - Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection, perforation/rupture - Tissue prolapse/plaque shift - Embolism (air, tissue, plaque, thrombotic material, or device) - Coronary or stent thrombosis (acute, subacute, late, very late) - Stenosis or restenosis - Pericardial complications which may require additional intervention, including: - Cardiac tamponade - Pericardial effusion - Pericarditis - Cardiac arrhythmias - Conduction disorders - Atrial arrhythmia - Ventricular arrhythmia - Cardiac ischemic conditions: - Myocardial ischemia - Myocardial infarction (including acute) - Coronary artery spasm - Unstable or stable angina pectoris PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 9 {9} - Neurologic complications: o Stroke/Cerebrovascular Accident (CVA) o Transient Ischemic Attack (TIA) - System organ failures: o Cardio-respiratory arrest o Cardiac failure o Cardiopulmonary failure (including pulmonary edema) o Renal insufficiency/failure o Shock - Bleeding - Blood cell disorders (including heparin induced thrombocytopenia (HIT)) - Hypotension/hypertension - Infection - Nausea and vomiting - Palpitations, dizziness, and syncope - Chest pain - Fever - Death Adverse events associated with daily oral administration of everolimus in doses varying from 1.5 mg to 10 mg daily can be found in the Summary of Product Characteristics (SPC) and labels for the drug¹. The risks described below include the anticipated adverse events relevant for the cardiac population referenced in the contraindications, warnings and precaution sections of the everolimus labels/SPCs and/or observed at incidences ≥10% in clinical trials with oral everolimus for different indications. Please refer to the drug SPCs and labels for more detailed information and less frequent adverse events. - Abdominal pain - Anemia - Angioedema (increased risk with concomitant ACE inhibitor use) - Arterial thrombotic events - Bleeding and coagulopathy (including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and thrombotic microangiopathy; increased risk with concomitant cyclosporine use) - Constipation - Cough - Diabetes mellitus - Diarrhea - Dyspnea - Embryo-fetal toxicity - Erythema ¹ Certican® UK label 2015, Afinitor® EU authorization SPC 2014, Votubia® EU SPC 2014, Afinitor® US label 2015, and Zortress® US label 2015. Refer to www.MHRA.gov.uk, www.ema.europa.eu, and www.fda.gov for the most recent versions of these SPC/labels. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 10 {10} - Erythroderma - Headache - Hepatic artery thrombosis (HAT) - Hepatic disorders (including hepatitis and jaundice) - Hypersensitivity to everolimus active substance, to other rapamycin derivates - Hypertension - Infections: bacterial, viral, fungal, and protozoan, including infections with opportunistic pathogens. Polyoma virus-associated nephropathy (PVAN), JC virus-associated progressive multiple leukoencephalopathy (PML), fatal infections and sepsis have been reported in patients treated with oral everolimus - Kidney arterial and venous thrombosis - Laboratory test alterations (elevations of serum creatinine, proteinuria, hypokalemia; hyperglycemia, dyslipidemia including hypercholesterolemia and hypertriglyceridemia; abnormal liver function tests; decreases in hemoglobin, lymphocytes, neutrophils, and platelets) - Lymphoma and skin cancer - Male infertility - Nausea - Nephrotoxicity (in combination with cyclosporine) - Non-infectious pneumonitis (including interstitial lung disease) - Oral ulcerations - Pain - Pancreatitis - Pericardial effusion - Peripheral edema - Pleural effusion - Pneumonia - Pyrexia - Rash - Renal failure - Upper respiratory tract infection - Urinary tract infection - Venous thromboembolism - Vomiting - Wound healing complications (including wound infections and lymphocele) Live vaccines should be avoided and close contact with those that have had live vaccines should be avoided. Fetal harm can occur when administered to a pregnant woman. There may be other potential adverse events that are unforeseen at this time. For the specific adverse events that occurred in the XIENCE 90 and XIENCE 28 clinical studies, please see Section X: Summary of Primary Clinical Studies, below. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 11 {11} ## **IX. SUMMARY OF NONCLINICAL STUDIES** A summary of previously reported preclinical studies can be found in the SSED for the original PMA. Because the previously collected data sufficiently represent the performance of the device for the new indications for use, no new non-clinical testing was conducted. ## **X. SUMMARY OF PRIMARY CLINICAL STUDIES** The applicant performed clinical studies to establish a reasonable assurance of safety and effectiveness of the XIENCE family of stents in patients at high bleeding risk (HBR) treated with shorter duration dual antiplatelet therapy (DAPT) in the US under IDE G170081. Data from the XIENCE Short DAPT studies were the basis for the PMA approval decision. A summary of the clinical studies is presented below. The XIENCE 90 trial, which was conducted in the United States, evaluated the safety of 3-month DAPT post-PCI, while the combined population from the XIENCE 28 USA (conducted in United States and Canada) and the XIENCE 28 Global (conducted in Europe and Asia) trials assessed the safety of 1-month DAPT post-PCI. Both XIENCE 28 trials had similar designs, and analysis of the combined population from the two XIENCE 28 trials was pre-specified in the statistical analysis plan (SAP) of the XIENCE 28 USA trial. The analysis of the combined populations from XIENCE 28 USA and XIENCE 28 Global will herein be referred to as “XIENCE 28”. For both XIENCE 90 and XIENCE 28 analyses, the results were compared to XIENCE V USA historical control, a US post-approval study to evaluate the safety and effectiveness of XIENCE V EECSS in an “all-comer” population under a real-world setting, for the primary and secondary endpoints. ### **(1) XIENCE 90 Clinical Trial** #### **A. Study Design** XIENCE 90 is a prospective, single arm, multi-center, open label trial to evaluate the safety of 3-month DAPT in subjects at high risk of bleeding undergoing PCI with the approved XIENCE family of stents. Subjects were considered to be high bleeding risk if, in the opinion of the referring physician, the risk of major bleeding with >3-month DAPT outweighed the benefit and they met one or more of the following criteria: ≥75 years of age; clinical indication for chronic (at least 6 months) or lifelong anticoagulation therapy; history of major bleeding which required medical attention within 12 months of the index procedure; history of stroke (ischemic or hemorrhagic); renal insufficiency (creatinine ≥2.0 mg/dl) or failure (dialysis dependent); systemic conditions associated with an increased bleeding risk (e.g., hematological disorders, including a history of or current thrombocytopenia defined as a platelet count <100,000/mm³, or any known coagulation disorder associated with increased bleeding risk); anemia with hemoglobin < 11g/dl. Subjects were prescribed DAPT (P2Y₁₂ inhibitor + aspirin) between 0-3 months post-procedure. Subjects were considered as PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 12 {12} “3-month clear” and were to discontinue P2Y₁₂ inhibitor at 3 months if they were compliant with the prescribed DAPT and were free from events between 0-3 months (myocardial infarction, repeat coronary revascularization, stroke, or stent thrombosis). Subjects that discontinued P2Y₁₂ inhibitor at 3 months were prescribed aspirin through the end of the study. For the primary endpoint of all death or all MI and the secondary endpoint of BARC² 2-5 bleeding, the primary analysis population for the XIENCE 90 study was the 3-month clear subjects, and these subjects were compared with the 3-month clear population of the historical control of non-complex HBR subjects treated with DAPT duration of up to 12 months from the XIENCE V USA study. For the powered secondary endpoint of stent thrombosis, XIENCE 90 3-month clear subjects were evaluated against a performance goal. For these primary and secondary endpoints, the comparison with the 3-month clear population of the historical control was done after propensity score (PS) adjustment. ### 1. Clinical Inclusion and Exclusion Criteria Enrollment in the XIENCE 90 trial was limited to subjects who met the inclusion criteria listed in Table 5. Subjects were not permitted to enroll in the XIENCE 90 trial if they met any of the exclusion criteria in Table 5. Table 5. XIENCE 90 Trial Enrollment Inclusion and Exclusion Criteria | General Inclusion Criteria | 1. Subject is considered at high risk for bleeding, defined as meeting one or more of the following criteria at the time of registration and in the opinion of the referring physician, the risk of major bleeding with >3 months of DAPT outweighs the benefit: • ≥75 years of age, • clinical indication for chronic (at least 6 months) or lifelong anticoagulation therapy, • history of major bleeding that required medical attention within 12 months of the index procedure, • history of stroke (ischemic or hemorrhagic), • renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure (dialysis dependent), • systemic conditions associated with an increased bleeding risk (e.g., hematological disorders, including a history of or current thrombocytopenia defined as a platelet count <100,000/mm³, or any known coagulation disorder associated with increased bleeding risk), • anemia with hemoglobin <11g/dl. 2. Subject must be at least 18 years of age. 3. Subject or a legally authorized representative must provide written informed consent as approved by the Institutional Review Board | | --- | --- | ² The BARC (Bleeding Academic Research Consortium) classification classifies bleeding events by severity, with BARC 1 being the least severe and BARC 5 being the most severe (fatal bleeding), and BARC 0 being no bleeding. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 13 {13} | | (IRB)/Ethics Committee (EC) of the respective clinical site prior to any study related procedure. 1. Subject is willing to comply with all protocol requirements, including agreement to stop taking P2Y12 inhibitor at 3 months, if eligible per protocol. 2. Subject must agree not to participate in any other clinical trial for a period of one year following the index procedure. | | --- | --- | | General Exclusion Criteria | 1. Subject with an indication for the index procedure of acute ST-segment elevation MI (STEMI). 2. Subject has a known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, P2Y12 inhibitors (clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be adequately pre-medicated. 3. Subject with implantation of another drug-eluting stent (other than XIENCE) within 9 months prior to index procedure. 4. Subject has a known left ventricular ejection fraction (LVEF) <30%. 5. Subject judged by physician as inappropriate for discontinuation from P2Y_{12} inhibitor use at 3 months, due to another condition requiring chronic P2Y_{12} inhibitor use. 6. Subject with planned surgery or procedure necessitating discontinuation of P2Y_{12} inhibitor within 3 months following index procedure. 7. Subject with a current medical condition with a life expectancy of less than 12 months 8. Subject intends to participate in an investigational drug or device trial within 12 months following the index procedure. 9. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year following index procedure. Female subjects of child-bearing potential must have a negative pregnancy test done within 7 days prior to the index procedure per site standard test. **Note:** Female patients of childbearing potential should be instructed to use safe contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, implants, transdermal patches, hormonal vaginal devices, injections with prolonged release.) It is accepted, in certain cases, to include subjects having a sterilised regular partner or subjects using a double barrier contraceptive method. However, this should be explicitly justified in special circumstances arising from the study design, product characteristics and/or study population. 10. Subject is part of a vulnerable population, defined as subject whose willingness to volunteer in a clinical investigation could be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples of populations which may contain vulnerable subjects include: individuals with lack of or loss of autonomy due to immaturity or through mental disability, persons in nursing homes, children, | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 14 {14} | | impoverished persons, subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and those incapable of giving informed consent. Other vulnerable subjects include, for example, members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed forces, and persons kept in detention. 11. Subject is currently participating in another clinical trial that has not yet completed its primary endpoint. | | --- | --- | | Angiographic Inclusion Criteria | 1. Up to three target lesions with a maximum of two target lesions per epicardial vessel. Note: • The definition of epicardial vessels means left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) and their branches. For example, the patient must not have >2 lesions requiring treatment within both the LAD and a diagonal branch in total. • If there are two target lesions within the same epicardial vessel, the two target lesions must be at least 15 mm apart per visual estimation; otherwise this is considered as a single target lesion. 2. Target lesion ≤ 32 mm in length by visual estimation. 3. Target lesion must be located in a native coronary artery with visually estimated reference vessel diameter between 2.25 mm and 4.25 mm. 4. Exclusive use of XIENCE family of stent systems during the index procedure. 5. Target lesion has been treated successfully, which is defined as achievement of a final in-stent residual diameter stenosis of <20% with final TIMI (Thrombolysis in Myocardial Infarction)-3 flow assessed by online quantitative angiography or visual estimation, with no residual dissection NHLBI (National Heart Lung and Blood Institute) grade ≥ type B, and no transient or sustained angiographic complications (e.g., distal embolization, side branch closure), no chest pain lasting >5 minutes, and no ST segment elevation >0.5 mm or depression lasting >5 minutes. | | Angiographic Exclusion Criteria | 1. Target lesion is in a left main location. 2. Target lesion is located within an arterial or saphenous vein graft. 3. Target lesion is restenotic from a previous stent implantation. 4. Target lesion is a total occluded lesion (TIMI flow 0). 5. Target lesion contains thrombus as indicated in the angiographic images (per SYNTAX score thrombus definition). 6. Target lesion is implanted with overlapping stents, whether planned or for bailout. | ## 2. Follow-up Schedule All patients were scheduled to have follow-up examinations at the following time points: 3, 6, and 12 months post index procedure. Study follow-up through 12 months PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 15 {15} is complete. Preoperatively, laboratory assessments were conducted per standard of care (SOC) to determine subject's eligibility for PCI and confirm eligibility for the study. Post-procedure, ECG and cardiac enzyme collection were performed per SOC. Use and compliance of protocol required antiplatelet medication and adverse events and complications were recorded at all visits. The key time points are shown below in the tables summarizing safety and effectiveness. ### 3. Clinical Endpoints # *Primary Endpoint* The primary endpoint is a composite rate of all death or all myocardial infarction (MI, modified ARC³) from 3 to 12 months post index procedure. # *Major Secondary Endpoints* - Major bleeding rate (BARC type 2-5) from 3 to 12 months - Stent thrombosis (ARC definite/probable) from 3 to 12 months # *Other Secondary Endpoints* The following endpoints were assessed from 3 to 12 months: - All death, cardiac death, vascular death, non-cardiovascular death - All MI (modified ARC) and MI attributed to target vessel (TV-MI, modified ARC) - Composite of cardiac death or MI (modified ARC) - All stroke, ischemic stroke and hemorrhagic stroke - Clinically-indicated target lesion revascularization (CI-TLR) - Clinically-indicated target vessel revascularization (CI-TVR) - Target lesion failure (TLF, composite of cardiac death, TV-MI and CI-TLR) - Target vessel failure (TVF, composite of cardiac death, TV-MI and CI-TVR) - Major bleeding defined by the Bleeding Academic Research Consortium (BARC) type 3-5 ³ Modified Academic Research Consortium (ARC) MI definition: clinical or imaging evidence of ischemia (any of the following: clinical symptoms of ischemia, ECG changes indicative of new ischemia – new ST-T changes or new left bundle branch block (LBBB), development of pathological Q waves, imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality) AND elevated cardiac biomarkers (peri-procedural MI within 48 hours after PCI: creatine kinase myocardial band (CK-MB) >3 x URL or Troponin > 3 x URL (Upper Range Limit) with baseline value < URL; peri-procedural MI within 72 hours after CABG: CK-MB >5 x URL or Troponin > 5 x URL with baseline value < URL; Spontaneous MI (> 48h following Percutaneous Coronary Intervention (PCI), > 72h following CABG): CK-MB > URL or Troponin > URL with baseline value < URL). PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 16 {16} # **B. Accountability of PMA Cohort** Between July 19, 2017 and August 9, 2019, 2047 subjects were enrolled in XIENCE 90 from 101 US sites. Of the 2047 subjects, 1693 subjects met the 3-month clear criteria and are the primary analysis group. A total of 274 subjects did not meet the 3-month clear criteria and these subjects were not included in the primary analysis population. At 12 months, 1653 of the 3-month clear subjects completed their visit (97.6%). The subject enrollment and disposition up to 12 months for XIENCE 90 are shown below in **Figure 3**. ![img-3.jpeg](img-3.jpeg) **Figure 3. Subject Enrollment and Disposition** Note: LTFU = Lost to Follow Up PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 17 {17} ### C. Study Population Demographics and Baseline Parameters **Table 6** presents demographics for the primary analysis group (XIENCE 90 3-month clear subjects) and the historical control group (XIENCE V USA 3-month clear subjects). The mean age in the XIENCE 90 3-month clear subjects was 75.25 years and 35.2% were female. Subjects were predominantly white (88.4%) and obese (mean body mass index (BMI) 30.13). Demographics were similar in the XIENCE 90 group and historical control group. **Table 6. XIENCE 90 Primary Analysis Demographics** | | XIENCE 90 3-Month Clear Subjects (N=1693) | XIENCE V USA 3-Month Clear Subjects (N=1280) | | --- | --- | --- | | Age (years) | 75.25 ± 9.29 (1693) (39.0, 98.0) | 72.70 ± 10.26 (1280) (34.9, 100.4) | | Gender | | | | Male | 64.8% (1097/1693) | 59.1% (756/1280) | | Female | 35.2% (596/1693) | 40.9% (524/1280) | | Race | | | | American Indian or Alaska Native | 0.6% (11/1693) | 0.7% (9/1280) | | Asian | 2.2% (37/1693) | 1.3% (17/1280) | | Black or African American | 5.7% (96/1693) | 8.6% (110/1280) | | Hispanic or Latino | 2.7% (45/1689) | 3.2% (41/1280) | | Native Hawaiian or Pacific Islander | 0.3% (5/1693) | 0.3% (4/1280) | | White | 88.4% (1496/1693) | 86.0% (1101/1280) | | Did not wish to disclose | 2.8% (47/1693) | NA | | Not available | 0.1% (1/1693) | 0.3% (4/1280) | | BMI (kg/m^{2}) | 30.13 ± 6.46 (1692) (14.0, 67.4) | 29.52 ± 6.40 (1265) (13.7, 82.1) | | **Note:** Numbers presented here are % (n/N) or mean ± SD (N). | | | **Table 7** shows the baseline clinical characteristics and medical history for the primary analysis group (3-month clear subjects). Thirty-nine percent of XIENCE 90 3-month clear subjects had diabetes, 15.8% had prior MI, and 34.7% presented with an acute coronary syndrome (ACS). In general, baseline clinical characteristics were comparable between the XIENCE 90 and XIENCE V USA 3-month clear subjects. Any imbalances were mitigated after propensity score stratification. **Table 7. XIENCE 90 Primary Analysis Baseline Clinical Characteristics** | | XIENCE 90 3-Month Clear Subjects (N=1693) | XIENCE V 3-Month Clear Subjects (N=1280) | | --- | --- | --- | | Current/Recent Smoker* | 11.6% (197/1693) | 11.9% (144/1210) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 18 {18} | | **XIENCE 90** 3-Month Clear Subjects (N=1693) | **XIENCE V** 3-Month Clear Subjects (N=1280) | | --- | --- | --- | | Diabetes Mellitus | 39.2% (663/1692) | 42.7% (546/1273) | | Diabetic (Medically Treated) | 24.3% (412/1692) | 27.3% (347/1273) | | Diabetic (Insulin Dependent) | 15.6% (264/1692) | 16.5% (210/1273) | | Dyslipidemia | 82.8% (1401/1693) | 90.7% (1140/1257) | | Hypertension | 89.5% (1516/1693) | 91.7% (1167/1272) | | History of Major Bleeding | 2.9% (49/1693) | 2.7% (34/1280) | | Chronic Kidney Disease (eGFR < 60 mL/min) | 40.2% (677/1682) | 44.3% (532/1202) | | History of MI | 15.8% (264/1669) | 30.1% (353/1174) | | Prior CABG | 12.1% (205/1693) | 14.1% (174/1230) | | ACS at Presentation | 34.7% (588/1693) | 33.9% (405/1195) | | NSTEMI | 7.1% (120/1693) | 10.4% (113/1089) | | Unstable angina | 28.7% (486/1693) | 21.6% (257/1190) | | History of Stroke | 10.7% (181/1693) | 12.1% (155/1280) | | PARIS score | 6.0 ± 2.3 (1693) | 5.2 ± 2.2 (1280) | | PRECISE-DAPT score | 26.1 ± 11.5 (1606) | 25.4 ± 10.9 (1154) | eGFR: estimated Glomerular Filtration Rate; CABG: Coronary Artery Bypass Graft; NSTEMI: Non-ST Elevation Myocardial Infarction * In XIENCE 90, “current/recent smoker” is defined as actively smoking or quit < 1 year ago. In XIENCE V USA “current/recent smoker” is defined as actively smoking or quit < 1 month ago. Key Baseline Lesion Characteristics: In XIENCE 90 three-month clear subjects, visually estimated mean reference vessel diameter was 2.99 ± 0.49 mm, mean lesion length was 16.0 ± 7.1 mm, and mean percent diameter stenosis was 83.7 ± 10.3%. The target lesion location distribution is generally reflective of patients presenting for PCI with approximately 43% in the LAD, 25% in the LCX, and 32% in the RCA. Approximately one third of lesions were classified as complex (B2/C). Additional baseline lesion characteristics can be found in Table 8. Table 8. XIENCE 90 Primary Analysis Baseline Lesion Characteristics | | **XIENCE 90** 3-Month Clear (N=1693 Subjects N=2078 Lesions) | **XIENCE V USA** 3-Month Clear (N=1280 Subjects N=1668 Lesions) | | --- | --- | --- | | **Pre-Procedure** | | | | Target Vessel | | | | LAD | 43.2% (898/2078) | 42.8% (711/1661) | | LCX | 24.7% (513/2078) | 24.9% (414/1661) | | RCA | 32.0% (665/2078) | 32.3% (536/1661) | | Left Main | 0.1% (2/2078) | 0.0% (0/1661) | | Mean lesion length (mm) | 16.0 ± 7.1 (2078) | 14.3 ± 6.2 (1579) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 19 {19} | | **XIENCE 90 3-Month Clear (N=1693 Subjects N=2078 Lesions)** | **XIENCE V USA 3-Month Clear (N=1280 Subjects N=1668 Lesions)** | | --- | --- | --- | | Mean RVD (mm) | 2.99 ± 0.49 (2078) | 2.97 ± 0.43 (1589) | | % Diameter Stenosis (DS) | 83.7 ± 10.3 (2078) | 82.8 ± 10.6 (1661) | | TIMI flow | | | | 0 | 0.1% (2/2078) | 0.0% (0/1598) | | 1 | 1.3% (28/2078) | 1.7% (27/1598) | | 2 | 11.3% (235/2078) | 11.5% (184/1598) | | 3 | 87.2% (1813/2078) | 86.8% (1387/1598) | | B2/C lesion | 32.1% (667/2078) | 46.2% (658/1425) | | Thrombus | 0.1% (2/2078) | NA | | Bifurcation | 6.6% (138/2078) | 8.7% (145/1666) | | **Post-Procedure** | | | | TIMI Flow of 3 | 100.0% (2078/2078) | NA | | % DS | 0.44 ± 2.12 (2078) | 0.90 ± 3.68 (1662) | | Dissection | 0.18% (3/1693) | NA | | Perforation | 0.05% (1/1693) | NA | **Key Procedural Characteristics:** The majority of the XIENCE 90 3-month clear subjects had 1 lesion treated (80.2%) and 1 vessel treated (89.7%). In addition, most subjects had 1 stent implanted (79.1%). Additional procedural characteristics can be found in **Table 9**. **Table 9. XIENCE 90 Primary Analysis Procedural Characteristics** | | **XIENCE 90 3-Month Clear Subjects (N=1693 Subjects) N=2078 Lesions N=2119 Stents)** | **XIENCE V USA 3-Month Clear Subjects (N=1280 Subjects N=1668 Lesions N=1822 Stents)** | | --- | --- | --- | | Number of Lesions Treated/Subject | 1.2 (1693) | 1.3 (1280) | | 1 | 80.2% (1358/1693) | 74.0% (947/1280) | | 2 | 16.9% (286/1693) | 21.7% (278/1280) | | 3 or more | 2.9% (49/1693) | 4.3% (55/1280) | | Number of Vessels Treated/Subject | 1.1 (1693) | 1.1 (1274) | | 1 | 89.7% (1518/1693) | 88.3% (1125/1274) | | 2 | 10.0% (170/1693) | 11.5% (147/1274) | | 3 | 0.3% (5/1693) | 0.2% (2/1274) | | Number of Stents Placed/Subject | 1.25 (1693) | 1.42 (1280) | | 1 | 79.1% (1339/1693) | 66.6% (852/1280) | | 2 | 17.1% (289/1693) | 25.9% (332/1280) | | 3 or more | 3.8% (65/1693) | 7.5% (96/1280) | | Stent Type | | | | XIENCE Sierra | 66.4% (1406/2119) | 0.0% (0/1822) | | XIENCE Alpine | 33.6% (711/2119) | 0.0% (0/1822) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 20 {20} | | **XIENCE 90** **3-Month Clear Subjects** **(N=1693 Subjects)** **N=2078 Lesions** **N=2119 Stents)** | **XIENCE V USA** **3-Month Clear Subjects** **(N=1280 Subjects)** **N=1668 Lesions** **N=1822 Stents)** | | --- | --- | --- | | XIENCE V | 0.0% (0/2119) | 100.0% (1822/1822) | | Stents Other than XIENCE | 0.1% (2/2119) | 0.0% (0/1822) | | Total XIENCE Stent Length (mm)/Subject | 20.4 ± 7.7 (2117) | 17.6 ± 6.0 (1821) | **HBR Characteristics of Patients Enrolled in XIENCE 90: Table 10** below provides an overview of the study HBR criteria met by all registered subjects. The mean number of HBR criteria met per XIENCE 90 subject was 1.5 ± 0.7. The most common HBR criteria met were age ≥ 75 years (65.6% of all XIENCE 90 subjects) and the need for chronic or lifelong oral anticoagulation (40.8% of all XIENCE 90 subjects). Most of the HBR criteria in XIENCE 90 are comparable with the XIENCE V USA historical control arm, with the exception of “Clinical Indication for Chronic or Lifelong Anticoagulation Therapy” (40.8% for XIENCE 90 vs. 10.7% for XIENCE V USA control) and “Renal Insufficiency (Creatinine ≥ 2.0 mg/dl) or Failure (Dialysis Dependent)” (9.0% for XIENCE 90 vs. 30.2% for the XIENCE V USA control arm). These imbalances may reflect the PCI subject baseline demographic shift and the change in site standard of care over time since the XIENCE V USA study was completed in 2012. The imbalances in baseline characteristics were mitigated after the subjects were stratified based on their propensity scores. **Table 10. XIENCE 90 Subjects Meeting One or More of the HBR Inclusion Criteria** | **HBR Inclusion Criteria** | **XIENCE 90** **All Registered** **(N = 2047)** | **XIENCE 90** **3-Month Clear** **(N = 1693)** | **XIENCE V** **USA 3-Month** **Clear** **(N=1280)** | | --- | --- | --- | --- | | **Patients satisfying one or more of the following criteria:** | | | | | ≥ 75 years of age | 65.6% (1342/2047) | 66.5% (1125/1693) | 55.3% (708/1280) | | ≥ 75 years of age only (and no other criteria met) | 35.5% (727/2047) | 36.5% (618/1693) | 38.5% (493/1280) | | Clinical indication for chronic or lifelong anticoagulation therapy | 40.8% (836/2047) | 41.6% (705/1693) | 12.5% (160/1280) | | History of major bleeding which required medical attention within 12 months of the index procedure | 2.9% (60/2047) | 2.9% (49/1693) | 2.7% (34/1280) | | History of stroke (ischemic or hemorrhagic) | 11.3% (232/2047) | 10.7% (181/1693) | 12.1% (155/1280) | | Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure (dialysis dependent) | 8.0% (164/2047) | 7.7% (131/1693) | 29.9% (383/1280) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 21 {21} | **HBR Inclusion Criteria** | **XIENCE 90 All Registered (N = 2047)** | **XIENCE 90 3-Month Clear (N = 1693)** | **XIENCE V USA 3-Month Clear (N=1280)** | | --- | --- | --- | --- | | Systemic conditions associated with an increased bleeding risk | 3.0% (61/2047) | 2.8% (48/1693) | 1.6% (20/1280) | | Anemia with hemoglobin < 11g/dl | 16.2% (332/2047) | 15.0% (254/1693) | 16.3% (209/1280) | | Number of HBR criteria met | 1.5 ± 0.7 (2047) | 1.5 ± 0.7 (1693) | 1.3 ± 0.6 (1280) | | One criterion met | 61.7% (1262/2047) | 61.9% (1048/1693) | 74.4% (952/1280) | | ≥ 2 criteria met | 38.3% (784/2047) | 38.1% (645/1693) | 25.6% (328/1280) | | ≥ 3 criteria met | 8.2% (167/2047) | 7.9% (133/1693) | 4.2% (54/1280) | | **Note:** Numbers presented here are % (n/N) or mean ± SD (N). | | | | **Antiplatelet Medication Usage:** Use of dual antiplatelet therapy (aspirin plus a P2Y$_{12}$ inhibitor) at procedure, discharge, 3 months, 6 months, and 12 months are shown in **Table 11**. Antiplatelet compliance was generally good. Clopidogrel was the predominant P2Y$_{12}$ inhibitor (81.7% usage) used at discharge. After 3 months, there were 18.8% (318/1693) of 1-month clear subjects who were P2Y$_{12}$ non-adherent (meaning subjects took P2Y$_{12}$ for a certain amount of time between 3-12 months when they should have stopped P2Y$_{12}$) and 1.7% (29/1693) who were aspirin non-adherent (did not continue to take aspirin for a certain amount of time between 1-6 months when they should have continued). There were 0.6% (11/1693) 1-month clear subjects who were medication non-adherent for both P2Y$_{12}$ and aspirin between 1-6 months. **Table 11. XIENCE 90 Antiplatelet Medication Usage** | | **XIENCE 90 3-Month Clear Subjects (N=1693)** | **XIENCE 90 Other Registered Subjects* (N=354)** | **XIENCE V USA 3-Month Clear Subjects (N=1280)** | | --- | --- | --- | --- | | **Procedure** | | | | | P2Y_{12} Inhibitor | 99.6% (1687/1693) | 99.7% (353/354) | 74.8% (775/1036) | | Clopidogrel | 74.0% (1253/1693) | 73.4% (260/354) | 73.2% (758/1036) | | Prasugrel | 4.7% (80/1693) | 3.7% (13/354) | 4.5% (13/289) | | Ticagrelor | 24.9% (422/1693) | 27.4% (97/354) | NA | | Aspirin | 96.6% (1636/1693) | 97.1% (344/354) | 72.3% (749/1036) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 22 {22} | | **XIENCE 90 3-Month Clear Subjects (N=1693)** | **XIENCE 90 Other Registered Subjects* (N=354)** | **XIENCE V USA 3-Month Clear Subjects (N=1280)** | | --- | --- | --- | --- | | DAPT (Aspirin and P2Y_{12}) | 96.3% (1630/1693) | 97.1% (344/354) | 48.7% (505/1036) | | **Discharge** | | | | | P2Y_{12} Inhibitor | 100.0% (1693/1693) | 100.0% (354/354) | 99.5% (1274/1280) | | Clopidogrel | 81.7% (1384/1693) | 80.8% (286/354) | 98.0% (1252/1277) | | Prasugrel | 2.2% (38/1693) | 2.2% (8/354) | 4.2% (16/382) | | Ticagrelor | 16.2% (274/1693) | 16.9% (60/354) | NA | | Aspirin | 91.2% (1544/1693) | 91.8% (325/354) | 98.8% (1262/1277) | | DAPT (Aspirin and P2Y_{12}) | 91.2% (1544/1693) | 91.8% (325/354) | 98.6% (1260/1278) | | Anticoagulant | 40.7% (689/1693) | 37.3% (132/354) | 8.9% (114/1274) | | Double Therapy (Anticoagulant and P2Y_{12} Inhibitor) | 8.8% (149/1693) | 8.2% (29/354) | 0.8% (10/1274) | | Triple Therapy (Anticoagulant, Aspirin, and P2Y_{12} Inhibitor) | 31.9% (540/1693) | 29.1% (103/354) | 8.1% (103/1274) | | **3 months** | | | | | P2Y_{12} Inhibitor | 99.4% (1682/1693) | 86.9% (253/291) | 100.0% (1280/1280) | | Clopidogrel | 84.2% (1426/1693) | 76.6% (223/291) | 98.0% (1254/1280) | | Prasugrel | 2.7% (46/1693) | 1.7% (5/291) | 1.3% (16/1280) | | Ticagrelor | 12.5% (212/1693) | 8.9% (26/291) | NA | | Aspirin | 89.5% (1515/1693) | 78.3% (228/291) | 99.1% (1253/1265) | | DAPT (Aspirin and P2Y_{12}) | 88.3% (1495/1693) | 68.7% (200/291) | 97.9% (1253/1280) | | **6 months** | | | | | P2Y_{12} Inhibitor | 11.4% (191/1671) | 73.6% (184/250) | 99.1% (1254/1266) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 23 {23} | | XIENCE 90 3-Month Clear Subjects (N=1693) | XIENCE 90 Other Registered Subjects* (N=354) | XIENCE V USA 3-Month Clear Subjects (N=1280) | | --- | --- | --- | --- | | Clopidogrel | 10.1% (168/1671) | 66.0% (165/250) | 97.2% (1231/1266) | | Prasugrel | 0.2% (4/1671) | 2.4% (6/250) | 1.0% (13/1266) | | Ticagrelor | 1.1% (19/1671) | 5.6% (14/250) | NA | | Aspirin | 96.5% (1613/1671) | 80.0% (200/250) | 97.7% (1225/1254) | | DAPT (Aspirin and P2Y_{12}) | 9.8% (163/1671) | 57.6% (144/250) | 96.1% (1217/1266) | | **12 months** | | | | | P2Y_{12} Inhibitor | 12.2% (199/1627) | 64.8% (147/227) | 95.6% (1145/1198) | | Clopidogrel | 10.7% (174/1627) | 57.7% (131/227) | 93.7% (1122/1198) | | Prasugrel | 0.2% (4/1627) | 2.2% (5/227) | 1.1% (13/1198) | | Ticagrelor | 1.3% (21/1627) | 4.8% (11/227) | NA | | Aspirin | 95.1% (1548/1627) | 78.4% (178/227) | 95.1% (1129/1187) | | DAPT (Aspirin and P2Y_{12}) | 10.1% (165/1627) | 48.4% (110/227) | 91.1% (1091/1198) | *Includes all subjects not categorized as “3 month clear”, including subjects with events prior to 3 months, subjects non-compliant with DAPT, losses to follow up, etc. NA, not available. Ticagrelor usage was not collected for the XIENCE V USA study, as Ticagrelor was not commercially available at that time. ### D. Safety and Effectiveness Results #### 1. Study Results The analysis of safety and effectiveness was based on the 1653 3-month clear patients evaluable at 12 months. The primary study safety results between 3-12 months for the primary analysis population (3-month clear subjects) in the XIENCE 90 trial are summarized in Tables 12, 13 and 14. Additional supportive individual and composite safety and effectiveness outcomes are presented in Table 15. Primary Endpoint (Safety): PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 24 {24} The primary endpoint of all death/all MI was met. Non-inferiority of the primary endpoint of all death or all MI (modified ARC) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT compared to the XIENCE V USA historical control arm was demonstrated after propensity score adjustment (as pre-specified in the XIENCE 90 SAP). Propensity score stratification was performed by an independent statistician. Based on the number of patients and observed rates in each stratum, the results show a non-inferiority p-value of 0.0063, meeting the pre-specified significance level of 0.025. The 3-12 months propensity score stratification mean rate for all death/all MI in 3-month clear patients was 5.4% for both XIENCE 90 and the XIENCE V USA historical control (Table 12). This demonstrated that the 3-12 months composite rate of all death/all MI following XIENCE implantation in HBR subjects treated with 3 months of DAPT was non-inferior to the historical control subjects treated with up to 12 months of DAPT. ### Major Secondary Endpoint - Bleeding (Effectiveness): The propensity score stratification method was also used to compare the XIENCE 90 trial arm to the XIENCE V USA historical control for the major secondary endpoint of BARC 2-5 bleeding. Based on the number of patients and observed rates in each stratum, the results show a superiority p-value of 0.0687, which did not meet the pre-specified significance level of 0.025. Although the significance level was not met, the 3-12 months propensity score stratification mean rate of BARC 2-5 bleeding, in 3-month clear patients, was numerically lower in XIENCE 90 as compared to the historical control (5.1% vs 7.0%; Table 12). Table 12. XIENCE 90 Primary Death/MI and Secondary Bleeding Endpoint Results Between 3-12 Months | | XIENCE 90 (N=1693) | XIENCE V USA (N=1280) | Difference [95% CI] | *p-value | | --- | --- | --- | --- | --- | | All Death/All MI | 5.4% | 5.4% | 0.15% [-1.93%, 2.23%] | **0.0063 | | BARC 2-5 Bleeding | 5.1% | 7.0% | -1.72% [-4.00%, 0.55%] | ***0.0687 | *Stratified Farrington-Manning method is carried out using propensity score stratified data in each imputed dataset, and Rubin's combination rule is applied to integrate the final test results from each imputed dataset. **The test is carried out with a non-inferiority margin of 2.8% against a one-sided significance level of 0.025. ***The superiority test is carried out against a one-sided significance level of 0.025. Note: - Subjects are only counted once for each type of event in each time period. - Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. - Subjects who are lost to follow-up without any DMR event (death, MI (modified ARC), revascularization) are excluded - Subjects who are lost to follow-up without any bleeding event (BARC 1-5) are excluded. In a post-hoc analysis, the propensity score stratification methodology was used to compare BARC 3-5 bleeding rates between XIENCE 90 and the XIENCE V USA historical control. BARC 3-5 excludes less severe bleeds. The observed 3-12 months PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 25 {25} BARC 3-5 bleeding rate was 2.2% in XIENCE 90 subjects as compared to 6.3% in XIENCE V USA HBR subjects after propensity score adjustment. **Major Secondary Endpoint – Stent Thrombosis (Safety):** The stent thrombosis rate for the XIENCE 90 trial arm was 0.2% between 3 to 12 months, which was significantly lower than the pre-specified performance goal (PG) of 1.2% (p-value < 0.0001; Table 13). Table 13. XIENCE 90 Secondary Stent Thrombosis Endpoint Result | | 3-Month Clear Subjects (N=1693) | Upper Limit of Two-Sided 95% Confidence Interval | PG | p-value | | --- | --- | --- | --- | --- | | Stent Thrombosis (ARC Definite/Probable) | 0.2% (4/1635) | 0.63% | 1.2% | < 0.0001 | | Note: – Subjects are only counted once for each type of event in each time period. – Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. – Subjects who are lost to follow-up without any Stent Thrombosis event are excluded. | | | | | Other supportive individual and composite safety and effectiveness endpoints between 3 and 12 months are listed in Table 14. Most adverse clinical events in the “not clear” population were higher than those in the overall “clear” population for the primary analysis time window (3-12 months). The values provided are without propensity score adjustment. Table 14. XIENCE 90 Unadjusted Additional Secondary Endpoint Results 3-12 Months | | XIENCE 90 3-Month Clear Subjects (N=1693) | XIENCE 90 3-Month Not Clear Subjects with 3-Month Visit (N=230) | XIENCE V USA 3-Month Clear Subjects (N=1280) | | --- | --- | --- | --- | | Safety | | | | | All Death/All MI (Modified ARC) | 5.5% (92/1672) | 13.8% (30/218) | 4.4% (55/1246) | | All Death | 3.2% (54/1672) | 7.8% (17/218) | 2.6% (32/1246) | | Cardiac Death | 1.7% (29/1672) | 4.6% (10/218) | 1.2% (15/1246) | | Vascular Death | 0.1% (2/1672) | 0.0% (0/218) | 0.2% (3/1246) | | Non-cardiovascular Death | 1.4% (23/1672) | 3.2% (7/218) | 1.1% (14/1246) | | All MI (Modified ARC) | 2.9% (48/1672) | 7.8% (17/218) | 2.2% (28/1246) | | Target Vessel MI (TV-MI, Modified ARC) | 2.4% (40/1672) | 5.0% (11/218) | 2.1% (26/1246) | | Cardiac Death/All MI (Modified ARC) | 4.0% (67/1672) | 11.0% (24/218) | 3.1% (39/1246) | | Major Bleeding (BARC 2-5) | 5.8% (95/1629) | 9.4% (19/203) | 5.2% (63/1217) | | Major Bleeding (BARC 3-5) | 2.5% (41/1629) | 4.9% (10/203) | 4.4% (53/1217) | | Stent Thrombosis (ARC Definite/Probable) | 0.2% (4/1635) | 0.5% (1/209) | 0.3% (4/1225) | | All Stroke | 1.3% (21/1624) | 1.5% (3/202) | 0.6% (2/355) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 26 {26} | | XIENCE 90 3-Month Clear Subjects (N=1693) | XIENCE 90 3-Month Not Clear Subjects with 3-Month Visit (N=230) | XIENCE V USA 3-Month Clear Subjects (N=1280) | | --- | --- | --- | --- | | Ischemic Stroke | 1.2% (19/1624) | 1.5% (3/202) | 0.6% (2/355)* | | Hemorrhagic Stroke | 0.1% (2/1624) | 0.0% (0/202) | NA* | | **Effectiveness** | | | | | Clinically-indicated Target Lesion Revascularization (CI-TLR) | 1.0% (16/1672) | 3.2% (7/218) | 1.4% (18/1246) | | Clinically-indicated Target Vessel Revascularization (CI-TVR) | 1.6% (26/1672) | 5.5% (12/218) | 2.9% (36/1246) | | **Safety and Effectiveness** | | | | | Target Lesion Failure (TLF) | 3.9% (66/1672) | 10.6% (23/218) | 4.1% (51/1246) | | Target Vessel Failure (TVF) | 4.2% (70/1672) | 12.8% (28/218) | 5.0% (62/1246) | | **Note:** - Subjects are only counted once for each type of event in each time period. - Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. - Subjects who are lost to follow-up without any DMR event (death, MI (modified ARC), revascularization) are excluded; for Stent Thrombosis, Major Bleeding, and Stroke, subjects who are lost to follow-up without a related event (Stent Thrombosis, BARC (1-5), or Stroke, respectively) are excluded. *Hemorrhagic and ischemic strokes not collected for XIENCE V USA Phase I; hemorrhagic strokes not collected for XIENCE V USA Phase II. | | | | ## 2. Results by Subgroups The following preoperative characteristics were evaluated for potential association with outcomes: ### Sex/Gender Although not powered to evaluate safety or effectiveness of the XIENCE family of stents in gender-specific subgroups, outcomes for male and female subjects from the XIENCE 90 trial are available (Table 15). The composite rate of all death/all MI in the 3-month clear XIENCE 90 subjects between 3-12 months was 5.3% in male subjects and 5.8% in female subjects. The stent thrombosis rate from 3-12 months was 0.2% in males and 0.3% in females. The BARC 2-5 bleeding rate was 5.5% in male subjects and 6.5% in female subjects. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 27 {27} **Table 15. Unadjusted Primary and Secondary Endpoints By Sex/Gender** | | XIENCE 90 3-Month Clear Subjects (N=1693) | | XIENCE V USA 3-Month Clear Subjects (N=1280) | | | --- | --- | --- | --- | --- | | | Male (N=1097) | Female (N=596) | Male (N=756) | Female (N=524) | | ***All Death/All MI** | 5.3% (58/1085) | 5.8% (34/587) | 4.3% (32/738) | 4.5% (23/508) | | ****BARC 2-5** | 5.5% (58/1059) | 6.5% (37/570) | 4.6% (33/721) | 6.0% (30/496) | | *****Stent thrombosis** | 0.2% (2/1061) | 0.3% (2/574) | 0.3% (2/725) | 0.4% (2/500) | | All Death | 3.1% (34/1085) | 3.4% (20/587) | 2.6% (19/738) | 2.6% (13/508) | | Cardiac Death | 1.6% (17/1085) | 2.0% (12/587) | 1.2% (9/738) | 1.2% (6/508) | | Vascular Death | 0.2% (2/1085) | 0.0% (0/587) | 0.4% (3/738) | 0.0% (0/508) | | Non-cardiovascular Death | 1.4% (15/1085) | 1.4% (8/587) | 0.9% (7/738) | 1.4% (7/508) | | All MI (modified ARC) | 2.6% (28/1085) | 3.4% (20/587) | 2.2% (16/738) | 2.4% (12/508) | | Target Vessel MI (TV-MI, modified ARC) | 2.1% (23/1085) | 2.9% (17/587) | 1.9% (14/738) | 2.4% (12/508) | | Cardiac Death/All MI (modified ARC) | 3.8% (41/1085) | 4.4% (26/587) | 3.1% (23/738) | 3.1% (16/508) | | Major Bleeding (BARC 3-5) | 2.8% (30/1059) | 1.9% (11/570) | 3.9% (28/721) | 5.0% (25/496) | | All Stroke | 1.2% (13/1054) | 1.4% (8/570) | 0.9% (2/221) | 0.0% (0/134) | | Ischemic Stroke | 1.0% (11/1054) | 1.4% (8/570) | 0.9% (2/221) | 0.0% (0/134) | | Hemorrhagic Stroke | 0.2% (2/1054) | 0.0% (0/570) | NA | NA | | Clinically-indicated Target Lesion Revascularization (CI-TLR) | 1.1% (12/1085) | 0.7% (4/587) | 1.4% (10/738) | 1.6% (8/508) | | Clinically-indicated Target Vessel Revascularization (CI-TVR) | 1.8% (19/1085) | 1.2% (7/587) | 2.4% (18/738) | 3.5% (18/508) | | Target Lesion Failure (TLF) | 3.8% (41/1085) | 4.3% (25/587) | 3.9% (29/738) | 4.3% (22/508) | | Target Vessel Failure (TVF) | 4.1% (44/1085) | 4.4% (26/587) | 4.6% (34/738) | 5.5% (28/508) | Note: Subjects are only counted once for each type of event. Note: *Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any DMR event (death, MI (modified ARC), revascularization) are excluded. Note: **Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any bleeding event (BARC 1-5) are excluded. Note: ***Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any Stent Thrombosis event are excluded. The overall conclusions of the trial regarding the safety of the XIENCE family of stents when used with 3 months of DAPT in patients at high risk of bleeding can be generalized to males and females. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 28 {28} # **Age** Of the 1693 3-month clear subjects in XIENCE 90, 1446 were $\geq 65$ years old at the time of registration. The rates of all death/all MI, BARC 2-5 bleeding and ST between 3 and 12 months, in subjects age 65 or older were 5.5%, 5.3% and 0.2%, respectively. These rates were comparable to those observed in the overall 3-month clear population. # **Race and Ethnicity** Outcomes by race in the 1693 3-month clear subjects from XIENCE 90 are presented in **Table 16**. 1496 (88.4%) were white, while 149 (8.80%) subjects were non-white (identified as American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, Native Hawaiian or Other Pacific Islander, or Other). The available race and ethnicity information is too limited to comment on any potential associations. **Table 16. Unadjusted Primary and Secondary Endpoints By Race** | | XIENCE 90 3-Month Clear Subjects (N=1693) | | | | | | XIENCE V USA 3-Month Clear Subjects (N=1280) | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | White (N=1496) | American Indian or Alaska Native (N=11) | Asian (N=37) | Black or African American (N=96) | Hispanic or Latino (N=45) | Native Hawaiian or Pacific Islander (N=5) | White (N=1101) | American Indian or Alaska Native (N=9) | Asian (N=17) | Black or African American (N=110) | Hispanic or Latino (N=41) | Native Hawaiian or Pacific Islander (N=4) | | ***All Death/All MI** | 5.8% (85/1478) | 0.0% (0/11) | 0.0% (0/36) | 6.3% (6/95) | 8.9% (4/45) | 0.0% (0/5) | 3.8% (41/1076) | 11.1% (1/9) | 6.7% (1/15) | 9.4% (10/106) | 5.4% (2/37) | 0.0% (0/4) | | ****BARC 2-5 bleeding** | 5.7% (82/1438) | 0.0% (0/11) | 5.6% (2/36) | 6.5% (6/92) | 11.1% (5/45) | 20.0% (1/5) | 5.3% (56/1053) | 0.0% (0/8) | 6.7% (1/15) | 4.0% (4/101) | 5.4% (2/37) | 0.0% (0/4) | | *****Stent Thrombosis (ARC definite/probable)** | 0.3% (4/1444) | 0.0% (0/11) | 0.0% (0/36) | 0.0% (0/92) | 0.0% (0/44) | 0.0% (0/5) | 0.3% (3/1058) | 0.0% (0/9) | 0.0% (0/15) | 1.0% (1/103) | 0.0% (0/37) | 0.0% (0/4) | | All Death | 3.3% (49/1478) | 0.0% (0/11) | 0.0% (0/36) | 5.3% (5/95) | 2.2% (1/45) | 0.0% (0/5) | 2.4% (26/1076) | 11.1% (1/9) | 0.0% (0/15) | 4.7% (5/106) | 0.0% (0/37) | 0.0% (0/4) | | Cardiac Death | 1.7% (25/1478) | 0.0% (0/11) | 0.0% (0/36) | 4.2% (4/95) | 0.0% (0/45) | 0.0% (0/5) | 1.0% (11/1076) | 11.1% (1/9) | 0.0% (0/15) | 2.8% (3/106) | 0.0% (0/37) | 0.0% (0/4) | | Vascular Death | 0.1% (2/1478) | 0.0% (0/11) | 0.0% (0/36) | 0.0% (0/95) | 2.2% (1/45) | 0.0% (0/5) | 0.3% (3/1076) | 0.0% (0/9) | 0.0% (0/15) | 0.0% (0/106) | 0.0% (0/37) | 0.0% (0/4) | | Non-cardiovascular Death | 1.5% (22/1478) | 0.0% (0/11) | 0.0% (0/36) | 1.1% (1/95) | 0.0% (0/45) | 0.0% (0/5) | 1.1% (12/1076) | 0.0% (0/9) | 0.0% (0/15) | 1.9% (2/106) | 0.0% (0/37) | 0.0% (0/4) | | All MI (modified ARC) | 2.9% (43/1478) | 0.0% (0/11) | 0.0% (0/36) | 4.2% (4/95) | 6.7% (3/45) | 0.0% (0/5) | 1.8% (19/1076) | 0.0% (0/9) | 6.7% (1/15) | 5.7% (6/106) | 5.4% (2/37) | 0.0% (0/4) | | Target Vessel MI (TV-MI, modified ARC) | 2.4% (35/1478) | 0.0% (0/11) | 0.0% (0/36) | 4.2% (4/95) | 6.7% (3/45) | 0.0% (0/5) | 1.7% (18/1076) | 0.0% (0/9) | 6.7% (1/15) | 4.7% (5/106) | 5.4% (2/37) | 0.0% (0/4) | | Cardiac Death/All MI (modified ARC) | 4.1% (61/1478) | 0.0% (0/11) | 0.0% (0/36) | 5.3% (5/95) | 6.7% (3/45) | 0.0% (0/5) | 2.5% (27/1076) | 11.1% (1/9) | 6.7% (1/15) | 7.5% (8/106) | 5.4% (2/37) | 0.0% (0/4) | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 29 {29} | | XIENCE 90 3-Month Clear Subjects (N=1693) | | | | | | XIENCE V USA 3-Month Clear Subjects (N=1280) | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | White (N=1496) | American Indian or Alaska Native (N=11) | Asian (N=37) | Black or African American (N=96) | Hispanic or Latino (N=45) | Native Hawaiian or Pacific Islander (N=5) | White (N=1101) | American Indian or Alaska Native (N=9) | Asian (N=17) | Black or African American (N=110) | Hispanic or Latino (N=41) | Native Hawaiian or Pacific Islander (N=4) | | Major Bleeding (BARC 3-5) | 2.6% (38/1438) | 0.0% (0/11) | 0.0% (0/36) | 2.2% (2/92) | 4.4% (2/45) | 0.0% (0/5) | 4.5% (47/1053) | 0.0% (0/8) | 0.0% (0/15) | 4.0% (4/101) | 5.4% (2/37) | 0.0% (0/4) | | All Stroke | 1.3% (19/1435) | 0.0% (0/11) | 0.0% (0/36) | 2.2% (2/90) | 2.2% (1/45) | 0.0% (0/5) | 0.6% (2/313) | 0.0% (0/1) | 0.0% (0/6) | 0.0% (0/27) | 0.0% (0/8) | 0.0% (0/2) | | Ischemic Stroke | 1.3% (18/1435) | 0.0% (0/11) | 0.0% (0/36) | 1.1% (1/90) | 2.2% (1/45) | 0.0% (0/5) | 0.6% (2/313) | 0.0% (0/1) | 0.0% (0/6) | 0.0% (0/27) | 0.0% (0/8) | 0.0% (0/2) | | Hemorrhagic Stroke | 0.1% (1/1435) | 0.0% (0/11) | 0.0% (0/36) | 1.1% (1/90) | 0.0% (0/45) | 0.0% (0/5) | NA | NA | NA | NA | NA | NA | | Clinically-indicated Target Lesion Revascularization (CI-TLR) | 1.0% (15/1478) | 0.0% (0/11) | 0.0% (0/36) | 1.1% (1/95) | 0.0% (0/45) | 0.0% (0/5) | 1.4% (15/1076) | 0.0% (0/9) | 6.7% (1/15) | 0.9% (1/106) | 2.7% (1/37) | 0.0% (0/4) | | Clinically-indicated Target Vessel Revascularization (CI-TVR) | 1.7% (25/1478) | 0.0% (0/11) | 0.0% (0/36) | 1.1% (1/95) | 0.0% (0/45) | 0.0% (0/5) | 2.8% (30/1076) | 0.0% (0/9) | 6.7% (1/15) | 3.8% (4/106) | 2.7% (1/37) | 0.0% (0/4) | | Target Lesion Failure (TLF) | 4.1% (60/1478) | 0.0% (0/11) | 0.0% (0/36) | 5.3% (5/95) | 6.7% (3/45) | 0.0% (0/5) | 3.6% (39/1076) | 11.1% (1/9) | 6.7% (1/15) | 6.6% (7/106) | 8.1% (3/37) | 0.0% (0/4) | | Target Vessel Failure (TVF) | 4.3% (64/1478) | 0.0% (0/11) | 0.0% (0/36) | 5.3% (5/95) | 6.7% (3/45) | 0.0% (0/5) | 4.5% (48/1076) | 11.1% (1/9) | 6.7% (1/15) | 8.5% (9/106) | 8.1% (3/37) | 0.0% (0/4) | Note: Subjects can be counted in more than one race or ethnic group. Note: Subjects are only counted once for each type of event. Note: Hemorrhagic and Ischemic Strokes not collected for XIENCE V USA Phase I; Hemorrhagic Strokes not collected for XIENCE V USA Phase II. Note: Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any DMR event (death, MI (modified ARC), revascularization) are excluded; for Stent Thrombosis, Major Bleeding, and Stroke, subjects who are lost to follow-up without a related event (Stent Thrombosis, BARC (1-5), or Stroke, respectively) are excluded. *Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any DMR event (death, MI (modified ARC), revascularization) are excluded. **Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any bleeding event (BARC 1-5) are excluded. ***Subjects who have completed the required amount of follow-up at the time of data extraction are included in the denominators. Subjects who are lost to follow-up without any Stent Thrombosis event are excluded. ### 3. Pediatric Extrapolation In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 30 {30} ## (2) XIENCE 28 USA and XIENCE 28 Global Clinical Trials ### A. Study Design The XIENCE 28 analysis was conducted on the combined populations from XIENCE 28 USA and XIENCE 28 Global trials, as pre-specified in the XIENCE 28 USA SAP. Both trials are prospective, single arm, multi-center, open label trials to evaluate the safety of 1-month (as short as 28 days) DAPT in subjects at high risk of bleeding undergoing PCI with the approved XIENCE family of stents. Subjects were considered to be high bleeding risk if, in the opinion of the referring physician, the risk of major bleeding with >1-month DAPT outweighed the benefit and they met one or more of the same HBR criteria listed in XIENCE 90. Subjects were prescribed DAPT (P2Y$_{12}$ inhibitor + aspirin) between 0-1 month post-procedure. Subjects were considered as “1-month clear” and were to discontinue P2Y$_{12}$ inhibitor at 1 month if they were compliant with the prescribed DAPT and were free from events between 0-1 month (myocardial infarction, repeat coronary revascularization, stroke, or stent thrombosis). Subjects that discontinued P2Y$_{12}$ inhibitor at 1 month were prescribed aspirin through the end of the study. For the primary endpoint of all death or all MI and the secondary endpoint of BARC 2-5 bleeding, the primary analysis population for the XIENCE 28 analysis is the 1-month clear subjects. The 1-month clear population, combined from XIENCE 28 Global and XIENCE 28 USA, was compared with the 1-month clear population of the historical control of non-complex HBR subjects treated with DAPT duration of up to 12 months from the XIENCE V USA Study. For these primary and secondary endpoints, the comparison with the 1-month clear population of the historical control was done after propensity score adjustment. #### 1. Clinical Inclusion and Exclusion Criteria Enrollment in the XIENCE 28 trials was limited to subjects who met the inclusion criteria listed in **Table 17**. Subjects were not permitted to enroll in the XIENCE 28 trials if they met any of the exclusion criteria in **Table 17**. **Table 17. XIENCE 28 Trials Enrollment Inclusion and Exclusion Criteria** | General Inclusion Criteria | 1. Subject is considered at high risk for bleeding, defined as meeting one or more of the criteria previously listed in **Table 5** at the time of registration and in the opinion of the referring physician, the risk of major bleeding with > 1-month DAPT outweighs the benefit: 2. Subject must be at least 18 years of age. 3. Subject must provide written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site prior to any trial related procedure. 4. Subject is willing to comply with all protocol requirements, including agreement to stop taking P2Y_{12} inhibitor at 1 month, if eligible per protocol. | | --- | --- | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 31 {31} | | 5. Subject must agree not to participate in any other clinical trial for a period of one year following the index procedure, except for cases where subject is transferred to the XIENCE 90 study after the 1-month visit assessment. | | --- | --- | | General Exclusion Criteria | 1. Subject with an indication for the index procedure of acute ST-segment elevation MI (STEMI). 2. Subject has a known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, P2Y_{12} inhibitors (clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be adequately pre-medicated. 3. Subject with implantation of another drug-eluting stent (other than XIENCE) within 12 months prior to index procedure. 4. Subject has a known left ventricular ejection fraction (LVEF) <30%. 5. Subject judged by physician as inappropriate for discontinuation from P2Y_{12} inhibitor use at 1 month, due to another condition requiring chronic P2Y_{12} inhibitor use. 6. Subject with planned surgery or procedure necessitating discontinuation of P2Y_{12} inhibitor within 1 month following index procedure. 7. Subject with a current medical condition with a life expectancy of less than 12 months. 8. Subject intends to participate in an investigational drug or device trial within 12 months following the index procedure. Transferring to the XIENCE 90 study will not be an exclusion criterion. 9. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year following index procedure. Female subjects of child-bearing potential must have a negative pregnancy test done within 7 days prior to the index procedure per site standard test. Note: Female subjects of childbearing potential should be instructed to use safe contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, implants, transdermal patches, hormonal vaginal devices, injections with prolonged release.) It is accepted, in certain cases, to include subjects having a sterilized regular partner or subjects using a double barrier contraceptive method. However, this should be explicitly justified in special circumstances arising from the trial design, product characteristics, and/or trial population. 10. Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements, or impact the scientific soundness of the clinical investigation results. 11. Subject is currently participating in another clinical trial that has not yet completed its primary endpoint. | PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 32 {32} | Angiographic Inclusion Criteria | Identical to XIENCE 90, except target lesions ≤32 mm in length by visual estimation were not listed as inclusion criteria. | | --- | --- | | Angiographic Exclusion Criteria | 1. Target lesion is in a left main location. 2. Target lesion is located within an arterial or saphenous vein graft. 3. Target lesion is restenotic from a previous stent implantation. 4. Target lesion is a **chronic** total occlusion (CTO, defined as lesion with TIMI flow 0 for at least 3 months). 5. Target lesion is implanted with overlapping stents, whether planned or for bailout. | ## 2. Follow-up Schedule All patients were scheduled to have follow-up examinations at the following time points: 1, 3, 6, and 12 months post index procedure. Study follow-up through 6 months is complete. Per study design, the primary endpoint was to be evaluated at 6 months. Preoperatively, laboratory assessments were conducted per SOC to determine subject's eligibility for PCI and confirm eligibility for the study. Post-procedure, ECG and cardiac enzyme collection were performed per SOC. Use and compliance of protocol required antiplatelet medication and adverse events and complications were recorded at all visits. The key time points are shown below in the tables summarizing safety and effectiveness. ## 3. Clinical Endpoints ### Primary Endpoint The primary endpoint is a composite rate of all death or all myocardial infarction (MI, modified ARC) from 1 to 6 months post index procedure. ### Major Secondary Endpoint The major secondary endpoint is major bleeding rate (BARC type 2-5) from 1 to 6 months. ### Other Secondary Endpoints The following endpoints were assessed from 1 to 6 months: - Stent thrombosis (ARC definite/probable, ARC definite) - All death, cardiac death, vascular death, non-cardiovascular death - All MI (modified ARC) and MI attributed to target vessel (TV-MI, modified ARC) PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 33 {33} - • Composite of cardiac death or MI (modified ARC) - • Composite of all death or all MI (modified ARC) - • All stroke, ischemic stroke and hemorrhagic stroke - • CI-TLR - • CI-TVR - • TLF, (composite of cardiac death, TV-MI and CI-TLR) - • TVF, (composite of cardiac death, TV-MI and CI-TVR) - • Major bleeding defined by BARC type 3-5 # **B. Accountability of PMA Cohort** Between February 9, 2018 and April 22, 2019 (XIENCE 28 Global), and between February 25, 2019 and February 7, 2020 (XIENCE 28 USA), a total of 1605 subjects were enrolled in XIENCE 28, 642 from the US and Canada and 963 from Europe and Asia, at 110 sites. Of the 1605 subjects, 1392 subjects met the 1-month clear criteria and are the primary analysis group. A total of 154 subjects did not meet the 1-month clear criteria and these subjects were not included in the primary analysis population. At 6 months, 1375 of the 1-month clear subjects completed their visit (98.8%). The subject enrollment and disposition up to 6 months for XIENCE 28 are shown below in **Figure 4**. PMA P110019/S115: FDA Summary of Safety and Effectiveness Data Page 34 {34} ![img-4.jpeg](img-4.jpeg) Figure 4. XIENCE 28 Subject Enrollment and Disposition Note: LTFU = Lost to Follow Up ### C. Study Population Demographics and Baseline Parameters Table 18 presents demographics for the primary analysis group (XIENCE 28 1-month clear subjects) and the historical control group (XIENCE V USA 1-month clear subjects). The mean age in the XIENCE 28…

XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary

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XIENCE Alpine Everolimus Eluting Coronary Stent Systems (XIENCE Alpine EECSS), XIENCE Sierra Everolimus Eluting Coronary

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