Indications: The XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems are 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 Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems are indicated for treating de novo chronic total coronary occlusions.

Contraindications: The XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems are 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, fluoropolymer), or with contrast hypersensitivity.

Warnings:

• Each stent and the delivery system are for single use only. Do not reuse, reprocess, or resterilize. Note the product “Use by” date on the package. Reuse, reprocessing, or resterilization may compromise the structural integrity of the device and / or delivery system and / or lead to device failure, which may result in patient injury, illness, or death. Reuse, reprocessing, or resterilization may also create a risk of contamination of the device and / or cause patient infection or cross-infection, including, but not limited to, the transmission of infectious disease(s) from one patient to another. Contamination of the device and / or delivery system may lead to injury, illness, or death of the patient.
• It is not recommended to treat patients having a lesion that prevents complete inflation of an angioplasty balloon.
• Antiplatelet therapy should be administered post-procedure.
• This product should not be used in patients who are not likely to comply with the recommended antiplatelet therapy.
• Judicious selection of patients is necessary, since the use of this device carries the associated risk of stent thrombosis, vascular complications, and/or bleeding events.
• The XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems are coated with an everolimus and polymer coating at the full implant stent length.
• The distal and intermediate portions of the device, the tip, and tapers of the balloon are coated with HYDROCOAT™ Hydrophilic Coating.
• Failure to abide by the warnings in this labeling might result in damage to the device coating, which may necessitate intervention or result in serious adverse events.

Precautions:

• Implantation of the stent should be performed only by the physicians who have received appropriate training.
• Stent placement should be performed at centers where emergency coronary artery bypass graft surgery (CABG) can be readily performed.
• To confirm sterility has been maintained, ensure that the inner package sterile barrier has not been opened or damaged prior to use.
• Subsequent restenosis may require repeat dilatation of the arterial segment containing the stent. The long-term outcome following repeat dilatation of the stent is unknown at present.
• Care should be taken to control the guiding catheter tip during stent delivery, deployment, and balloon withdrawal. Before withdrawing the stent delivery system, visually confirm complete balloon deflation by fluoroscopy to avoid guiding catheter movement into the vessel and subsequent arterial damage.
• When the XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems are used outside the specified Indications for Use, patient outcomes may differ from the results observed in the SPIRIT family of clinical trials.
• Compared to use within the specified indications for use, the use of the XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems in patients and lesions outside of the labeled indications, including more tortuous anatomy, may have an increased risk of adverse events, including stent thrombosis, stent embolization, MI, or death.
• The extent of the patient’s exposure to drug and polymer is directly related to the number of stents implanted. See Instructions for Use for current data on multiple stent implantation.
• Safety and effectiveness of the XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems have not been established for subject populations with the following clinical settings:
  - Patients with prior brachytherapy of the target lesion or the use of brachytherapy for treated site restenosis.
  - Conjunctive use of the XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems with either mechanical atherectomy devices or laser angioplasty catheters.
  - Women who are pregnant or lactating, men intending to father children, pediatric.
  - Unresolved vessel thrombus at the lesion site, coronary artery reference vessel diameters < 2.25 mm or > 4.25 mm or lesion lengths > 32 mm, lesions located in saphenous vein grafts, lesions located in unprotected left main coronary artery, ostial lesions, or lesions located at a bifurcation or previously stented lesions, diffuse disease or poor flow (TIMI < 1) distal to the identified lesions, excessive tortuosity proximal to or within the lesion, recent Acute Myocardial Infarction (AMI) or evidence of thrombus in target vessel, multivessel disease, and in-stent restenosis.

• Formal drug interaction studies have not been performed with the XIENCE Skypoint™, XIENCE Sierra™ or XIENCE Alpine™ Stent Systems because of limited exposure to everolimus eluted from XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems.
  - Everolimus, the active ingredient in the stents, is an immunosuppressive agent. Consideration should be given to patients taking other immunosuppressive agents or who are at risk for immune suppression.
  - Oral everolimus use in renal transplant and advanced renal cell carcinoma patients was associated with increased serum cholesterol and triglyceride levels, which in some cases required treatment.
  - Nonclinical testing has demonstrated that the XIENCE Skypoint™, XIENCE Sierra™ and XIENCE Alpine™ Stent Systems in single and in overlapped configurations up to 71 mm in length, are MR Conditional. See Instructions for Use for detailed scanning conditions

Potential Adverse Events: Adverse events that may be associated with PCI treatment procedures and the use of a stent in native coronary arteries include, but are not limited to, the following:

• Allergic reaction or hypersensitivity to latex, contrast agent anesthesia, device materials, and drug reactions to everolimus, anticoagulation, or antiplatelet drugs
• Vascular access complications which may require transfusion or vessel repair, including: Catheter site reactions, Bleeding, Arteriovenous fistula; pseudoaneurysm, aneurysm, dissection, perforation/rupture, Embolism, 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, Coronary or stent thrombosis, Stenosis or restenosis
• Pericardial complications which may require additional intervention, including: Cardiac tamponade, Pericardial effusion, Pericarditis.
• Cardiac arrhythmias
• Cardiac ischemic conditions (including myocardial ischemia, myocardial infarction (including acute), coronary artery spasm, and unstable or stable angina pectoris)
• Stroke/Cerebrovascular Accident (CVA) and Transient Ischemic Attack (TIA)
• System organ failures: Cardio-respiratory arrest, Cardiac failure, Cardiopulmonary failure, Renal Insufficiency/failure, Shock
• Bleeding
• Blood cell disorders
• Hypotension and/or hypertension
• Infection
• Nausea and vomiting
• Palpitations
• Dizziness
• Syncope
• Chest Pain
• Fever
• Pain
• Death

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 / SmPCs and / or observed at incidences ≥ 10% in clinical trials with oral everolimus for different indications. Please refer to the drug SmPCs and labels for more detailed information and less frequent adverse events.

• Abdominal pain
• Anemia
• Angioedema
• Arterial Thrombotic Events
• Bleeding and coagulopathy
• Constipation
• Cough
• Diabetes mellitus
• Diarrhea
• Dyspnea
• Embryo-fetal toxicity
• Erythema
• Erythroderma
• Headache
• Hepatic artery thrombosis
• Hepatic disorders
• Hypersensitivity to everolimus active substance, or to other rapamycin derivates
• Hypertension
• Infections (bacterial, fungal, viral or protozoan infections, 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
• Lymphoma and skin cancer
• Male infertility
• Menstrual irregularities
• Nausea
• Nephrotoxicity
• Non-infectious pneumonitis
• 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

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.

INDICATION FOR USE

The Amplatzer™ Amulet™ Left Atrial Appendage Occluder is a percutaneous transcatheter device intended to reduce the risk of thrombus embolization from the left atrial appendage (LAA) in patients who have nonvalvular atrial fibrillation and who are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores, are suitable for short term anticoagulation therapy, and have appropriate rationale to seek a non-pharmacologic alternative to oral anticoagulation, taking into consideration the safety and effectiveness of the device.

CONTRAINDICATIONS

The Amplatzer™ Amulet™ Left Atrial Appendage (LAA) Occluder is contraindicated for patients:

• with the presence of intracardiac thrombus,
• with active endocarditis or other infections producing bacteremia.
• where placement of the device would interfere with any intracardiac or intravascular structures.

WARNINGS

• If the device is retracted while it is in the sheath, the device and the sheath must both be removed and replaced. Failure to replace both the device and the sheath may result in sheath and/or device malfunction.
• If the device is retracted farther than the radiopaque markers (fully recaptured), the device and the sheath must both be removed and replaced.
• Failure to replace both the device and the sheath may result in sheath and/or device malfunction.
• Physicians must be prepared to deal with urgent situations, such as pericardial effusion or device embolization, which can require removal of the device.
• This device should be used only by physicians who are trained in standard transcatheter techniques. The physician should determine which patients are candidates for procedures that use this device.
• Late pericardial effusion events were observed in the clinical study. The use of post-procedure anticoagulation therapy may be associated with an increased potential for a late pericardial effusion. Physicians should monitor for signs and symptoms of pericardial effusion and obtain appropriate imaging when indicated. Physicians should also consider routine echocardiography to screen for pericardial effusion.
• Remove embolized devices. Do not remove an embolized device unless the device is fully captured inside a sheath.
• The Amplatzer™ Amulet™ device contains a nickeltitanium alloy, which is generally considered safe. However, in vitro testing has demonstrated that nickel is released from this device for a minimum of 120 days. Patients who are allergic to nickel may have an allergic reaction to this device, especially those with a history of metal allergies. Certain allergic reactions can be serious; patients should be instructed to seek medical assistance immediately if they suspect they are experiencing an allergic reaction. Symptoms may include difficulty in breathing or swelling of the face or throat.
• While data are currently limited, it is possible that some patients may develop an allergy to nickel if this device is implanted.
• Do not use this device if the sterile package is open or damaged.
• The device was sterilized with ethylene oxide and is for single use only. Do not reuse or resterilize this device. Attempts to resterilize this device can cause a malfunction, insufficient sterilization, or harm to the patient.
• Use on or before the expiration date that is printed on the product packaging label.

PRECAUTIONS

• The physician should exercise clinical judgment in situations that involve the use of antithrombotic drugs before, during, and/or after the use of this device.
• The physician should exercise caution if implanting a device in a patient who has an implantable cardioverter defibrillator (ICD) or pacemaker leads.
• The physician should have the guidewire in the left upper pulmonary vein when making exchanges in the left atrium.
• Ensure that the vasculature is adequate for the sheath size being selected.
• The physician should exercise caution if performing ablation at or near the implant site after the device is implanted.
• Use standard interventional cardiovascular catheterization techniques when using Amplatzer™ products.
• Use in specific populations
• Pregnancy – Minimize the radiation exposure to the fetus and the mother.
• Nursing mothers – There has been no quantitative assessment for the presence of leachables in breast milk.

MRI SAFETY INFORMATION

Non-clinical testing has demonstrated that the Amplatzer™ Amulet™ Left Atrial Appendage Occluder device is MR Conditional. A patient with the Amplatzer™Amulet™ device can be safely scanned in an MR system under the following conditions:

• Static magnetic fields of 1.5 Tesla (1.5T) and 3.0 Tesla (3.0T)
• Maximum spatial gradient field of 19 T/m (1900 G/cm)
• Maximum MR system reported, whole-body averaged specific absorption rate (SAR) of 2.0 W/kg (normal operating mode)

Under the scan conditions defined above, the device is expected to produce a maximum temperature rise of less than or equal to 4°C after 15 minutes of continuous scanning.

In non-clinical testing, the image artifact caused by the device extends radially up to 20 mm from the device when imaged with a gradient echo pulse sequence in a 3.0T MR system.

POTENTIAL ADVERSE EVENTS

Potential adverse events associated with the device or implant procedure include, but are not limited to, the following:

• Air embolism
• Airway trauma
• Allergic reaction
• Anemia
• Anesthesia reaction (nausea, vasovagal reaction, confusion/altered mental status or other)
• Arrhythmia
• Atrial septal defect
• Bleeding
• Cardiac arrest
• Cardiac tamponade
• Chest pain/discomfort
• Congestive heart failure
• Death
• Device embolization
• Device erosion
• Device malfunction
• Device malposition
• Device migration
• Device-related thrombus
• Fever
• Hematuria
• Hypertension/hypotension
• Infection
• Multi-organ failure
• Myocardial infarction
• Perforation
• Pericardial effusion
• Pleural effusion
• Renal failure/dysfunction
• Respiratory failure
• Seizure
• Significant residual flow
• Stroke
• Thrombocytopenia
• Thromboembolism: peripheral and pulmonary
• Thrombus formation
• Transient ischemic attack
• Valvular regurgitation/insufficiency
• Vascular access site injury (hematoma, pseudoaneurysm, arteriovenous fistula, groin pain or other)
• Vessel trauma/injury

INDICATIONS FOR USE

The Amplatzer™ Talisman™ PFO Occluder is indicated for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude other causes of ischemic stroke.

CONTRAINDICATIONS

• Presence of thrombus at the intended site of implant, or documented evidence of venous thrombus in the vessels through which access to the defect is gained.
• Patients with intra-cardiac thrombus, mass, vegetation, or tumor.
• Patients whose vasculature, through which access to the PFO is gained, is inadequate to accommodate the appropriate sheath size.
• Patients with anatomy in which the required Amplatzer™ Talisman™ PFO device size would interfere with other intracardiac or intravascular structures, such as valves or pulmonary veins.
• Patients with another source of right-to-left shunts, including an atrial septal defect and/or fenestrated septum.
• Patients with active endocarditis or other untreated infections.
• Patients who are unable to tolerate intra-procedural anticoagulation or post-procedural anti-platelet therapy.

WARNINGS

• Do not use an open or damaged pouch; do not use a damaged device.
• Patients who are at increased risk for venous thromboembolic events should be managed with thromboembolic risk reduction regimen after the PFO closure following standard of care.
• The safety and effectiveness of the Amplatzer™ Talisman™ PFO Occluder has not been established in patients with a hypercoagulable state.
• Prepare for situations that require percutaneous or surgical removal of this device. This includes availability of a surgeon and access to operating room.
• Embolized devices must be removed as they may disrupt critical cardiac functions. Do not remove an embolized occluder through intracardiac structures unless the occluder is fully recaptured inside a catheter or sheath.
• The Amplatzer™ Talisman™ PFO Occluder device consists of a nickel-titanium alloy, which is generally considered safe. However, in vitro testing has demonstrated that nickel is released from this device for a minimum of 60 days. Patients who are allergic to nickel may have an allergic reaction to this device, especially those with a history of metal allergies. Certain allergic reactions can be serious; patients should be instructed to notify their physicians immediately if they suspect they are experiencing an allergic reaction such as difficulty breathing or inflammation of the face or throat. Some patients may also develop an allergy to nickel if this device is implanted.
• Transient hemodynamic compromise may be encountered during device placement, which may require fluid replacement or other medications as determined by the physician.
• Prior to device detachment, evaluate the position of the device relative to the free atrial wall and the aortic root using echocardiography.
• Use echocardiography to ensure that the device does not impinge on the free atrial wall or aortic root.
• Do not release the device from the delivery cable if the device does not conform to its original configuration, or if the device position is unstable or if the device interferes with any adjacent cardiac structure (such as Superior Vena Cava (SVC), Pulmonary Vein (PV), Mitral Valve (MV), Coronary Sinus (CS), aorta (AO)). If the device interferes with an adjacent cardiac structure, recapture the device and redeploy. If still unsatisfactory, recapture the device and either replace with a new device or consider alternative treatments.
• DO NOT use the Amplatzer™ Talisman™ PFO Occluder after the Use-by date stated on the package label.
• This device was sterilized with ethylene oxide and is for single use only. Never reuse or re-sterilize the system. Use of expired, reused, or re-sterilized devices may result in infection.
• This device should be used only by physicians who are trained in standard transcatheter techniques.

PRECAUTIONS FOR SPECIAL POPULATIONS

• Pregnancy: The safety and effectiveness of this occluder has not been established during pregnancy. Fluoroscopic x-ray guidance is used during placement of the device. The risk of increased X-ray exposure for patients who are pregnant must be weighed against the potential benefits of this technique.
• Nursing mother: The safety and effectiveness of this occluder has not been established in lactating mothers. There has been no quantitative assessment for the presence of leachables in breast milk.
• Pediatric Population: The safety and effectiveness of this occluder has not been established in a pediatric population.

PRECAUTIONS

• Aspirin (325 mg/day) (or alternative antiplatelet/anticoagulant, if patient has aspirin intolerance) is recommended to be started at least 24 hours prior to the procedure.
• Antibiotics should be administered peri-procedurally.
• Patients should be fully heparinized throughout the procedure using adequate dosing so as to keep the activated clotting time (ACT) greater than 200 seconds.

CAUTION: Intracardiac echocardiography (ICE) or transesophageal echocardiography (TEE) is recommended as an aid in evaluating the PFO and placing the Amplatzer™ Talisman™ PFO Occluder. If TEE is used, the patient’s esophageal anatomy must be adequate for placement.

CAUTION: Be cautious when using fluoroscopic X-ray guidance, which may be used during placement of the device.

CAUTION: Do not use a power injection system to put contrast solution through the sheath.

The safety and effectiveness of the Amplatzer™ Talisman™ PFO Occluder has not been established in patients (with):

• Age less than 18 years or greater than 60 years because enrollment in the pivotal study (the RESPECT trial) was limited to patients 18 to 60 years old
• A hypercoagulable state including those with a positive test for a anticardiolipin antibody (IgG or IgM), Lupus anticoagulant, beta-2 glycoprotein-1 antibodies, or persistently elevated fasting plasma homocysteine despite medical therapy
• Unable to take antiplatelet therapy
• Atherosclerosis or other arteriopathy of the intracranial and extracranial vessels associated with a ≥50% luminal stenosis
• Acute or recent (within 6 months) myocardial infarction or unstable angina
• Left ventricular aneurysm or akinesis
• Mitral valve stenosis or severe mitral regurgitation, irrespective of etiology
• Aortic valve stenosis (mean gradient greater than 40 mmHg) or severe aortic valve regurgitation
• Mitral or aortic valve vegetation or prosthesis
• Aortic arch plaques protruding greater than 4 mm into the aortic lumen
• Left ventricular dilated cardiomyopathy with left ventricular ejection fraction (LVEF) less than 35%
• Chronic, persistent, or paroxysmal atrial fibrillation or atrial flutter
• Uncontrolled hypertension or uncontrolled diabetes mellitus
• Diagnosis of lacunar infarct probably due to intrinsic small vessel as qualifying stroke event
• Arterial dissection as cause of stroke
• Index stroke of poor outcome (modified Rankin score greater than 3)
• Pregnancy at the time of implant
• Multi-organ failure

PATIENT COUNSELING INFORMATION
Physicians should review the following information when counseling patients about the Amplatzer™ Talisman™ PFO Occluder and the implant procedure:

• The safety and effectiveness of PFO closure with the Amplatzer™ Talisman™ PFO Occluder in combination with the required postimplant antiplatelet therapy.
• PFO closure with the Amplatzer™ Talisman™ PFO Occluder can only reduce the risk for a recurrent stroke due to a paradoxical embolism through a PFO.
  - With aging, there is an increased likelihood that non-PFO related risks for stroke may develop and cause a recurrent ischemic stroke independent of PFO closure.

• The procedural risks associated with Amplatzer™ Talisman™ PFO Occluder.
• The need for adherence to a defined adjunctive antithrombotic therapy following implantation of the Amplatzer™ Talisman™ PFO Occluder.
• Patients with a history of DVT or PE may benefit from continuation or resumption of anticoagulation therapy following implantation of the Amplatzer™ Talisman™ PFO Occluder to reduce the risk of recurrent DVT or PE.

It is recommended that the medical team (neurologist and cardiologist) and the patient engage in a shared decision-making process and discuss the risks and benefits of PFO closure in comparison to using antithrombotic therapy alone, while taking into account the patient’s values and preferences.

POTENTIAL ADVERSE EVENTS
Potential adverse events that may occur during or after a procedure using this device may include, but are not limited to:

• Air embolus
• Allergic reaction/toxic effect due to: anesthesia, contrast media, medication, or metal
• Arrhythmia
• Arteriovenous fistulae
• Bleeding
• Cardiac perforation
• Cardiac tamponade
• Chest pain
• Death
• Deep vein thrombosis
• Device embolization
• Device erosion
• Endocarditis
• Esophagus injury
• Fever
• Headache/migraine
• Hematoma
• Hypertension/hypotension
• Infection
• Myocardial infarction
• Pacemaker placement secondary to PFO device closure
• Pain
• Pericardial effusion
• Pericarditis
• Peripheral embolism
• Pseudoaneurysm
• Pulmonary embolism
• Reintervention for residual shunt/device removal
• Stroke
• Transient ischemic attack
• Thrombus formation
• Valvular regurgitation
• Vascular access site injury
• Vessel perforation

INDICATIONS

The Portico™ Transcatheter Aortic Valve Implantation System is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis who are judged by a heart team, including a cardiac surgeon, to be high or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 8% at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical comorbidities unmeasured by the STS risk calculator).

CONTRAINDICATIONS

The valve is contraindicated for patients with inability to tolerate antiplatelet/anticoagulant therapy or nitinol alloy (nickel and titanium), or who have active infections, including endocarditis.

WARNINGS

Carefully read all warnings, precautions, and instructions for use for all components of the system before use. Failure to read and follow all instructions or failure to observe all stated warnings could cause serious injury or death to the patient.

• Perform Portico™ valve implantation in a facility where emergency aortic valve surgery is available.
• Verify that the patient’s anatomy is consistent with the specifications set forth in the anatomical specifications tables 2 and 3 (found in IFU).
• For single use only. Do not reuse, reprocess, or resterilize the valve, delivery system, or the loading system. Reuse, reprocessing, and/or resterilization creates a risk of contamination of the devices and/or device failure, which could cause patient injury, illness or death.
• Do not manipulate or handle the valve with sharp or pointed objects.
• Rinse the valve as directed before loading the valve onto the delivery system.
• Do not use the valve, the delivery system, or the loading system if the “USE BY” date has elapsed.
• Exercise care to prevent kinking of the delivery system when removing it from the packaging.
• This device contains nitinol, an alloy of nickel and titanium. Persons with allergic reactions to these metals may suffer an allergic reaction to this implant. Prior to implantation, patients should be counseled on the materials contained in the device, as well as potential for allergy/hypersensitivity to these materials.
• Accelerated deterioration of the valve due to calcific degeneration may occur in children, adolescents, young adults, or patients with altered calcium metabolism.

PRECAUTIONS

Pre-Implantation Precautions

• The safety, effectiveness, and durability of a Portico™ valve implanted within a surgical or transcatheter bioprosthesis have not been demonstrated.
• Long-term durability has not been established for the Portico valve. Regular medical follow-up is advised to evaluate valve performance.
• For transaortic access, ensure the access site and trajectory are free of internal patent right internal mammary artery (RIMA) or pre-existing patent RIMA graft.
• For subclavian/axillary access, use caution in patients with mammary artery grafts.
• Balloon aortic valvuloplasty (BAV) of the native aortic valve is recommended prior to delivery system insertion. The balloon size chosen should be appropriate, not exceeding the minimum diameter of the native aortic annulus as assessed by CT imaging to minimize risk of annular rupture and not undersized to minimize risk of stent under-expansion which could lead to paravalvular leak (PVL) or device migration.
• Do not use the valve if the shipping temperature indicator on the product package has turned red, or if the valve has been improperly stored in temperature conditions outside of the 5°C–25°C (41°F–77°F) range.
• Do not use the valve if the tamper-evident container seal is damaged, broken, or missing, or if fluid is leaking from the packaging.
• Do not advance the delivery system without the guidewire extending from the tip.
• Do not use the valve without thoroughly rinsing as directed.
• Do not use the delivery system without thoroughly flushing as described in the "Directions for Use" section.
• The safety and effectiveness of the Portico™ valve and FlexNav™ delivery system have not been evaluated in the following patient populations:
  - Congenital unicuspid or bicuspid valve, or any leaflet configuration other than tricuspid
  - Severe ventricular dysfunction with left ventricular ejection fraction <20%
  - Non-calcific aortic annulus
  - Echocardiographic evidence of intracardiac mass, thrombus or vegetation
  - Patients at low or intermediate surgical risk
  - Patients who are pregnant or breastfeeding
  - Pediatric patients (less than 21 years of age)
  - Patients with a pre-existing prosthetic heart valve or prosthetic ring in any position
  - Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation > 3+)
  - Patients with severe circumferential mitral annular calcification (MAC) which is continuous with calcium in the LVOT, severe (greater than 3+) mitral insufficiency, or severe mitral stenosis with pulmonary compromise
  - Blood dyscrasias as defined: leukopenia (WBC<3000 mm³), acute anemia (Hb < 9 g/dL), thrombocytopenia (platelet count <50,000 cells/mm³)
  - Patients with untreated clinically significant coronary artery disease requiring revascularization
  - Patients with bulky calcified aortic valve leaflets in close proximity to coronary ostia
  - Hypertrophic cardiomyopathy with or without obstruction (HOCM)
  - Renal insufficiency (creatinine > 3.0 mg/dL) and/or end stage renal disease requiring chronic dialysis
  - Hemodynamic instability requiring inotropic support or mechanical heart assistance
  - Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5cm or greater; marked tortuosity (hyperacute bend), aortic arch atheroma (especially if thick [> 5 mm], protruding or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta
  - Patients with known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or clopidogrel (Plavix), or sensitivity to contrast media which cannot be adequately premedicated
  - Patients with access characteristics that would preclude safe placement of the introducer sheath, when necessary, such as severe obstructive calcification, or severe tortuosity

Implantation Precautions

• To minimize risk of guidewire perforations in the left ventricle, a manufacturer pre-shaped guidewire should be used during the procedure and during valve deployment.
• Do not deploy the valve if excessive resistance to deployment is encountered. If the valve does not deploy easily, re-sheath the valve, remove it from the patient, and use a different valve and delivery system.
• Follow the procedure in “Implanting the Valve” to reposition the valve or to remove the valve from the patient.
• Do not attempt to reposition the valve by advancing it distally unless the valve has been fully re-sheathed within the delivery system.
• Do not re-sheath the valve more than two times prior to final valve release. Additional re-sheath attempts may compromise product performance.
• To minimize likelihood of permanent pacemaker implantation (PPI): a) maintain implant depth of 3mm, and b) limit manipulations across the LVOT.

Post-Implantation Precautions

• In the event that a post-implant balloon dilatation is performed to address paravalvular leak (PVL), valve size, patient anatomy, and implant depth must be considered when selecting the size of the balloon for dilatation. The balloon size chosen should not exceed the mean diameter of the native aortic annulus. Moderate or Severe PVL should be addressed at the time of the TAVI procedure.
• Exercise care when removing the delivery system from the patient.
• Exercise care when crossing the valve with adjunctive devices.
• Once the valve is fully deployed, repositioning and retrieval of the valve is not possible. Attempted retrieval (e.g., use of a guidewire, snare, or forceps) may cause aortic root, coronary artery, and/or myocardial damage.
• Valve recipients should be maintained on antiplatelet and/or anticoagulant therapy post procedure, per institutional standards and established guidelines, except when contraindicated, using individualized treatment as determined by their physician.
• Post-implant monitoring and/or possible electrophysiology evaluation may be considered in patients with transient high degree or complete AV block or other conduction disturbances during or following implantation of the valve. This may include continuous ECG monitoring after hospital discharge.

POTENTIAL ADVERSE EVENTS

Adverse events potentially associated with the use of transcatheter bioprosthetic heart valves include but are not limited to:

• access site complications (e.g., pain, bleeding, infection, hematoma, pseudoaneurysm, etc.)
• acute coronary obstruction
• acute myocardial infarction
• allergic reaction to antiplatelet agents, contrast medium, or valve components
• aortic rupture
• ascending aorta trauma
• atrio-ventricular node block
• cardiac arrhythmias
• conduction system injury
• conversion to open surgical procedure
• death
• dissection
• embolism
• emergent balloon valvuloplasty
• emergent percutaneous coronary intervention (PCI)
• emergent surgery (i.e., coronary artery bypass, heart valve replacement)
• endocarditis
• explantation
• heart failure
• hemodynamic compromise
• hemolysis
• hemolytic anemia
• hemorrhage
• hypotension or hypertension
• infection
• myocardial ischemia
• mitral valve insufficiency
• multi-organ failure
• non-structural dysfunction (i.e., entrapment by pannus, paravalvular leak, inappropriate sizing or positioning)
• pannus
• pericardial effusion
• perforation of the myocardium, ventricle, or a blood vessel
• permanent disability
• permanent pacemaker
• regurgitation
• renal insufficiency or renal failure
• reoperation
• respiratory failure
• sepsis
• stroke
• structural deterioration (i.e., calcification, leaflet tear)
• thrombosis
• tamponade
• transfusion
• valve embolization or migration
• vessel dissection or spasm

INDICATION FOR USE

The Epic™ Plus valve is indicated for patients requiring replacement of a diseased, damaged, or malfunctioning native aortic and/or mitral heart valve. It may also be used as a replacement for a previously implanted aortic and/or mitral prosthetic heart valve.

The Epic™ Plus Supra valve is indicated for patients requiring replacement of a diseased, damaged, or malfunctioning native aortic heart valve. It may also be used as a replacement for a previously implanted aortic prosthetic heart valve.

CONTRAINDICATIONS

None known.

WARNINGS

• Valve size selection is based on the size of the recipient annulus, and for supra-annular aortic placement, the anatomy of the sinotubular space. Implantation of an inappropriately large bioprosthesis may result in stent deformation, valvular incompetence, valve damage, diminished tissue durability and/or damage to the surrounding tissues. The use of an inappropriately small bioprosthesis may result in suboptimal hemodynamics. Use only the E2000 Epic™ Plus Heart Valve Sizer Set with the Epic™ Plus and Epic™ Plus Supra valves.
• Accelerated deterioration due to calcific degeneration of the Epic Plus and Epic Plus Supra valve may occur in: children, adolescents, or young adults; patients with altered calcium metabolism (e.g., patients with hyperparathyroidism or chronic renal failure); or individuals requiring hemodialysis.
• For single use only. Do not reuse or resterilize. Attempts to resterilize the valve may result in valve malfunction, inadequate sterilization, or patient harm.
• Passage of a catheter or transvenous pacing lead through any bioprosthesis may damage the valve and is therefore not recommended.
• Do not use if:
  - the valve has been dropped, damaged, or mishandled in any way, or if there is any sign of deterioration;
  - the expiration date has elapsed;
  - the tamper-evident container seal is damaged, broken, or missing, or if fluid is leaking from the packaging; or
  - the storage solution does not completely cover the valve.

PRECAUTIONS

• The safety and effectiveness of the Epic™ Plus and Epic™ Plus Supra valves has not been established for the following specific populations:
  - patients who are pregnant
  - nursing mothers
  - patients with chronic renal failure
  - patients with aneurysmal aortic degenerative conditions (e.g., cystic medial necrosis, Marfan’s syndrome)
  - patients with chronic endocarditis
  - patients requiring pulmonic or tricuspid valve replacement
  - children, adolescents, or young adults
• Sizers are supplied non-sterile, and must be cleaned and sterilized prior to each use. Do not use cracked, deformed, or damaged sizer set components.
• Do not pass the flanged portion of the valve replica sizing tool through the annulus.
• Do not place the non-sterile exterior of the valve container in the sterile field.
• Do not expose the valve to solutions other than the formaldehyde valve storage solution in which it was shipped, the sterile isotonic saline solution used during the rinsing procedure, or the sterile isotonic saline solution used to irrigate the valve.
• Do not add antibiotics to either the formaldehyde valve storage solution or the rinse solution.
• Do not apply antibiotics to the valve.
• Do not allow the valve tissue to dry. Place the valve in sterile isotonic saline rinse solution immediately upon removal from the valve storage solution. Once removed from this solution, the valve should be periodically irrigated during implantation.
• Do not use the valve if shipping temperature indicators on the product carton have turned red, or if the valve has been improperly stored in temperature conditions outside of the 5 °C to 25 °C range.
• Do not implant the valve without thoroughly rinsing as directed.
• Do not lacerate the valve tissue. If a valve is damaged, the valve must be explanted and replaced.
• Do not attempt to repair a valve. Damaged valves must not be used.
• Do not use cutting edge needles, unprotected forceps, or sharp instruments as they may cause structural damage to valve.
• Never handle the leaflet tissue.
• Position the mitral valve in a manner to avoid commissure obstruction of the left ventricular outflow tract, and minimize any potential of commissure contact with the ventricular wall.
• Position the aortic valve so that the stent posts do not obstruct the coronary ostia or come in direct contact with the aortic wall.
• When implanting the Epic™ Plus heart valve, assess the suitability of the selected valve size and stent post position for a potential future valve-in-valve procedure and whether the transcatheter valve-in-valve procedure may result in left ventricular outflow tract or coronary ostia obstruction. For future valve-in-valve procedure in an Epic Plus valve, refer to the instructions for use supplied with the transcatheter heart valve along with reference dimensions in Table 1 (in the IFU) to determine compatibility. The safety and effectiveness of valve-in-valve procedures in an Epic™ Plus or an Epic™ Plus Supra valve have not been established.
• Avoid prolonged contact with the formaldehyde storage solution. Immediately after contact, thoroughly flush any skin exposed to the solution with water. In case of contact with eyes, flush with water and seek appropriate medical care.

ADVERSE EVENTS

The clinical investigation of the Epic valve supports the safety and effectiveness of the Epic™ Plus valve and the Epic™ Plus Supra valve. Between January 2003 and March 2006, seven-hundred and sixty-two (762) subjects were implanted with 791 Epic Valve(s) at 19 investigational sites in the United States (U.S.), and three sites in Canada. Five-hundred and fifty-seven (557) subjects received isolated aortic replacement, 176 received isolated mitral replacement, and 29 received replacement of both the aortic and mitral valves. The cumulative follow-up for all subjects was 773.51 patient-years with a mean follow-up of 1.02 patient-years (s.d. = 0.71 patient-years, range 0 – 3.10 patient-years).

Potential Adverse Events

Adverse events potentially associated with the use of bioprosthesis heart valves (in alphabetical order) include:

• angina
• cardiac arrhythmias
• endocarditis
• heart failure
• hemolysis
• hemolytic anemia
• hemorrhage, anticoagulant/antiplatelet-related
• leak, transvalvular or paravalvular
• myocardial infarction
• nonstructural dysfunction (entrapment by pannus or suture, inappropriate sizing or positioning, or other)
• prosthesis regurgitation
• stroke
• structural deterioration (calcification, leaflet tear, or other)
• thromboembolism
• valve thrombosis

It is possible that these complications could lead to:

• reoperation
• explantation
• permanent disability
• death