← Product Code LWR · P100029 # ST JUDE MEDICAL TRIFECTA VALVE (P100029) _ABBOTT MEDICAL · LWR · Apr 20, 2011 · Cardiovascular · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P100029 ## Device Facts - **Applicant:** ABBOTT MEDICAL - **Product Code:** LWR - **Decision Date:** Apr 20, 2011 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Cardiovascular - **Attributes:** Therapeutic ## Intended Use The Trifecta Valve is indicated as a replacement for a diseased, damaged, or malfunctioning native or prosthetic aortic heart valve. ## Device Story The Trifecta Valve is a tri-leaflet stented pericardial valve for supra-annular aortic placement. It consists of a polyester-covered titanium stent and bovine pericardial leaflets, with a silicone insert in the sewing cuff. The tissue is glutaraldehyde-fixed and processed with Linx anticalcification technology. The device is implanted by a surgeon in an OR setting. It functions as a mechanical replacement for native or prosthetic aortic valves, restoring hemodynamic flow. The healthcare provider assesses the valve's performance via echocardiography post-implantation. The device benefits patients by improving cardiac function, as evidenced by NYHA functional classification improvements. ## Clinical Evidence Prospective, non-randomized, observational study of 1014 subjects (mean age 72.5 years) implanted with the Trifecta Valve. Primary endpoints included adverse event rates, NYHA functional classification, and hemodynamic performance (echocardiography). At 1 year, 98.7% of subjects were NYHA Class I/II (vs 50.7% preoperatively, p<0.0001). Mean gradients at 1 year ranged from 4.7 to 10.7 mmHg across sizes. Freedom from valve-related mortality at 1 year was 99.4%. Results demonstrated safety and effectiveness comparable to literature-based controls for stented tissue valves. ## Technological Characteristics Tri-leaflet stented pericardial valve. Materials: bovine pericardial leaflets, polyester-covered titanium alloy stent, silicone sewing cuff ring. Processing: glutaraldehyde cross-linking, Linx anticalcification technology. Sizes: 19-29mm. MR Conditional (3T). Sterilization: multi-component liquid chemical sterilant. Complies with ISO 5840 (cardiovascular implants). ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). {0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA I. GENERAL INFORMATION Device Generic Name: Replacement Heart Valve Device Trade Name: Trifecta™ Valve: aortic sizes 19, 21, 23, 25, 27, and 29mm Applicant's Name and Address: St. Jude Medical 177 County Rd B East St. Paul, MN 55117 Date of Panel Recommendation: none Premarket Approval Application (PMA) Number: P100029 Date of Notice of Approval: April 20, 2011 Expedited: not applicable II. INDICATIONS FOR USE The Trifecta Valve is indicated as a replacement for a diseased, damaged, or malfunctioning native or prosthetic aortic heart valve. III. CONTRAINDICATIONS None known. IV. WARNINGS AND PRECAUTIONS The warnings and precautions are provided in the device labeling for the Trifecta Valve. V. DEVICE DESCRIPTION The Trifecta Valve is a tri-leaflet stented pericardial valve designed for supra-annular placement in the aortic position. The valve is fabricated using a polyester-covered titanium stent. The stent, excluding the sewing cuff, is next covered with porcine pericardial tissue. This covering provides protection from mechanical wear by allowing only tissue-to-tissue contact during valve function. A silicone insert within the polyester sewing cuff is slightly contoured to conform to the shape of the native annulus. The valve leaflets are made from bovine pericardium. The porcine and bovine pericardium are preserved and cross-linked in glutaraldehyde. Glutaraldehyde, formaldehyde, and ethanol are used in the valve sterilization process. The Trifecta Valve is processed using Linx™ anticalcification technology. Non-clinical testing has demonstrated that the Trifecta Valve is MR Conditional. {1} The Trifecta Valve is available for aortic annulus sizes 19mm, 21mm, 23mm, 25mm, 27mm and 29mm. The Trifecta Valve is supplied sterile and non-pyrogenic. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES The alternative treatments to the Trifecta Valve include drug therapy or surgical treatments such as annuloplasty or valvuloplasty (with or without the use of implantable materials). If a patient requires replacement of their native or previously implanted prosthetic valve, the alternatives include other commercially available mechanical valves, homografts, or bioprosthetic valves. The choice of replacement valve depends on an assessment of patient factors which include age, preoperative condition, anatomy, and the patient's ability to tolerate long-term anticoagulant therapy. 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 lifestyles. ## VII. MARKETING HISTORY Commercial distribution of the Trifecta Valve outside the U.S. began in 2010, and the valve is currently available in the following countries: Austria, Belgium, Bulgaria, Canada, Cyprus, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Latvia, Liechtenstein, Luxembourg, Malta, Netherlands, Portugal, Romania, Slovenia, Spain, Switzerland, Sweden, and the United Kingdom. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 2 of 20 {2} Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 3 of 20 # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Adverse events potentially associated with the use of bioprosthetic heart valves (in alphabetical order) include: - angina - cardiac arrhythmias - endocarditis - heart failure - hemolysis - hemolytic anemia - hemorrhage - leak, transvalvular or perivalvular - myocardial infarction - nonstructural dysfunction (entrapment by pannus or suture, inappropriate sizing or positioning, or other) - prosthesis regurgitation - stroke - structural deterioration (calcification, leaflet tear, perforation, or other) - thromboembolism - valve thrombosis It is possible that these complications could lead to: - reoperation - explantation - permanent disability - death For the specific adverse events that occurred in the clinical study, please see Section X below. # IX. SUMMARIES OF PRECLINICAL STUDIES ## A. Laboratory Studies ### A.1 Biocompatibility Based on the results of the biocompatibility testing performed, the materials used in the Trifecta Valve were determined to be biocompatible, non-mutagenic, and non-toxic. #### Non-Biological Components The non-biological components of the Trifecta Valve consist of polyester fabric (knitted and spun), polyester/PTFE surgical sutures, a titanium alloy stent, and a silicone ring within the sewing cuff. These materials have a long history of use in cardiovascular implantation devices. {3} Biocompatibility testing of the non-biological components including the polyester fabric, polyester /PTFE suture, and the titanium stent were performed in accordance with the requirements detailed in International Standards Organization 10993-1 and United States Food and Drug Administration General Program Memorandum G95-1. The tests performed, the test objective and test results are provided in Table 1. Carcinogenicity, chronic and reproductive toxicity testing were not conducted since the chemical residual profile of the valve did not indicate that these long-term chronic studies were necessary. Table 1: Biocompatibility Tests and Results - Non-Biological Components | Test Performed | Objectives | Test Article | Results | | --- | --- | --- | --- | | Cytotoxicity (ISO MEM L929) | Evaluate cytotoxic effects of the test article on a mouse fibroblast monolayer. | Stent Stent Covering Suture Sewing cuff | Passed Non-cytotoxic | | Sensitization (LLNA or ISO Maximization) | Evaluate the chemically processed stent to determine if it causes a sensitization reaction | Stent Stent Covering | Passed No evidence of sensitization | | Intracutaneous Reactivity (ISO Rabbit Intracutaneous Reactivity) | Evaluation of local dermal irritation or toxic effects of leachables extracted from the test article following intra-cutaneous injection in rabbits (ISO, USP) and mice (USP). | Stent Stent Covering | Passed Non-irritant | | Acute Systemic Toxicity (ISO Mouse Systemic Injection) | Evaluation of acute systemic toxicity of leachables extracted from the test article following a single intravenous or intraperitoneal injection in mice or guinea pigs. | Stent Stent Covering | Passed Non=toxic | | Pyrogen Test (USP Rabbit Pyrogen) | Determine if a febrile response occurs in New Zealand white rabbits either from a material mediated reaction or as a result of endotoxin or other possible pyrogens that may be present. | Stent | Passed Non-pyrogenic | | Hemocompatibility (ASTM Direct Contact and NIH Direct Contact) | Determine if leachables extracted from the test article will cause a significant level of hemolysis in blood. | Stent Stent Covering Suture Sewing cuff | Passed Non-hemolytic | | Genotoxicity (Ames) | Evaluation of the potential of the titanium stent to induce reverse mutations in four strains of Salmonella and one strain of Escherichia coli in the presence and absence of exogenous mammalian metabolic activation system (S9). | Stent | Passed Non-mutagenic | | Implantation (ISO Rabbit Subcutaneous and Intramuscular) | Evaluation of a test article to local pathological effects on living tissue in rabbit (macro and histopathological examinations of implant tissue/muscle sites). | Stent Stent Covering | Passed Non-irritant | Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 4 of 20 {4} # Biological Components Glutaraldehyde-fixed porcine and bovine pericardial tissue is well established for use in bioprosthetic devices and each has a long history of safe usage in clinical applications. The tissues incorporated in the Trifecta Valve are liquid chemically processed in a similar fashion to other commercially available tissue valves incorporating animal tissues. A thorough assessment of potential leachables from the Trifecta valves has been performed which includes a study of extractable residuals during rinsing. The results of the biocompatibility testing performed confirm that the extractable chemical residues from the Trifecta valves are similar in type and concentration as compared to a clinically approved (U.S.) control valve. # Valve Accessories and Packaging Components The non-implantable valve accessories and packaging components (valve holders, valve sizer sets, jar, lid, and lid liner) were subjected to a number of biocompatibility tests as appropriate for these components. All results were found to be acceptable. ## A.2 Hydrodynamic Performance Hydrodynamic performance studies were completed on the Trifecta Valve in accordance with the ISO 5840, Cardiovascular Implants-Cardiac Valve Prosthesis (1996). Testing included steady flow pressure drop, steady backflow leakage, pulsatile flow pressure drop, pulsatile flow regurgitation, flow visualization, and verification of the Bernoulli relationship. Commercially available bioprosthetic heart valves were used as controls. Test results are summarized in Table 2. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 5 of 20 {5} Table 2: Hydrodynamic Performance Summary | Test Type | Sample Size | Control Size | Results | | --- | --- | --- | --- | | Steady Flow Pressure Drop | 5 each size | 1 valve, sizes 19, 25, and 29mm | Steady flow pressure drop is directly correlated to and consistent with pulsatile flow pressure drop results. | | Steady Back Flow Leakage | 5 each size | 1 valve, sizes 19, 25, and 29mm | Valve closes completely and maintains complete coaptation under a back pressure of 200mmHg. | | Pulsatile Flow Pressure Drop | 5 each size | 1 valve, sizes 19, 25, and 29mm | Meets the requirements in ISO 5840/FDIS: 5840 2005 (E), Cardiovascular Implants-Cardiac valve prosthesis. | | Pulsatile Flow Regurgitation | 5 each size | 1 valve, sizes 19, 25, and 29mm | Valve maintains complete coaptation and meets requirements in ISO/FDIS: 5840 2005 (E), Cardiovascular implants-Cardiac valve prostheses | | Flow Visualization | 1 vale, size 19mm | NA | Results indicate the valve opens efficiently and symmetrically. The flow field produced by the Trifecta Valve is a centralized flow field and is evenly distributed over a wide region. | | Bernoulli Relationship | 1 each, sizes 19, 25 and 29mm | NA | The Bernoulli equation accurately projects true pressure gradient for the valve. | ## A.3 Structural Performance Structural performance studies on the Trifecta Valve were conducted in accordance with the ISO 5840, Cardiovascular Implants – Cardiac Valve Prosthesis (1996). Testing included accelerated wear, dynamic failure mode, fatigue, stent creep, and sewing cuff integrity. The structural performance testing summary is provided in Table 3. The valve passed all of the tests performed. Commercially available bioprosthetic heart valves were used as controls. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 {6} Table 3: Structural Performance Summary | Test Type | Sample Size | Control Size | Results | | --- | --- | --- | --- | | Accelerated Wear | 5 each, sizes 19, 25, and 29mm | 1 valve, sizes 19, 25, and 29mm | Trifecta valves maintained their performance and did not demonstrate significant wear out to 200 million cycles. One valve showed a slight change in coaptation line, however the valve continued to function normally throughout duration of test. | | Dynamic Failure Mode | 6 valves, 19mm 5 each, sizes 21, 23, 25,27, and 29mm | 1 valve, size 19mm 2 valves, size 21mm 3 valves size 25mm 1 valve, size 19mm 2 valves, size 33mm | The failure mode observed was excessive regurgitation due to leaflet tear at the commissure apex. For Trifecta valves which failed, the failures occurred between 460 million and 1020 million cycles. The control valves which failed, failed between 140 million and 210 million cycles. | | Finite Element Analysis | All stent sizes included in analysis | NA | The largest stress observed was 269 MPa (42.9 ksi) for the size 23mm stent. | | Stent Fatigue | 30 stents, size 25mm | NA | No failures observed through 600 million cycles at 586 MPa (85 ksi). | | Stent Creep | 30 stents, size 25mm | NA | No sign of yielding or dynamic creep was observed through 600 million cycles at 586 MPa (85 ksi). | | Sewing Cuff Integrity | 3 each size stent | NA | All test samples exhibited cuff retention in excess of the minimum device specification. | ## B. Animal Studies Chronic GLP animal studies were performed with the Trifecta Valve using both the adult and juvenile ovine model. The studies were completed following the requirements specified in the ISO 5840, Cardiovascular Implants – Cardiac Valve Prosthesis (1996). A total of 6, size 19mm, Trifecta valves were implanted in the aortic position of adult female sheep between 1 to 3 years of age for a minimum of 90 days. A total of 6, size 25mm, Trifecta valves were implanted in the mitral position of juvenile sheep between 18 to 20 weeks of age for a minimum of 140 days. Commercially available bioprosthetic heart valves with an anticalcification treatment were used as controls. The study included an evaluation of handling and implant characteristics, animal survival, hemodynamic performance, valve pathology, hematology and mineralization. The Trifecta Valve demonstrated normal valve tissue response, Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 {7} acceptable hemodynamic performance, good animal survival rates, and favorable mineralization rates. ## B.1 Handling and Implant Characteristics Handling and implantation characteristics of the Trifecta Valve were evaluated by the implanting surgeons and were considered comparable to the control valve. ## B.2 Animal Survival There was one early animal death at day 33 in the test group implanted in the adult sheep model (aortic position); however, cause of death was not attributed to valve performance. There was one early death at day 21 in the test group implanted in the juvenile sheep model (mitral position); however, cause of death was not attributed to valve performance. ## B.3 Hemodynamic Performance At the time of explant, all animals were subjected to standard heart (direct) catheterization to obtain hemodynamic measurements. Hemodynamic parameters obtained on all animals were typically within the normal physiologic range. ## B.4 Valve Pathology Valve pathology included photographic analysis of the explanted valves. Gross observations of the mitral and aortic valves indicated a similar pathology for both the Trifecta valves and the control valves. In general, the valves were well seated in the annulus. The base of leaflets and sewing cuffs were covered with minimal white translucent-shining tissue (pannus). There were minimal fibrinous deposits on the commissures and margins. The degree of host tissue reaction to the valve appeared to be similar in all groups. There was minimal diffuse pannus growth on the base of the leaflets and sewing cuff, and minimal focal fibrinoid thrombosis on the valve margin and commissures. ## B.5 Hematology The overall blood chemistries appeared normal when compared to juvenile ovine reference values (Nemi C. Jain Veterinary Hematology - Fourth Edition).² There were no observable negative effects of the test valves on any serial blood parameters. The blood chemistries and hematological profiles were similar to the control valves. ## B.6 Mineralization Mineralization was evaluated by X-ray radiographs of whole valves, histopathological analysis of leaflet sections and quantitative analysis using inductively coupled plasma atomic emission spectroscopy (ICP). Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 8 of 20 13 {8} A correlation between pathological observations (gross pathology, X-ray, and histology) of the explanted valve and leaflets and the chemical confirmation of calcium was noted. Only minimal calcium content was measured in the Trifecta leaflet tissue and was comparable to the control valves via ICP analysis. One of the two control valves in the mitral position was severely calcified based upon gross pathology, X-ray, and histology. ## C. Additional Studies ### C.1 Sterilization The Trifecta Valve is sterilized with a multi-component liquid chemical sterilant. Microbial screening studies were conducted with a variety of organisms exposed to the sterilant in a simulated manufacturing sterilization process. The D-values derived from the screening studies showed *Bacillus atraphaeus* to be the most resistant microbial organism to this sterilization process. The D-value obtained from the *B. atraphaeus* microbial survival study was used to calculate the minimum sterilization time required to meet a minimum Sterility Assurance Level (SAL) of $10^{-6}$. ### C.2 Magnetic Resonance Imaging (MRI) Compatibility Non-clinical testing has demonstrated that the Trifecta Valve is MR conditional. It can be scanned safely under the following conditions: - Static magnetic field of 3 Tesla or less - Spatial gradient of 525 Gauss/cm or less - Maximum whole-body-averaged specific absorption rate (SAR) of 2.0-W/kg for 15 minutes of scanning. ### C.3 Shelf Life The shelf life for the Trifecta Valve was validated to ensure that both the package integrity and the product integrity were maintained for 2 years. ### C.4 Package Integrity The packaging used for the Trifecta Valve has been shown to maintain sterility for the 2-year product shelf-life. Structural integrity of the package was evaluated after exposure to thermal shock cycling, vibration, drop conditioning and accelerated aging to 2 years. Performance evaluation of the package included vacuum leakage testing, temperature indicator testing and microbial challenge after real-time aging to two years. The results demonstrate that the package integrity is acceptable for a 2-year shelf life. ### C.5 Product Integrity Integrity of the finished devices was evaluated after real-time aging to 2 years. The evaluation included shrinkage temperature, collagen content (i.e., hydroxyproline content), tissue microstructure, biomechanical properties, storage solution Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 {9} concentration, storage solution pH, effectiveness of the physician’s rinse, and hydrodynamic testing. The results demonstrate that the product integrity of the Trifecta Valve is acceptable for a 2-year shelf life. ## X. SUMMARY OF PRIMARY CLINICAL STUDY ### A. Study Design The clinical study that formed the basis for FDA’s finding that the Trifecta Valve is safe and effective for its intended use was a prospective, non-randomized, observational study without concurrent or matched controls. Adverse event (AE) rates as compared to a set of Objective Performance Criteria (OPC) and to literature-based control data were used for the design and analysis of this study. New York Heart Association (NYHA) functional classification status and hemodynamic performance of the valve by echocardiography were evaluated using a comparison to literature-based control data. ### A.1 Clinical Inclusion and Exclusion Criteria Clinical inclusion criteria for the Trifecta Valve clinical study included the following: - Patient requires aortic valve replacement (Note: Patients undergoing concomitant procedures, e.g., coronary artery bypass grafting, or valve repair, are eligible for this study). - Patient is legal age in host country - Patient (or legal guardian) has given written informed consent for participation prior to surgery. - Patient is willing to undergo all study procedures and adhere to data collection and follow-up requirements. Clinical exclusion criteria for the Trifecta Valve Clinical Study included the following: Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 10 of 20 15 {10} - Patient is pregnant or nursing (women of child bearing potential must have a documented negative pregnancy test within one week prior to surgery). - Patient already has a prosthetic valve(s) at a site other than the aortic valve. - Patient requires concomitant replacement of the tricuspid, pulmonary, or mitral valve. - Patient has an inability or is unwilling to return for the required follow-up visits. - Patient has active endocarditis (patients with previous endocarditis must have two documented negative blood culture results prior to enrollment). - Patient has had an acute preoperative neurological event defined as: patient has not returned to baseline or has not stabilized 30 days prior to the planned valve implantation surgery. - Patient is undergoing renal dialysis. - Patient has a documented history of substance abuse within one year of enrollment, or is currently a prison inmate. - Patient is currently participating in the study of an investigational drug or device, or the patient was previously participating in an investigational drug study and has not completed a 30-day washout period. - Preoperative evaluation indicates other significant cardiovascular abnormalities such as aortic dissection or ventricular aneurysm. - Patient has a life expectancy less than two years. ## A.2 Follow-up Schedule Preoperative demographic and baseline data including NYHA functional classification were collected. Postoperative data, including blood and echocardiography data were collected at discharge, 6 months, one year, and annually thereafter. All echos were sent to the Echocardiography Core Laboratory for interpretation. Postoperative NYHA functional classifications were collected at 6 months, one year, and annually thereafter. Adverse event data were collected at the time of occurrence or site notification using definitions from Edmunds et al., 1996.¹ ## A.3 Clinical Endpoint The clinical endpoints for the study were to confirm the clinical safety and effectiveness of the Trifecta Valve by establishing the following: - Adverse Event (AE) rates (early, linearized late, and Kaplan-Meier) - New York Heart Association (NYHA) functional classification status - Hemodynamic performance of the valve by echocardiography ## B. Accountability of PMA Cohort At the time of database freeze, one thousand and twenty-two (1022) subjects were implanted with the Trifecta Valve in the aortic position at a total of 31 investigational sites between June 2007 and November 2009. Data are being presented on the one thousand fourteen (1014) subjects who met eligibility criteria. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 11 of 20 {11} The number of subjects who were eligible as well as the number and percentage of subjects who had follow-up at each visit interval are presented in Table 4. Table 4: Number of Subjects at Each Interval All Subjects, N=1014 | Interval | Eligible Subjects n | Follow-up %^{1} (n_{1}) | Censored^{2} Subjects N_{1} | | --- | --- | --- | --- | | Preoperative | 1014 | 100% (1014) | 16 | | Discharge | 998 | 100% (998) | 72 | | 6 Month | 926 | 97.8% (906) | 277 | | 1 Year | 649 | 97.7% (634) | 548 | | 2 Year | 101 | 98.0% (99) | 101 | | Overall | 3688 | 99.0% (3651) | 1014 | 1 %=(n1/n)*100 2 N1 Censoring can be due to pending visit, explant, death or lost to follow-up ## C. Study Population Demographics and Baseline Parameters ### C.1 Description of Subjects Between June 2007 and November 2009, one thousand and twenty-two (1022) subjects were implanted with the Trifecta Valve in the aortic position at 31 investigational sites: 18 sites in the United States, 7 sites in Canada, and 6 sites in Europe. Data are being presented on the one thousand fourteen (1014) subjects who met eligibility criteria. Table 5 presents the mean age at implant and preoperative NYHA. The mean age at implant was 72.5 years (standard deviation (SD) 9.0 years, range 32 to 95 years), and 64.1% of subjects were male. Preoperatively, 49.3% of subjects were NYHA functional classification III/IV. Table 6 presents the number of eligible subjects meeting all inclusion/exclusion criteria, cumulative and late patient-years, and mean follow-up. The cumulative follow-up was 924.18 patient-years with a mean follow-up of 0.91 years (SD 0.49 years, range 0-2.38 years). Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 12 of 20 {12} Table 5: Preoperative Subject Demographics All subjects included in data analysis, N=1014 | Variable | N=1014 | | --- | --- | | Age at Implant (years) | 72.5 ± 9.0 (32,95) | | Preoperative NYHA | | | Class I | 6.6% (67) | | Class II | 44.1% (447) | | Class III | 43.9% (445) | | Class IV | 5.4% (55) | Table 6: Eligible Subjects, Cumulative and Late Patient-Years, and Mean Follow-up All subjects included in data analysis, N=1014 | Implant Duration | Number of subjects | Total Patient-years | Mean | SD | Minimum | Maximum | | --- | --- | --- | --- | --- | --- | --- | | Cumulative Patient-years | 1014 | 924.18 | 0.91 | 0.49 | 0.00 | 2.38 | | Late Patient-years* | 955 | 844.31 | 0.88 | 0.45 | 0.01 | 2.30 | *Late patient-years are calculated from 31 days post-implant to the last follow-up visit (or contact), or adverse event. ## D. Safety and Effectiveness Results ### D.1 Safety Results Table 7 provides the early adverse event rates, linearized late adverse event rates, and 1-year and 2-year Kaplan-Meier analysis results. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 13 of 20 {13} Table 7: Observed Adverse Event Rates All subjects analyzed: N=1014 Cumulative follow-up: 924.18 patient-years | Adverse Event | Early Events^{1} %^{2} (n) | Late Events^{3} %/pt-yr^{4} (n) [One-Sided Upper 95% CL] | Freedom From Event 1 Year^{5} % [95% CI] | Freedom From Event 2 Year^{5} % [95% CI] | | --- | --- | --- | --- | --- | | Thromboembolism | 2.7% (27) | 1.90% (16) [2.88%] | 96.2% [94.7%,97.2%] | 92.9% [88.5%,95.6%] | | Valve Thrombosis | 0.0% (0) | 0.00% (0) [0.35%] | 100.0% [100.0%,100.0%] | 100.0% [100.0%,100.0%] | | Major Bleed | 8.0% (81) | 2.61% (22) [3.72%] | 90.4% [88.3%,92.2%] | 86.0% [81.0%,89.8%] | | Anticoagulant and/or Antiplatelet | 1.4% (14) | 1.90% (16) [2.88%] | 96.8% [95.4%,97.8%] | 93.7% [88.7%,96.5%] | | Nonstructural Dysfunction | 0.3% (3) | 0.12% (1) [0.56%] | 99.6% [98.9%,99.8%] | 99.6% [98.9%,99.8%] | | All Perivalvular Leak | 0.1% (1) | 0.00% (0) [0.35%] | 99.9% [99.3%,100.0%] | 99.9% [99.3%,100.0%] | | Major Perivalvular Leak | 0.0% (0) | 0.00% (0) [0.35%] | 100.0% [100.0%,100.0%] | 100.0% [100.0%,100.0%] | | Endocarditis | 0.0% (0) | 1.07% (9) [1.86%] | 99.1% [98.1%,99.5%] | 98.6% [97.1%,99.4%] | | Clinically Significant Hemolysis | 0.0% (0) | 0.00% (0) [0.35%] | 100.0% [100.0%,100.0%] | 100.0% [100.0%,100.0%] | | Structural Deterioration | 0.0% (0) | 0.12% (1) [0.56%] | 99.9% [99.3%,100.0%] | 99.9% [99.3%,100.0%] | | Reoperation | 0.1% (1) | 0.59% (5) [1.25%] | 99.4% [98.6%,99.7%] | 99.4% [98.6%,99.7%] | | Explant | 0.1% (1) | 0.59% (5) [1.25%] | 99.4% [98.6%,99.7%] | 99.4% [98.6%,99.7%] | | Valve-Related Mortality | 0.2% (2) | 0.36% (3) [0.92%] | 99.4% [98.6%,99.8%] | 99.4% [98.6%,99.8%] | 1. Early events are those occurring on or before 30 days post-implant 2. The early adverse event rate (%) is calculated as the number of early adverse events divided by the total number of subjects, times 100 3. Late events are those occurring 31 days post-implant or thereafter 4. Late adverse event rate (%/pt-yr) is calculated as the number of late events divided by the total late patient-years, times 100. The late adverse event rates were calculated based on 844.31 late patient-years 5. Freedom from event estimates at 1 year and at 2 years from Kaplan-Meier analysis are calculated based on 12 months and 24 months, respectively (where 30.4 days = 1 month) Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 14 of 20 {14} # D.2 Effectiveness Results Quantitative data were collected throughout the study (i.e., NYHA functional classification, echo parameters) to evaluate effectiveness. Table 8a presents subject NYHA classification preoperatively and at one year follow-up. Table 8b presents subject NYHA classification preoperatively and at two years follow-up. Table 9 presents the hemodynamic follow-up results at one year follow-up. Table 8a: Effectiveness Outcomes, NYHA Functional Classification: 1 Year Follow-up* Subjects with both preoperative and 1 year NYHA measurements, N=606; n₁=number per subgroup | NYHA Class | N=606 | | | | | --- | --- | --- | --- | --- | | | Preoperative | | 1 Year | | | | n₁ | % (n₁/N) | n₁ | % (n₁/N) | | I | 34 | 5.6% | 517 | 85.3% | | II | 275 | 45.4% | 82 | 13.5% | | III | 273 | 45.0% | 7 | 1.2% | | IV | 24 | 4.0% | 0 | 0.0% | | All | 606 | 100.0% | 606 | 100% | *Subjects with both preoperative and 1 year NYHA measurements available are included in table Table 8b: Effectiveness Outcomes, NYHA Functional Classification: 2 Year Follow-up* Subjects with both preoperative and 2 year NYHA measurements, N=97; n₁=number per subgroup | NYHA Class | N=97 | | | | | --- | --- | --- | --- | --- | | | Preoperative | | 2 Year | | | | n₁ | % (n₁/N) | n₁ | % (n₁/N) | | I | 8 | 8.2% | 81 | 83.5% | | II | 45 | 46.4% | 14 | 14.4% | | III | 36 | 37.1% | 2 | 2.1% | | IV | 8 | 8.2% | 0 | 0.0% | | All | 97 | 100.0% | 97 | 100.0% | *Subjects with both preoperative and 2 year NYHA measurements available are included in table Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 15 of 20 {15} Table 9: Effectiveness Outcomes at 1 Year Follow-up Visit, Hemodynamic Results All subjects included in data analysis, N=1014 | Hemodynamic Parameter | 19mm | 21mm | 23mm | 25mm | 27mm | 29mm^{1} | | --- | --- | --- | --- | --- | --- | --- | | 1 year postoperative | N^{2}=68 | N=160 | N=198 | N=136 | N=40 | N=15 | | Mean Gradient^{4} | n^{2}=66 | n=160 | n=197 | n=135 | n=40 | n=15 | | Mean ± SD | 10.7 ± 4.6 | 8.1 ± 3.5 | 7.2 ± 2.8 | 6.2 ± 2.7 | 4.8 ± 2.0 | 4.7 ± 1.6 | | Min, Max | 3.3, 26.4 | 0.6, 23.7 | 1.0, 19.5 | 1.4, 20.3 | 0.5, 9.8 | 2.0, 7.1 | | EOA^{5} | n=60 | n=151 | n=190 | n=129 | n=38 | n=13 | | Mean ± SD | 1.41 ± 0.24 | 1.63 ± 0.29 | 1.81 ± 0.30 | 2.02 ± 0.32 | 2.20 ± 0.20 | 2.35 ± 0.22 | | Min, Max | 0.91, 2.19 | 0.87, 2.58 | 0.78, 2.77 | 1.15, 2.76 | 1.86, 2.82 | 2.02, 2.73 | | Regurgitation^{6} | n=68 | n=160 | n=198 | n=136 | n=40 | n=15 | | None | 64.7% (44) | 74.3% (119) | 73.7% (146) | 74.2% (101) | 75.0% (30) | 80.0% (12) | | Trivial | 25.0% (17) | 22.5% (36) | 23.2% (46) | 19.1% (26) | 22.5% (9) | 20.0% (3) | | Mild | 2.9% (2) | 1.8% (3) | 0.5% (1) | 3.6% (5) | 0.0% (0) | 0.0% (0) | | Moderate | 1.4% (1) | 0.6% (1) | 0.5% (1) | 1.4% (2) | 2.5% (1) | 0.0% (0) | | Severe | 0.0% (0) | 0.0% (0) | 1.0% (2) | 0.7% (1) | 0.0% (0) | 0.0% (0) | | Unknown^{7} | 5.8% (4) | 0.6% (1) | 1.0% (2) | 0.7% (1) | 0.0% (0) | 0.0% (0) | 1 Data for size 29 mm are based on follow-up cutoff date of 10/26/2010. All other data in table are based on follow-up cutoff date of 3/25/2010 2 N = number of subjects with a completed echo per valve size 3 n = number of subjects per valve size with available hemodynamic parameter 4 Mean Gradient = pressure drop measured across the valve recorded in mmHg 5 EOA = calculated effective orifice area measured in cm² 6 Aortic Regurgitation presented as 'Percentage (Count)' 7 Unknown - Includes echos that did not contain the appropriate images to evaluate aortic regurgitation Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 16 of 20 {16} # D.3 Analysis for Sex Differences Of the 1014 subjects implanted with the Trifecta Valve, 64.1% (n=650) were male and 35.9% (n=364) were female. This percentage of males is comparable to the results obtained from a 2008 STS database search for those patients undergoing aortic valve replacement with a biological prosthetic valve (62% male). Table 10 presents the gender distribution. Table 11 presents the baseline and operative information by gender. Table 10: Gender Distribution | Gender | All Implants | | --- | --- | | Male | 64.1% (650/1014) | | Female | 35.9% (364/1014) | Table 11: Baseline and Operative Information - by Gender All subjects, N=1014 | Variable | Male N=650 | Female N=364 | P-value | | --- | --- | --- | --- | | Age at implant | 71.3 ± 9.1 (650) | 74.5 ± 8.5 (364) | <.0001 | | Preoperative NYHA (III or IV) | 46.6% (303/650) | 54.1% (197/364) | 0.0221 | | Small valve size (19mm or 21mm) | 17.4% (113/650) | 78.6% (286/364) | <.0001 | | Valve Dysfunction | | | | | Regurgitation | 6.9% (45/650) | 4.4% (16/364) | 0.1294 | | Stenosis | 50.6% (329/650) | 62.4% (227/364) | 0.0004 | | Mixed | 42.5% (276/650) | 33.2% (121/364) | 0.0040 | To more carefully evaluate possible gender-based differences in outcome of treatment with the Trifecta Valve, several sex/gender-specific analyses were performed on safety and effectiveness endpoints. The results suggest that the general conclusions of the overall study regarding both safety and effectiveness can be generalized for males and females. Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 17 of 20 22 {17} Safety Results by Sex: Kaplan-Meier analysis and Log-Rank tests were performed to compare each adverse event by gender. One year survival rates are provided in Table 12. Males had a significantly lower incidence of all cause mortality than females. However, when only valve-related deaths were considered the difference between genders was no longer significant. In addition, the observed difference for all cause mortality could be partially attributable to the fact that on average the women implanted in the study were 3 years older than the men. This observed higher rate of all cause mortality in women is consistent with what has been published in literature.³ There were no significant differences between males and females for other adverse events such as embolism, major bleed, paravalvular leak, endocarditis, structural deterioration, or reoperation rates. Effectiveness Results by Sex: The results from the Signed Rank test demonstrate significant improvement of NYHA from preoperative to 1 year for males and females. The Wilcoxon Rank-sum test was performed by gender for NYHA functional classification improvement from preoperative to one year. There is no significant difference in NYHA functional classification improvement between genders. Key hemodynamic performance at 1 year was evaluated for all subjects by gender across all valve sizes (29mm were all males). Data observed are equivalent by male and female for all sizes except for 21mm. However, the differences observed for size 21mm for peak gradient, mean gradient, and effective orifice area index are very small and not considered to be clinically significant. Table 12: Kaplan-Meier Analysis Freedom From Adverse Event at 1 Year by Gender | Adverse Event | Female | Male | Log Rank p-value* | | --- | --- | --- | --- | | Thromboembolism | 0.9594 | 0.9630 | 0.5070 | | Valve Thrombosis | 1.0000 | 1.0000 | -- | | Major Bleed | 0.8990 | 0.9067 | 0.8271 | | All Perivalvular Leak | 1.0000 | 0.9985 | 0.4541 | | Major Perivalvular Leak | 1.0000 | 1.0000 | -- | | Endocarditis | 0.9850 | 0.9935 | 0.5292 | | Structural Deterioration | 0.9970 | 1.0000 | 0.1702 | | Clinically Significant Hemolysis | 1.0000 | 1.0000 | -- | | Reoperation | 0.9879 | 0.9967 | 0.1031 | | Mortality | 0.9345 | 0.9707 | 0.0121 | | Mortality -Valve Related | 0.9938 | 0.9969 | 0.5386 | *p-value for the entire study experience is presented Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 18 of 20 23 {18} Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 19 of 20 # XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION In accordance with the provisions of section 515(c)(2) of the Act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory Systems Device panel, a FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel. # XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES ## A. Safety Conclusions The results from the *in-vitro* pre-clinical studies performed for biocompatibility, hydrodynamic performance and structural performance demonstrate that the Trifecta Valve is safe and effective and, therefore, suitable for long-term implant. The *in-vivo* animal studies in sheep demonstrate that the Trifecta Valve is safe for valve replacement. The results of the Trifecta Valve clinical investigation demonstrate that the adverse event rates for the major safety variables were significantly lower than the established standard of twice the FDA’s Objective Performance Criteria for a tissue valve, with the exception of Major Bleed. There was no clear indication that the major bleeding events were directly related to the Trifecta valve. Mortality, reoperation, and explant rates also support the safety of the valve. ## B. Effectiveness Conclusions The analysis of effectiveness was based on the change in NYHA functional classification between preoperative and one year for those subjects with available data at both intervals. Additionally, hemodynamic data change between discharge and one year, for those subjects with echocardiography data available at both intervals was assessed. Key effectiveness outcomes are presented in Table 8a, Table 8b, and Table 12. There was a statistically significant improvement in NYHA functional classification, (p-value <0.0001) from the preoperative to one year visit. More than 95% of subjects had none or trivial regurgitation at one year. Mean gradients at one year across all valve sizes were ≤10.7mmHg. A comparison of Trifecta hemodynamic data to current literature indicates better than or equal performance to other aortic stented tissue valves. {19} Summary of Safety and Effectiveness Data: Trifecta™ Valve P100029 Page 20 of 20 C. Overall Conclusion The results of the clinical study presented in the PMA application demonstrate a reasonable assurance that the Trifecta Valve is a safe and effective replacement for a malfunctioning native or prosthetic aortic heart valve. XIII. CDRH DECISION FDA issued an approval order on April 20, 2011. The applicant's manufacturing facilities were inspected on February 3, 15, and 17, 2011 and were found to be in compliance with the Quality System Regulation (21 CFR 820). XIV. APPROVAL SPECIFICATION Instructions for Use: See device labeling Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse events in the device labeling. Post approval Requirements: See approval order. XV. REFERENCES 1. Edmunds LH, Clark RE, Cohn LH, Grunkemeier GL, Miller CM, Weisel RD. Guidelines for Reporting Morbidity and Mortality after Cardiac Valvular Operations. Ann Thorac Surg 1996;62:932-5. 2. Nemi C. Jain Veterinary Hematology - Fourth Edition 3. Brown J. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: Changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J thorac Cardiovasc Surg. 2009;137:82-90 25 --- **Source:** [https://fda.innolitics.com/device/P100029](https://fda.innolitics.com/device/P100029) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. 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