← Product Code NKM · P100009
# MITRACLIP DELIVERY SYSTEM (P100009)
_ABBOTT MEDICAL · NKM · Oct 24, 2013 · Cardiovascular · APPR_
**Canonical URL:** https://fda.innolitics.com/device/P100009
## Device Facts
- **Applicant:** ABBOTT MEDICAL
- **Product Code:** NKM
- **Decision Date:** Oct 24, 2013
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Expedited Review
## Intended Use
The MitraClip Clip Delivery System is indicated for the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to primary abnormality of the mitral apparatus [degenerative MR] in patients who have been determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease, and in whom existing comorbidities would not preclude the expected benefit from reduction of the mitral regurgitation.
## Device Story
The MitraClip Clip Delivery System is a percutaneous, catheter-based device used to treat significant symptomatic degenerative mitral regurgitation (MR). It consists of a delivery catheter, a steerable sleeve, and a mechanical clip. The system is introduced via the femoral vein and advanced through the interatrial septum into the left atrium under echocardiographic and fluoroscopic guidance. The physician manipulates the device to grasp and coapt the mitral valve leaflets, creating a double-orifice valve that reduces MR by approximating the leaflets throughout the cardiac cycle. The procedure is performed without cardiopulmonary bypass or arresting the heart. The device is intended for patients at prohibitive surgical risk, providing a mechanical alternative to surgery. Successful implantation reduces MR severity, which leads to reverse left ventricular remodeling, improved NYHA functional class, reduced heart failure hospitalizations, and improved quality of life.
## Clinical Evidence
Evidence includes the EVEREST II RCT (n=279), EVEREST II High Risk Registry (n=78), REALISM High Risk (n=581), and REALISM Non-High Risk (n=272). The primary approval basis was a post-hoc cohort of 127 prohibitive-risk degenerative MR (PR DMR) patients. Results showed 6.3% procedural mortality, 82.1% MR reduction to ≤2+ at discharge, and sustained improvements in NYHA class and SF-36 QOL scores at 12 months. Heart failure hospitalizations were reduced by 73% (0.67 to 0.18 per patient-year).
## Technological Characteristics
System includes a 16 Fr delivery catheter, steerable sleeve, and a single-sized mechanical clip. Materials include metal alloys (Elgiloy, Nitinol) and polyester fabric. Sensing/actuation is mechanical via catheter-based manipulation. MR conditional (up to 3 Tesla). Sterilized via ethylene oxide. Software is not described as an active component; device is mechanical.
## Regulatory Identification
To repair the mitral valve by coapting the valve leaflets to prevent mitral regurgitation. These devices are different from the classified device (annuloplasty rings) in that a cardiotomy is not required to place them, some of them are placed percutaneously, and they definitely are not rings that are sewn on to the valve annulus.
## Reference Devices
- Steerable Guide Catheter ([K083793](/device/K083793.md), [K091596](/device/K091596.md), [K093866](/device/K093866.md), [K100789](/device/K100789.md), [K112239](/device/K112239.md))
## Submission Summary (Full Text)
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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I. GENERAL INFORMATION
Device Generic Name: Mitral Valve Repair Device
Device Trade Name: MitraClip® Clip Delivery System
Device Procode: NKM
Applicant Name and Address: Abbott Vascular
4045 Campbell Avenue
Menlo Park, CA 94025
Date of Panel Recommendation: March 20, 2013
Premarket Approval Application (PMA) Number: P100009
Date of FDA Notice of Approval: October 24, 2013
Priority Review: Granted on December 18, 2008 because the MitraClip device is intended to treat mitral regurgitation and addresses an unmet clinical need in that it represents a breakthrough technology that provides a clinically meaningful advantage over existing technology by being the first available percutaneous mitral valve repair device.
II. INDICATIONS FOR USE
The MitraClip Clip Delivery System is indicated for the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to primary abnormality of the mitral apparatus [degenerative MR] in patients who have been determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease, and in whom existing comorbidities would not preclude the expected benefit from reduction of the mitral regurgitation.
PMA P100009: FDA Summary of Safety and Effectiveness Data
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# III. CONTRAINDICATIONS
The MitraClip Clip Delivery System is contraindicated in DMR patients with the following conditions:
- Patients who cannot tolerate procedural anticoagulation or post procedural anti-platelet regimen
- Active endocarditis of the mitral valve
- Rheumatic mitral valve disease
- Evidence of intracardiac, inferior vena cava (IVC) or femoral venous thrombus
# IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the MitraClip Clip Delivery System labeling (Instructions for Use).
# V. DEVICE DESCRIPTION
The MitraClip Clip Delivery System (CDS) consists of three major components: 1) the Delivery Catheter 2) the Steerable Sleeve, and 3) the MitraClip Device (Figure 1). The 16 Fr Clip Delivery System is introduced into the body through a 24 Fr Steerable Guide Catheter which includes a dilator. The Steerable Guide Catheter and dilator are 510(k) cleared under K083793 on April 27, 2009, K091596 on July 2, 2009, K093866 on January 13, 2010, K100789 on April 21, 2010 and K112239 on August 31, 2011.
The MitraClip Clip Delivery System is used to advance and manipulate the implantable MitraClip Device for proper positioning and placement on the mitral valve leaflets. The MitraClip Device is a single-sized, percutaneously implanted mechanical clip for the reduction of mitral regurgitation. The MitraClip Device grasps and coapts the mitral valve leaflets resulting in fixed approximation of the mitral leaflets throughout the cardiac cycle. The MitraClip Device is placed without the need for arresting the heart or cardiopulmonary bypass. The MitraClip Device is fabricated with metal alloys and polyester fabric (Clip cover) that are commonly used in cardiovascular implants. The MitraClip Device arms can be adjusted to any position from fully opened fully inverted and fully closed. The Grippers can be raised or lowered repeatedly. The key dimensions of the MitraClip Clip Delivery System are listed in Table 1.
Figure 1: The MitraClip Clip Delivery System
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Table 1: Key Dimensions for the MitraClip Clip Delivery System
| Dimensional Component | Dimension |
| --- | --- |
| Delivery Catheter | |
| Extended Length (from Sleeve curved at 90 degrees) | 45mm - 70 mm |
| Catheter Shaft Outer Diameter (OD) | 3.4 mm (10 Fr) |
| Steerable Sleeve | |
| Working Length | 1095 mm |
| Catheter Distal Shaft Outer Diameter (OD) | 5.3 mm (16Fr) |
| MitraClip Device | |
| Closed Clip Length | 15 mm maximum |
| Grasping Width at 120 degrees | 17 mm maximum |
| Clip Width at 180 degrees | 20 mm maximum |
| Arm Width | 5 mm maximum |
| Arm Length (Coaptation Length) | 9 mm maximum |
The Steerable Guide Catheter is used to introduce the MitraClip Clip Delivery System into the left side of the heart through the interatrial septum. The Steerable Guide Catheter is also used to position and orient the MitraClip Clip Delivery System to the appropriate location above the mitral valve. The Dilator is used for the introduction of the Steerable Guide Catheter into the femoral vein and left atrium.
Several accessories are used in conjunction with the MitraClip Clip Delivery System including: 1) a Stabilizer, 2) a Lift, 3) a Support Plate, 4) a Silicone Pad and 5) Fasteners. These Class I accessories are assembled to provide a stable working platform for the MitraClip Clip Delivery System.
VI. ALTERNATIVE PRACTICES AND PROCEDURES
- Mitral valve repair surgery is the treatment of choice for operable patients with severe DMR regardless of symptoms.
- Mitral valve replacement surgery is another alternative for operable DMR candidates, typically performed when repair cannot be successfully performed or when possibility of reoperation to correct a repair is not feasible.
- Medical therapy is an option for DMR patients with less than severe MR with normal LV dimensions who are asymptomatic or for DMR patients at prohibitive risk for surgery.
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.
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# VII. MARKETING HISTORY
The MitraClip Clip Delivery System received CE mark in March 2008. The device is currently approved for commercial distribution in the following countries. Marketing approval for the device has not been withdrawn for any reason related to its safety or effectiveness.
- Australia
- Austria
- Belgium
- Canada (special Access)
- Colombia
- Czech Republic
- Denmark
- Estonia
- Finland
- France
- Germany
- Greece
- Hong Kong
- Hungary
- Iceland
- Indonesia
- Ireland
- Israel
- Italy
- Kuwait
- Latvia
- Liechtenstein
- Lithuania
- Luxembourg
- Malaysia
- Malta New
- Netherlands
- New Zealand
- Norway
- Poland
- Portugal
- Romania
- Saudi Arabia
- Singapore
- Slovakia
- Slovenia
- Spain
- Sweden
- Switzerland
- Turkey
- UK
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# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
The following adverse events have been identified as possible complications of the MitraClip procedure.
- Allergic reaction (anesthetic, contrast, Heparin, nickel alloy, latex)
- Aneurysm or pseudo-aneurysm
- Arrhythmias
- Atrial fibrillation
- Atrial septal defect requiring intervention
- Arterio-venous fistula
- Bleeding
- Cardiac arrest
- Cardiac perforation
- Cardiac tamponade/Pericardial Effusion
- MitraClip erosion, migration or malposition
- MitraClip Device thrombosis
- MitraClip System component(s) embolization
- Coagulopathy
- Conversion to standard valve surgery
- Death
- Deep venous thrombus (DVT)
- Dislodgement of previously implanted devices
- Drug reaction to anti-platelet/anticoagulation agents/contrast media
- Dyspnea
- Edema
- Emboli (air, thrombus, MitraClip Device)
- Emergency cardiac surgery
- Endocarditis
- Esophageal irritation
- Esophageal perforation or stricture
- Failure to deliver MitraClip to the intended site
- Failure to retrieve MitraClip System components
- Fever or hyperthermia
- Gastrointestinal bleeding or infarct
- Hematoma
- Hemolysis
- Hemorrhage requiring transfusion
- Hypotension/hypertension
- Infection and pain at insertion site
- Infection and pain at incision site
- Injury to mitral valve complicating or preventing later surgical repair
- Lymphatic complications
- Mesenteric ischemia
- Mitral stenosis
- Mitral valve injury
- Multi-system organ failure
- Myocardial infarction
- Nausea/vomiting
- Peripheral ischemia
- Prolonged angina
- Prolonged ventilation
- Pulmonary congestion
- Pulmonary thrombo-embolism
- Renal insufficiency or failure
- Respiratory failure/atelectasis/pneumonia
- Septicemia
- Single leaflet device attachment (SLDA)
- Skin injury or tissue changes due to exposure to ionizing radiation
- Stroke or transient ischemic attack (TIA)
- Urinary tract infection
- Vascular trauma, dissection or occlusion
- Vessel spasm
- Vessel perforation or laceration
- Worsening heart failure
- Worsening mitral regurgitation
- Wound dehiscence
For the specific adverse events that occurred in the clinical studies, please see Section X below.
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IX. SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to determine the safety and effectiveness of the MitraClip Clip Delivery System. Studies were conducted on the MitraClip Clip Delivery System, its individual components/materials and on the MitraClip Device.
A. Biocompatibility Testing
The materials that make up the Delivery Catheter, Steerable Sleeve and the MitraClip Device have an extensive history of use in the medical device industry. The Sponsor successfully completed a series of Good Laboratory Practices (GLP) biocompatibility tests of all contact materials in the MitraClip Clip Delivery System in accordance to ISO10993-1:2003 Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing and FDA’s Blue Book Memoranda #G95-1 – Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices or obtained the data from the material supplier.
Results demonstrate the components of the MitraClip Clip Delivery System are non-toxic and met the requirements of ISO 10993-1 for a vascular implant and ISO 10993-4 for a blood contacting device. Table 2 and Table 3 list the test performed, test conditions and results obtained from the biocompatibility studies conducted on the Delivery Catheter, Steerable Sleeve and MitraClip Device. There is extensive prior clinical history of the use of the materials utilized in the MitraClip Clip Delivery System in both human vascular tissue and bone implants. The Sponsor provided a scientific rationale for the omission of Chronic Toxicity and Carcinogenicity testing that was accepted by FDA.
Table 2: Biocompatibility Test Summary for Delivery Catheter and Steerable Sleeve
| Test Performed | Standards | Results/Comments (units when appropriate) |
| --- | --- | --- |
| Cytotoxicity | ISO 10993-5:1999 | PASS (Non cytotoxic), Grade 0 |
| Sensitization | ISO 10993-10:2002 | PASS (Non sensitizing) Grade 1 (0-8%), Not significant |
| Irritation / Intracutaneous Toxicity | ISO 10993-10:2002, ISO 10993-12:2002 ISO 10993-10:1995, ISO 10993-12:1996 | PASS (non-irritating) Test not significantly > the control, Negligible irritant |
| Intracutaneous Injection* | ISO 10993-10:2002 | PASS |
| Systemic Toxicity | | |
| Acute Systemic Toxicity | ISO 10993-11:2006, ISO 10993-11:1993 | PASS (non toxic) Test not significantly > the control, Negative |
| Acute Systemic Injection* | ISO 10993-11:1993 | PASS |
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Table 3: Biocompatibility Test Summary for MitraClip Device
| Test Performed | Standards | Results/Comments (units when appropriate) |
| --- | --- | --- |
| Cytotoxicity | | |
| Cytotoxicity | ISO 10993-5:1999 | PASS (Non-cytotoxic), Grade 0 |
| | | PASS (Non-cytotoxic), Grade 0 |
| Sensitization | ISO 10993-10:2002 | PASS (non-sensitizing) Grade 1 (0-8%), Not significant |
| Irritation/Intracutaneous Toxicity | ISO 10993-10:2002 | PASS (non irritating), Test not significantly > the control, Negligible irritant |
| Systemic toxicity | | |
| Acute Systemic Toxicity | ISO 10993-11:2006 | PASS, Test not significantly different from the control, Negative |
| Material Mediated Pyrogenicity | ISO 10993-11: 2006 | PASS (Non-pyrogenic) No increase in temperature > 0.5°C |
| Sub-chronic toxicity,72 hour | ISO 10993-11: 2006 | PASS (Non-toxic) |
| Sub-chronic toxicity, 14 day IV | ISO 10993-11: 2006 | PASS (Non-toxic) Negative for signs of systemic toxicity due to leachable components |
| Genotoxicity | | |
| Gene mutation (AMES) | ISO 10993-3:2003 | PASS (Non-mutagenic) |
| Chromosome aberration | ISO 10993-3:2003 | PASS (Non-genotoxic) |
| DNA damage | ISO 10993-3:2003 | PASS (Non-mutagenic) |
| Implantation | ISO 10993-6:2007 | PASS, Test 2: Non-reactive |
| | | PASS, Test 1: Mildly reactive |
| Hemocompatibility | | |
| Hemolysis | ISO 10993-4: 2002/Amd.1:2006(E) | PASS (Non-hemolytic) |
| Complement activation | ISO 10993-4:2002/Amd.1:2006(E) | PASS complement Activation Assay |
| Thrombogenicity | ISO 10993-4:2002/Amd.1:2006(E) | PASS, UPTT not significantly different than controls |
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| Test Performed | Standards | Results/Comments (units when appropriate) |
| --- | --- | --- |
| Chronic Toxicity | ISO 10993-11:2006 | N/A |
| Carcinogenicity | ISO 10993-3:2003 | N/A |
## B. Animal Studies
Abbott Vascular conducted multiple animal studies in the porcine model to assess the safety of the MitraClip Clip Delivery System.
Two acute GLP studies (n=3, n=4) were conducted in a porcine model to demonstrate that repeated deployment of the MitraClip Device does not cause clinically significant intraoperative trauma to the mitral valve and adjacent structures; and that the use of the MitraClip Device did not cause intracardiac trauma or trauma to the great vessels. The MitraClip Clip Delivery System performed as intended, in this animal model, without causing intracardiac trauma or trauma to the great vessels. There were no procedural deaths or MitraClip Device embolizations. In addition, several acute Non-GLP studies were conducted in a porcine model to help characterize device performance based on the defined product specifications, and gain experience and proficiency to develop appropriate device Instructions for Use and physician training materials. In each case, the MitraClip Clip Delivery System performed as intended and the MitraClip Device was successfully deployed, creating a double orifice.
A chronic GLP animal study (n=21) was conducted to demonstrate the safety, reliability, and performance characteristics of the MitraClip Device according to its intended use. Results were analyzed at 4 weeks, 12 weeks and 24 weeks. The MitraClip Device performed as intended and the long term healing response of the mitral valve leaflets indicate that the MitraClip Device maintains tissue approximation and in a relatively short time, is fully encapsulated within a fibrous endocardial capsule. The MitraClip Device was shown to be safe and effectively delivered when used as intended in a porcine model.
## C. Sterilization
The MitraClip Clip Delivery System is sterilized using ethylene oxide (EO) sterilization and has been validated per AAMI/ISO 11135:2007 "Medical Devices Validation and Routine Control of Ethylene Oxide Sterilization." Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of 10⁻⁶. In addition, the amount of EO residual and bacterial endotoxins was verified to be within the specifications limits.
## D. Packaging/Shelf Life
Packaging validation and shelf life studies were conducted on the packaging of the MitraClip Clip Delivery System to establish a shelf life/expiration date. Testing included simulated transit, visual inspection, bubble emission testing and peel strength test for the packaging of the MitraClip Clip Delivery System.
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In addition, testing to establish device shelf life for the MitraClip Clip Delivery System included double EO sterilization, accelerated aging, transit conditioning, and visual inspection. Further, testing was conducted to verify the functional performance of the MitraClip Clip Delivery System following 12 month accelerated aging and to verify adhesive bond strength following functional testing of the device. The data generated to date support a shelf life of 1 year for the packaging and device of the MitraClip Clip Delivery System.
## E. In Vitro Engineering Testing
Abbott Vascular successfully completed extensive in vitro engineering testing of the MitraClip Clip Delivery System in accordance with its product specification, Instructions for Use (IFU) and applicable standards, which demonstrated acceptable device performance. Testing was performed per internal Abbott Vascular test protocols and reports, which incorporated pre-determined and justified sample sizes, acceptance criteria, applicable standards and testing conditions. Testing was conducted using the MitraClip Clip Delivery System as a whole in conjunction with the Steerable Guide Catheter in a simulated use environment or on subassemblies, as applicable.
## Design Specific Performance Studies – Delivery Catheter
Multiple design specific characterization, mechanical and functional tests were performed on the Delivery Catheter and demonstrated acceptable results including: dimensional testing, radiopacity, echogenicity, lubricity, tensile strength, torque strength, compressive strength, axial and rotational stability, arm rotation, rotational ratio and accuracy, catheter cycling, gripper line cycling and removal, fluid management, elongation, actuation forces, clip deployment, lock/unlock testing, physical and mechanical integrity, device compatibility, insertion and retraction testing.
## Design Specific Performance Studies – Steerable Sleeve
Multiple design specific characterization, mechanical and functional tests were performed on the Steerable Sleeve and demonstrated acceptable results including: dimensional and visual inspection, radiopacity, leak testing, torsional strength, tensile strength, knob stability, force to curve, clip retraction into introducer, sleeve stability, starting angle and curving range.
## Design Specific Performance Studies – MitraClip Device
Multiple design specific mechanical and functional tests were performed on the MitraClip Device and demonstrated acceptable results including: device actuation (open, close, invert), lock engagement, establish final arm angle, clip settling, tensile testing, lock/unlock force, cover attachment, integrity testing, deliverability, and gripper raise/lower testing.
Non-clinical testing has demonstrated the MitraClip Device is magnetic resonance conditional. It can be scanned safely under the following conditions:
- Static magnetic field up to 3 Tesla;
- Maximum spatial gradient in static field of 2500 gauss/cm or less;
- Maximum whole-body averaged specific absorption rate (SAR) of 3.0 W/kg for 15 minutes of scanning.
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In non-clinical testing, the MitraClip produced a temperature rise of less than $1^{\circ}\mathrm{C}$ at a maximum whole body averaged specific absorption rate (SAR) of $3\mathrm{W / kg}$, as assessed by calorimetry for 15 minutes of MR scanning in a 3T system using a GE Signa HDx 3.0 T MR scanner.
Magnetic resonance image quality may be compromised if the area of interest is in the exact same area, or relatively close to the MitraClip Device. A maximum image artifact of $60 \times 70$ mm was measured in testing conducted in a 3T magnetic resonance system. It may be necessary to optimize the magnetic resonance imaging parameters due to the presence of the implant.
Material characterization, dimensional and structural performance durability studies were performed on the MitraClip Device and demonstrated acceptable results including: mechanical properties, open circuit potential, metrology, surface analysis, and in vivo load determination. Details of additional material characterization and structural performance durability testing performed on the MitraClip Device including the attribute tested, applicable standards, test description and results are provided in Table 4 and Table 5, respectively. A result of "Pass" denotes that the test results met the product specifications. A result of "NA" denotes test results were obtained for characterization purposes. All testing demonstrated the MitraClip Device performed acceptably and FDA had no further concerns regarding the preclinical testing.
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Table 4: MitraClip Device Material Characterization Testing Summary
| Attribute Tested | Standards | Test Description and Results Summary | Results |
| --- | --- | --- | --- |
| Material Analysis | ASTM F2633-07 ASTM F2063-05 ASTM F1058-08 | Suppliers are required to provide chemical analysis certification that Elgiloy and Nitinol raw material used to manufacture its components meets the chemistry requirements specified in ASTM F1058 and ASTM F2063 respectively. The chemical formulation of Grade 1 Elgiloy consists of Carbon (C 0.15% max), Manganese (Mn 1.5 – 2.5%), Silicon (Si 1.2%), Phosphorus (P 0.015% max), Sulfur (S 0.015% max), Cobalt (CO 39.0 – 41.0%), Chromium (CR 19.0 – 21.0%), Nickel (Ni 14.0 – 16.0%), Molybdenum (Mo 6.0 – 8.0%), Beryllium (Be 0.10% max) and Iron (Fe Balance). The chemical composition of Nitinol consists of Nickel (Ni 54.5 – 57.0%), Carbon (C 0.050% max), Cobalt (Co 0.050% max), Copper (Cu 0.010% max), Chromium (Cr 0.010% max), Hydrogen (H 0.005% max), Iron (Fe 0.050% max), Niobium (Nb 0.025% max), Nitrogen plus oxygen (0.05% max) and Titanium (Ti Balance). | NA |
| Mean Breakdown Potential (Eb) (Potentiodynamic) | ASTM F2129-08 | Corrosion testing was performed on the MitraClip Device according to ASTM F2129-08 "Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices" to demonstrate that prior to fatigue testing the finished devices exhibit acceptable corrosion resistance. Results met the product specification. | Pass |
| Clip Durability: Clip Must be Corrosion Resistant (Potentiodynamic) | ASTM F2129-08 | Corrosion testing was performed on the nitinol leaf spring component of the MitraClip Device according to ASTM F2129-08 "Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices" to demonstrate that prior to fatigue testing the nitinol leaf spring of the MitraClip exhibits acceptable corrosion resistance. Results met the product specification. | Pass |
| Clip Durability: Corrosion Performance Post Fatigue Test (Potentiodynamic) | ASTM F2129-06 | Corrosion testing was performed on the MitraClip Device according to ASTM F2129-06 "Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices" post accelerated fatigue testing to demonstrate that the MitraClip Device exhibits acceptable corrosion resistance post 600 million cycles accelerated fatigue testing. Results met the product specification. | Pass |
| Corrosion: Galvanic Corrosion Test | ASTM G71-81 (2009) | Corrosion testing was performed according to ASTM G71-81 (2009), "Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes" to demonstrate that the MitraClip Device exhibits acceptable corrosion resistance. SEM analysis was conducted to detect evidence of surface conditions compared to controls. Results met the product specification. | Pass |
| Compatibility with Standard Imaging Modalities (Radiopacity) | ASTM F640-07 | Testing was performed per Method B of ASTM F640-07, "Standard Test Methods for Determining Radiopacity for Medical Use" to demonstrate that the MitraClip Device is adequately visible under fluoroscopic imaging equipment. Three devices were tested against a reference 0.035 inch guidewire. Results confirmed that the MitraClip Device is adequately visible under fluoroscopic imaging equipment and met the product specification. | Pass |
| Compatibility with Standard Imaging Modalities (Echogenicity) | NA | Testing was performed to demonstrate that the MitraClip Device is adequately visible using standard echocardiographic imaging equipment. Results confirmed that the MitraClip Device is adequately visible under standard echocardiographic modalities and met the product specification. | Pass |
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Table 5: MitraClip Device Dimensions and Durability Testing Summary
| Attribute Tested | Standard | Test Description and Results Summary | Results |
| --- | --- | --- | --- |
| Finite Element Analysis (FEA) - MitraClip Device | None | An in-depth analysis of the MitraClip Device was conducted to ensure that the conditions to which the MitraClip Device will be subjected will not result in failure due to fatigue. The FEA evaluated the structural integrity of the MitraClip Device when subjected to the expected in vivo loading conditions. The analysis took into account manufacturing, delivery, implantation and clinical loading over the device life, and predicted that fatigue failures will not likely occur. | NA |
| Finite Element Analysis (FEA) - MitraClip Gripper | None | An in-depth analysis of the Gripper component of the MitraClip Device was conducted to ensure that the in vivo conditions to which the Grippers will be subjected will not result in failure due to fatigue. The FEA evaluated the structural integrity of the Grippers when subjected to the expected loading conditions generated in vivo. The analysis took into account manufacturing, delivery, implantation, and clinical loading over the device life, and predicted that fatigue failures will not likely occur. | NA |
| Finite Element Analysis (FEA) - MitraClip Leaf Spring | None | An in-depth analysis of the leaf spring component of the MitraClip Device was conducted to calculate the in vivo leaf spring output force that is applied to the binding plate when the MitraClip Device is in the locked position and deployed. The analysis took into account manufacturing, delivery, implantation, and clinical loading over the device life, and predicted that fatigue failures are not likely to occur. | NA |
| Clip Durability (Accelerated Fatigue Testing) | ASTM E466-07 | Testing was performed to demonstrate that the MitraClip Device with Grippers can adequately withstand expected in vivo cyclic loading conditions when deployed, and will not show fatigue failure during simulated 15 year fatigue testing. MitraClip Devices were dynamically cycled under simulated in vivo conditions for 1.2 billion cycles. Following cycling, the MitraClips were visually inspected under magnification and SEM. All MitraClip Devices remained locked and were free of fractures (under 20x magnification and X-ray), clip arm partial dislocation or component embolization at 40, 200, 400, and 600 million cycles. No cracks or fractures were observed. Wear was acceptable. | Pass |
| Clip Durability: SEM Visualization Post Fatigue Test | NA | Surface SEM analysis was performed to visualize the surfaces of the MitraClip Device for wear following fatigue testing to over 1.2 billion cycles. No cracks or breaks were observed. Evidence of wear was deemed to be acceptable. | Pass |
| Clip Durability (Post Durability Dynamic Load to Failure Testing) | ASTM E466-07 | Testing was performed to characterize the failure mode of the MitraClip Device due to excessive in vivo cyclic loading conditions post fatigue testing. MitraClip Devices fatigue cycled to over 1.2 billion cycles without failure. Eventual failure did occur after >880,000 additional cycles at increased load (well above the peak expected in vivo loading conditions). | Pass |
| Clip Durability (Gripper Component Fatigue Life) | ISO 5840: 2005 | Testing was performed to successfully establish durability of the Gripper component of the MitraClip Device during simulated 15 year (1.2 billion cycle) fatigue testing under 1.5 times the peak in vivo loading conditions. | Pass |
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# X. SUMMARY OF PRIMARY CLINICAL STUDIES
The applicant performed multiple clinical studies to establish a reasonable assurance of safety and effectiveness of the MitraClip for the percutaneous reduction of significant symptomatic mitral regurgitation (MR). These clinical studies included evaluation of MitraClip use in surgical candidates and high surgical risk patients as well as in patients with primary abnormality of the mitral apparatus (also referred to as degenerative MR or DMR) and patients with secondary MR (also referred to as functional MR or FMR). Patient follow-up periods for all studies included patient discharge, 30 days, 6, 12, 18 and 24 months, and annually thereafter through 5 years. A summary overview of these clinical studies is provided below.
The targeted patient population has evolved over time based upon emerging data and benefit-risk considerations. Data on patients with significant symptomatic mitral regurgitation due to primary abnormality of the mitral apparatus (DMR) determined to be at prohibitive risk for mitral valve surgery that were collected from these studies are provided in detail below and were the basis for the PMA approval decision.
# A. Overview of MitraClip Clinical Program
Beginning in 2003, the Sponsor conducted a series of clinical studies to evaluate the safety and effectiveness of the MitraClip for the treatment of mitral regurgitation. Table 6 provides an overview of the MitraClip clinical program in the United States including study design, enrollment criteria, endpoints and volumes.
The EVEREST II Randomized Controlled Trial (RCT) was a prospective, blinded, randomized, controlled, multi-center study initiated in 2005 as a pivotal study to compare the MitraClip to the standard of care mitral valve repair or replacement surgery in patients who were indicated for and could undergo mitral valve surgery. During the course of the RCT, there were a substantial number of patients with severe MR who could not be randomized because surgeons deemed them to be too high risk for surgery. Therefore, the MitraClip clinical program was expanded in 2007 to add the EVEREST II High Risk Registry (HRR) as a single-arm, self-controlled adjunctive study to evaluate the performance of the MitraClip in patients who were too high risk for mitral valve surgery. Patients were screened for the EVEREST II HRR concurrent with the RCT and enrolled in the arm in which they were eligible (RCT or HRR).
After the RCT and HRR were fully enrolled, a continued access study of the MitraClip (REALISM) was approved and began enrollment in 2009. The REALISM study allowed for collection of additional safety and effectiveness data and permitted patients and physicians continued access to the MitraClip during review of pre-market approval application (PMA). The REALISM Study consisted of two arms, one arm for "RCT eligible" (non-high surgical risk) patients and one arm for "HRR eligible" (high surgical risk) patients. The REALISM Study was closed to enrollment for non-high surgical risk patients in September 2011 and continued enrolling in the High Risk arm through PMA approval. The EVEREST II HRR and REALISM HR studies were adjunctive studies to the RCT and not prospectively planned as stand-alone studies to support approval.
The MitraClip device received CE Mark in March 2008, and the ACCESS-EU post-approval studies were initiated to study of the use of the MitraClip System in patients treated in Europe. The primary objective of the ACCESS-EU studies was to gain health economics and clinical care data, as well as further evidence of device safety and effectiveness in the commercial setting.
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Table 6: Overview of MitraClip US Clinical Trials
| Type | Study | Key Inclusion Criteria | Key Exclusion Criteria | Endpoint | sites | patients |
| --- | --- | --- | --- | --- | --- | --- |
| Feasibility | EVEREST I
enrollment 2003-2006 | • MR≥3+
• Symptomatic or asymptomatic with^{a}:
LVEF 30-50% and/or LVESD 50-55mm or
LVEF 50-60% and LVESD < 45 mm or
LVEF>60 and LVESD 45-55 mm
• Candidate for mitral valve surgery including cardiopulmonary bypass | • LVEF<30%, and/or LVESD >55mm
• Mitral valve orifice area <4.0 cm²
• Leaflet anatomy which may preclude MitraClip device implantation, proper MitraClip device positioning on the leaflets or sufficient reduction in MR | • Primary: Major Adverse Event rate through 30 days | 11 | 55 |
| Randomized Control Trial | EVEREST II RCT
enrollment 2005-2008 | • MR≥3+
• Symptomatic with LVEF > 25% and LVESD ≤ 55 mm or asymptomatic with^{a}:
LVEF 25% to 60%
LVESD ≥ 40 mm
New onset of atrial fibrillation
PASP>50mmHg at rest of >60 mmHg with exercise | • LVEF≤25%, and/or LVESD >55mm
• Mitral valve orifice area <4.0 cm²
• Leaflet anatomy which may preclude MitraClip device implantation, proper MitraClip device positioning on the leaflets or sufficient reduction in MR | • Primary Safety: Major Adverse Event rate through 30 days or discharge, whichever is greater
Primary Effectiveness: Freedom from death, MV surgery (for Device group) or re-operation (for Control group), and MR > 2+ at 12 months
• Secondary Effectiveness:
• Measures of LV Function
• SF-36 quality of life
• NYHA Functional Class | 37 | 60
roll-in
178^{b}
Device
80^{b}
Surgery Control |
| Single-Arm Registry | EVEREST II High Risk Registry Study
enrollment 2007-2008 | • MR≥3+
• Predicted procedural mortality risk calculated using the STS surgical risk calculator of ≥ 12% or in the judgment of a cardiac surgeon the patient is considered a high risk surgical candidate due to the presence of one of the following indications:
1. Porcelain aorta, mobile ascending aortic atheroma
2. Post-radiation mediastinum
3. Previous mediastinitis
4. Functional MR with EF<40
5. Over 75 years old with EF<40
6. Re-operation with patent grafts
7. Two or more prior chest surgeries
8. Hepatic cirrhosis
9. Three or more of the following STS high risk factors
9.1 Creatinine > 2.5 mg/dL
9.2 Prior chest surgery
9.3 Age over 75
9.4 EF<35 | • LVEF<20% and/or LVESD>60mm
• Mitral valve orifice area <4.0 cm²
• Leaflet anatomy which may preclude MitraClip device implantation, proper MitraClip device positioning on the leaflets or sufficient reduction in MR | • Primary Safety: Procedural mortality at 30 days
• Major Secondary:
• Measures of LV Function
• SF-36 quality of life
• NYHA Functional Class
• CHF Hospitalizations
• Secondary Safety:
• Major Adverse Event rate at 30 days and 12 months | 25 | 78 |
| Continued Access Registry | REALISM High Risk
enrollment 2009-2013 | • Same as High Risk Registry with the exception of the requirement for predicted procedural mortality risk ≥ 12% | • Same as High Risk Registry | • Same as High Risk Registry | 39 | 581^{c} |
| | REALISM Non-High Risk
enrollment 2009-2011 | • Same as RCT | • Same as RCT | • Same as RCT
• 6 Minute Walk Test (6MWT) Distance^{d} | 39 | 272 |
a Inclusion criteria based on the current indication for mitral valve surgery for mitral regurgitation in the ACC/AHA guidelines for management of valvular dysfunction..
b Of the 184 patients randomized to Device, 178 received Device. Of the 95 patients randomized to Control, 80 underwent mitral valve surgery.
c As of July 12, 2013
d In protocol version dated November 17, 2008, only patients with NYHA Functional Class III or IV in the Non-High Risk arm were considered for a 6-minute walk test. In the amended protocol version dated September 14, 2010, all patients enrolled in REALISM are required to perform the 6-minute walk test.
PMA P100009: FDA Summary of Safety and Effectiveness Data
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An original PMA was filed in March 2010 for an indication inclusive of surgical candidates and patients too high risk for surgery with either degenerative or functional MR etiologies. A summary of study design, patient population and results from the studies is provided below.
# EVEREST II RANDOMIZED CONTROL TRIAL (EVEREST II RCT)
The EVEREST II RCT was a prospective, randomized, controlled, multi-center study of 279 patients (184 MitraClip, 95 Surgery control) comparing the safety and effectiveness of the MitraClip to the standard of care mitral valve surgery. The intended population was patients with significant symptomatic mitral regurgitation $(\mathrm{MR} \geq 3+)$ of either FMR or DMR etiology that were non-high risk candidates indicated for and who could undergo mitral valve surgery. Study design elements including key inclusion/exclusion criteria and endpoints are provided in Table 6. Patients were evaluated at baseline, discharge, 30 days, 6, 12, 18 and 24 months, and annually thereafter through 5 years. A summary of baseline characteristics and safety and effectiveness results from the EVEREST II RCT are provided in Table 7.
Table 7: Summary of EVEREST II RCT Safety and Effectiveness Results
| Baseline Characteristic | RCT MitraClip % (n/N) (N = 184) | RCT Surgery Control % (n/N) (N = 95) | p-value |
| --- | --- | --- | --- |
| Age (years), Mean ± SD (N) | 67.3±12.8 (184) | 65.7±12.9 (95) | 0.321 |
| Patients over 75 years of age | 29.9% (55/184) | 27.4% (26/95) | 0.679 |
| Female Gender | 37.5% (69/184) | 33.7% (32/95) | 0.600 |
| Coronary Artery Disease | 47.0% (86/183) | 46.3% (44/95) | >0.99 |
| Prior Myocardial Infarction | 21.9% (40/183) | 21.3% (20/94) | >0.99 |
| Atrial Fibrillation History | 33.7% (59/175) | 39.3% (35/89) | 0.415 |
| Prior Stroke | 1.6% (3/184) | 3.2% (3/95) | 0.413 |
| Diabetes | 7.6% (14/184) | 10.5% (10/95) | 0.500 |
| Moderate to Severe Renal Disease | 3.3% (6/184) | 2.1% (2/95) | 0.720 |
| Chronic Obstructive Pulmonary Disease (w/ or w/o Home O2) | 14.8% (27/183) | 14.7% (14/95) | >0.99 |
| Previous Cardiovascular Surgery | 22.3% (41/184) | 18.9% (18/95) | 0.541 |
| Previous Percutaneous Coronary Intervention | 24.0% (44/183) | 15.8% (15/95) | 0.124 |
| NYHA Class III/IV Heart Failure | 51.1% (94/184) | 47.4% (45/95) | 0.614 |
| Functional MR Etiology | 26.6% (49/184) | 27.4% (26/95) | 0.888 |
| LV Ejection Fraction (%), Mean ± SD (N) | 60.0±10.1 (182) | 60.6±11.0 (95) | 0.649 |
| LV Internal Diameter systole (cm), Mean ± SD (N) | 3.7±0.9 (181) | 3.5±0.8 (94) | 0.161 |
| 30-Day Safety (Major Adverse Eventa) Endpoint Results | | | |
| Intention to Treat Analysis (Superiority δ = 2%) | | | |
| Safety Endpoint (%) | 15.0% (27/180) | 47.9% (45/94) | p-value (Superiority) |
| Difference (MitraClip – Surgery), 95% CI | -32.9% (-45.0%, -20.7%) | | < 0.0001 |
| 12-Month Effectiveness Endpoint Results | | | |
| Per Protocol Analysis (Margin of decreased effectiveness: δ = -31%) | | | p-value (Non-inferiorityb) |
| Freedom from death, MV surgery or re-op and MR > 2+, n (%)c | 72.4% (97/134) | 87.8% (65/74) | |
| MitraClip – Surgery, (95% LCB) | -15.4% (-25.4%) | | 0.0012 |
| Freedom from death, MV surgery or re-op and MR > 1+, n (%)d | 45.1% (37/82) | 68.9% (51/74) | |
| MitraClip – Surgery, (95% LCB) | -23.8% (-37.7%) | | 0.1692 |
a MAE defined as combined clinical endpoint of death, myocardial infarction (MI), re-operation for failed surgical repair or replacement, non-elective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for greater than 48 hours, gastrointestinal (GI) complication requiring surgery, new onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood.
PMA P100009: FDA Summary of Safety and Effectiveness Data
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b Non-inferiority statistical methods were used to calculate this p-value, however, non-inferiority is not implied due to the large margin. Therefore, this test shows whether the results show decreased effectiveness by the margin specified of <31%.
c Abbott Vascular pre-specified endpoint
d FDA pre-specified endpoint
Although the EVEREST II RCT provided evidence that the MitraClip device could be safely implanted and reduced MR severity in the majority of patients, the device did not reduce MR as often or as completely as the surgical control. Other limitations of the study included the definition of the primary success criterion, effectiveness margin and heterogeneity of MR etiology. Thus, FDA determined that the data did not demonstrate an appropriate benefit-risk profile when compared to standard mitral valve surgery and were inadequate to support approval for the device in a surgical candidate population. Although the trial fell short of supporting use of MitraClip in surgical candidates, it benchmarked the safety, effectiveness and durability of the MitraClip against the surgical gold standard. Additionally, as the RCT enrolled primarily DMR patients, the trial provides a comparison for symptomatic candidates with severe DMR who are at prohibitive risk for mitral valve surgery and treated with the MitraClip.
# EVEREST II HIGH RISK REGISTRY (EVEREST II HRR) and EVEREST II CONTINUED ACCESS REGISTRY (REALISM HR)
Following significant discussion with the FDA and physician advisors, the Sponsor narrowed the scope of the PMA indication in April 2011 to include only functional and degenerative MR patients with an unmet need for treatment, who were too high risk for mitral valve surgery.
EVEREST II HRR and REALISM HR were single-arm, self-controlled adjunctive studies to evaluate the safety and effectiveness of the MitraClip in high surgical risk patients. The intended population for these studies was patients with significant symptomatic mitral regurgitation (MR ≥ 3+) of either FMR or DMR etiology that were determined to be too high risk to undergo mitral valve surgery based upon the STS predicted procedural mortality replacement score or judgment of a cardiothoracic surgeon.
Study design elements including key inclusion/exclusion criteria and endpoints were identical for the two studies, and are provided in Table 6. Patients were evaluated at baseline, discharge, 30 days, 6, 12, 18 and 24 months, and annually thereafter through 5 years. A summary of baseline characteristics and safety and effectiveness results from the 351 high surgical risk patients from the EVEREST II HRR and REALISM HR studies treated with the MitraClip are provided in Table 8. These data were presented in support of the high risk indication at the FDA Circulatory System Devices Advisory Panel on March 20, 2013.
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Table 8: Summary of Integrated High Surgical Risk Cohort Safety and Effectiveness
| Baseline Characteristic | Integrated HSR Cohort
% (n/N)
(N = 351) |
| --- | --- |
| Age (years), Mean ± SD (N) | 75.7±10.5 (351) |
| Patients over 75 years of age | 58.1% (204/351) |
| Female Gender | 39.0% (137/351) |
| Coronary Artery Disease | 82.2% (287/349) |
| Prior Myocardial Infarction | 50.7% (177/349) |
| Atrial Fibrillation History | 68.5% (217/317) |
| Prior Stroke | 12.8% (45/351) |
| Diabetes | 39.4% (138/350) |
| Moderate to Severe Renal Disease | 30.5% (107/351) |
| Chronic Obstructive Pulmonary Disease
(w/ or w/o Home O2) | 28.9% (101/350) |
| Previous Cardiovascular Surgery | 59.8% (210/351) |
| Previous Percutaneous Coronary Intervention | 49.9% (175/331) |
| NYHA Class III/IV Heart Failure | 84.9% (298/351) |
| Functional MR Etiology | 70.1% (246/351) |
| LV Ejection Fraction (%), Mean ± SD (N) | 47.5 ± 14.2 (318) |
| LV Internal Diameter systole (cm), Mean ± SD (N) | 4.4 ± 1.1 (323) |
| Primary Safety Endpoint | |
| Procedural Mortality | 4.8% (17/351) |
| 97.5% Upper Confidence Bound | 7.6% |
| Average STS Predicted Replacement Mortality Risk (determined at enrollment) | 11.3% |
| Average STS Predicted Repair Mortality Risk (calculated retrospectively using STS version 2.61) | 7.6% |
| Major Effectiveness Endpoint | |
| Left Ventricular End Diastolic Volume (Change from baseline) | -17.9ml |
| Left Ventricular Internal Dimension, diastole (Change from baseline) | -0.2cm |
| Left Ventricular End Diastolic Volume (Change from baseline) | -8.1ml |
| Left Ventricular Internal Dimension, systole (Change from baseline) | -0.1cm |
Limitations of these studies included heterogeneity of MR etiology, data pooling, post hoc control group, post hoc analysis, data accountability, and difficulty defining the surgical risk status of the patient population. At the March 20, 2013 Advisory Panel of experts, Panelists determined that the data on these 351 high surgical risk patients demonstrated reasonable assurance that the MitraClip Clip Delivery System is safe for use in patients too high risk for surgery and the benefits of treatment outweigh the risks in these high surgical risk patients. However, due to the limitations described above, in particular because of difficulty understanding patient risk status and the heterogeneity of MR, the majority of the Advisory Panel were unable to conclude that there was reasonable assurance of effectiveness of the MitraClip in this patient population.
PMA P100009: FDA Summary of Safety and Effectiveness Data
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# DMR PATIENTS AT PROHIBITIVE RISK FOR SURGERY
Following the FDA Advisory Panel meeting, the Sponsor and FDA worked interactively and determined that patients with primary MR etiology (DMR) at prohibitive risk for surgery (PR DMR) were the appropriate patient population to evaluate the risks and benefits of the MitraClip device. While all patients with significant symptomatic MR who are not surgical candidates have an unmet clinical need, the value of intervention to reduce MR is clearest for patients with DMR etiology. It is broadly accepted that DMR is a mechanical problem in which there is a primary abnormality of the mitral apparatus and the "leaflets are broken". There is no medical therapy for reduction of DMR, which must be treated with mechanical correction of the mitral valve. For secondary or functional MR (FMR), the relative benefits of MR reduction versus optimal medical therapy are less clear because MR is secondary to left ventricular dysfunction, which can and does improve with medical therapy, revascularization, and/or cardiac resynchronization therapy in some patients. Thus, the clinical benefit of MitraClip in FMR could not be discerned with the existing single arm study results. For DMR patients considered surgical candidates, surgery remains the standard of care treatment option and the ACC/AHA Guidelines define surgery for these patients as Class I and IIa indications. The patients indicated for the MitraClip device are DMR patients at prohibitive risk for surgery and therefore have no other effective treatment options.
Patients from the MitraClip studies (EVEREST II, HRR, REALISM) were evaluated by a panel of physicians and 127 patients were determined to be at prohibitive risk for surgical mortality. Results from these 127 PR DMR patients were analyzed, incorporated into the PMA application, and are summarized below. The analysis cohort of 127 subjects was developed post-hoc; this severely limits the statistical interpretability of reported data.
These data were determined to adequately establish the safety, effectiveness, and positive benefit-risk profile of the MitraClip for the indicated population and are the basis for approval of this PMA application. The totality of evidence demonstrates reasonable assurance of safety and effectiveness of MitraClip to reduce MR and provide patient benefit in this discreet and specific patient population (PR DMR), as described below.
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Prohibitive Risk DMR MitraClip Patients – Demographics and Patient Accountability
Table 9: Prohibitive Risk DMR MitraClip Cohort – Key Baseline Characteristics
| Baseline Characteristic^{a} | Prohibitive Risk DMR MitraClip Patients % (n/N) (N = 127) |
| --- | --- |
| Age (years), Mean±SD (N) | 82.4±8.7 (127) |
| Patients over 75 years of age | 83.5% (106/127) |
| Female Gender | 44.9% (57/127) |
| Body Mass Index (kg/m²), Mean±SD (N) | 25.0±5.7 (127) |
| Coronary Artery Disease | 72.8% (91/125) |
| Prior Myocardial Infarction | 24.4% (31/127) |
| Atrial Fibrillation History | 70.5% (86/122) |
| Prior Stroke | 10.2% (13/127) |
| Diabetes | 29.9% (38/127) |
| Moderate to Severe Renal Disease | 28.3% (36/127) |
| Cardiomyopathy | 23.6% (30/127) |
| Chronic Obstructive Pulmonary Disease (w/ or w/o Home O2) | 31.5% (40/127) |
| Hypertension | 88.2% (112/127) |
| Previous Cardiovascular Surgery | 48.0% (61/127) |
| Previous Percutaneous Coronary Intervention | 33.3% (42/126) |
| NYHA Functional Class III/IV Heart Failure | 86.6% (110/127) |
| LV Ejection Fraction (%), Mean±SD (N) | 60.6±9.5 (112) |
| LV Internal Diameter, systole (cm), Mean±SD (N) | 3.4±0.8 (113) |
| STS Mortality Risk (determined at enrollment for replacement)^{b}, Mean±SD (N) | 13.6±7.9 (127) |
a Sample sizes or denominators smaller than the N reported for the group reflect missing data
b STS replacement score calculated using the version of the calculator at the time of enrollment
The PR DMR Cohort was elderly with a high rate of serious comorbidities.
The reasons for prohibitive risk are summarized in Table 10. Patients with STS replacement score ≥ 8% had high rates of additional risk factors not accounted for in the STS calculator, placing these patients at prohibitive risk of morbidity and mortality from mitral valve surgery beyond what is accounted for in the STS calculator. Hostile chest (15.8%), internal mammary artery (IMA) at high risk of injury (20.8%) and frailty (9.9%) were among the most common risk factors in these patients. Among patients with STS replacement score < 8%, one or more additional risk factors not accounted for in the STS calculator placed these patients at prohibitive risk of morbidity and mortality from mitral valve surgery. Porcelain aorta (30.8%), hostile chest (19.2%), severe liver disease or cirrhosis (15.4%), IMA at high risk of injury (15.4%), high risk of aspiration (15.4%) and severe pulmonary hypertension (11.5%) were among the most common reasons for prohibitive risk.
PMA P100009: FDA Summary of Safety and Effectiveness Data
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Table 10: Prohibitive Risk DMR MitraClip Cohort - Reasons for Prohibitive Risk
| Prohibitive Risk Factora | Patients with STS Replacement Score ≥ 8% (N = 101) | Patients with STS Replacement Score < 8% (N = 26) |
| --- | --- | --- |
| Porcelain Aorta | 5.0% (5/101) | 30.8%(8/26) |
| Frailty | 9.9% (10/101) | 7.7%(2/26) |
| Hostile chest | 15.8% (16/101) | 19.2%(5/26) |
| Severe liver disease or cirrhosis | 1.0% (1/101) | 15.4%(4/26) |
| Severe pulmonary hypertension | 5.0% (5/101) | 11.5%(3/26) |
| Unusual extensive circumstance: | | |
| RV dysfunction with severe tricuspid regurgitation | 5.0% (5/101) | 0.0% (0/26) |
| Chemotherapy for malignancy | 5.0% (5/101) | 3.8%(1/26) |
| Major bleeding diathesis | 5.9% (6/101) | 7.7%(2/26) |
| Immobility | 4.0% (4/101) | 3.8%(1/26) |
| AIDS | 0.0% (0/101) | 3.8%(1/26) |
| Severe dementia | 2.0% (2/101) | 7.7%(2/26) |
| High risk of aspiration | 3.0% (3/101) | 15.4%(4/26) |
| IMA at high risk of injury | 20.8% (21/101) | 15.4%(4/26)b |
a Patients may present at baseline with more than one prohibitive risk factor
b These 4 patients also had other risk factors on this list. No patient was considered prohibitive risk solely on the basis of IMA at high risk of injury because mitral valve repair surgery can be done via right thoracotomy.
Table 11 shows the follow-up compliance at 30 days, 12 months and 2 years in the PR DMR Cohort. Compliance to follow-up visits in continuing patients was $98.4\%$ , $98.4\%$ and $94.9\%$ and clinical follow-up occurred in $97.6\%$ , $95.3\%$ and $88.7\%$ , respectively.
Table 11: Prohibitive Risk DMR MitraClip Cohort - Compliance to Follow-up Visits
| Follow-up Visit | # Visits | # Missed Visit† | # Deaths before visit | # Withdrawn before visit | Not due for visit | Visit Compliance$ | Clinical Follow-up Occurred In$$ |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Baseline | 127 | - | - | - | - | 100% | 100% |
| 30-Day | 115 | 2 | 9 | 1 | 0 | 98.4% | 97.6% |
| 12-Month | 91 | 2 | 30 | 4 | 0 | 98.4% | 95.3% |
| 2-Year | 53 | 5 | 41 | 7 | 21 | 94.9% | 88.7% |
† A visit is counted as missed if the last date of the visit window is at least 30 days before the cut-off date for this report
$ Visit Compliance is calculated as (#Visits + #Deaths)/(127 - #Withdrawn before visit - # Not due for visit)
Clinical follow-up is calculated as (#Visits + #Deaths)/(127 - # Not due for visit)
PMA P100009: FDA Summary of Safety and Effectiveness Data
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Prohibitive Risk DMR MitraClip Patients - Procedural Results
The MitraClip procedure is performed under general anesthesia via echocardiographic and fluoroscopic guidance. Data on Procedure Time, Device Time and fluoroscopy duration are summarized in Table 12. The mean Procedure Time, defined as the start time of the transseptal procedure to the time the Steerable Guide Catheter is removed, was approximately 2.5 hours. Device time, defined as the time of insertion of the Steerable Guide Catheter to the time the MitraClip Delivery Catheter is retracted into the Steerable Guide Catheter, averaged 125 minutes. The mean fluoroscopy duration was 46 minutes. As this is primarily an echocardiographic guided procedure, fluoroscopy time is limited to a relatively short percentage of the overall Procedure Time (29%). There were no intra-procedural deaths.
Table 12: Prohibitive Risk DMR MitraClip Cohort - Procedural Results
| Procedural Result^a | Mean±SD (N) Median (Min, Max) |
| --- | --- |
| Procedure Time^b (min) | 157±81 (124) 134 (39, 524) |
| Device Time^c (min) | 125±75 (124) 110 (9, 511) |
| Fluoroscopy Duration (min) | 46±26 (126) 39 (3, 167) |
^a Sample sizes or denominators smaller than 127 reflect missing data.
^b Procedure time is measured from the time the transseptal procedure starts until the time the Steerable Guide Catheter is removed.
^c Device time is measured from the time the Steerable Guide Catheter is placed in the intra-atrial septum until the time the MitraClip Delivery System is retracted into the Steerable Guide Catheter.
The MitraClip device was implanted successfully in a majority (95.3%) of PR DMR patients. The distribution of number of MitraClip devices implanted is shown in Table 13 and the post-procedure ICU/CCU/PACU time is presented in Table 14.
Table 13: Prohibitive Risk DMR MitraClip Cohort - Number of MitraClip Devices Implanted
| # Devices Implanted | % (n/N) |
| --- | --- |
| 0 | 4.7% (6/127) |
| 1 | 44.1% (56/127) |
| 2 | 51.2% (65/127) |
Table 14: Prohibitive Risk DMR MitraClip Cohort - Post-Procedure through Discharge
| Post-Procedure Stay | Mean±SD (N) |
| --- | --- |
| Post-Procedure ICU/CCU/PACU Duration [Days] | 1.4±1.8 (127) |
| Post-Procedure Hospital Stay [Days] | 2.9±3.1 (127) |
PMA P100009: FDA Summary of Safety and Effectiveness Data
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Prohibitive Risk DMR MitraClip Patients – Safety Analysis and Results
A total of 8 PR DMR patients died within 30 days of the MitraClip procedure or discharge post-procedure (whichever is longer), resulting in a procedural mortality rate of 6.3%, which is less than both the mean and median predicted STS mortality risk using either the repair or replacement calculator. In addition, the upper bound of the 95% confidence interval on procedural mortality (12.0%) is lower than both the mean and median STS replacement score.
Table 15: Prohibitive Risk DMR MitraClip Cohort - Procedural Mortality
| Observed Procedural Mortality, % (n/N) | 6.3% (8/127) |
| --- | --- |
| 95% CIa,c | (2.8%, 12.0%) |
| STS v2.73 Replacement Risk Score | |
| Mean (95% CIb,c) | 13.2% (11.9%, 14.5%) |
| Median (95% CIb,c) | 12.4% (11.3%, 13.7%) |
| STS v2.73 Repair Risk Score | |
| Mean (95% CIb,c) | 9.5% (8.5%, 10.6%) |
| Median (95% CIb,c) | 8.5% (7.6%, 9.3%) |
a Based on Clopper-Pearson method
b CI for mean is calculated based on two-sample t-distribution and CI for median is based on non-parametric methods
c Confidence intervals are provided to illustrate the variability of the corresponding summary statistic. They should not be used to draw statistical inference.
At 12 months, MAEs occurred at a rate of 35.4% among Prohibitive Risk DMR MitraClip patients, with deaths (23.6%) and transfusions (19.7%) comprising the majority of events. The rate of stroke was 2.4% and rate of non-elective cardiovascular surgery (0.8%) at 12 months.
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Table 16: Prohibitive Risk DMR MitraClip Cohort - CEC Adjudicated Major Adverse Events at 30 Days
| Description of Event | Prohibitive Risk DMR MitraClip Patients % (n/N) (N = 127) |
| --- | --- |
| Death | 6.3% (8/127) |
| Myocardial infarction | 0.8% (1/127) |
| Re-operation for failed surgical repair or replacement | 0 |
| Non-elective cardiovascular surgery for adverse events | 0.8% (1/127) |
| Stroke | 2.4% (3/127) |
| Renal Failure | 1.6% (2/127) |
| Deep wound infection | 0 |
| Ventilation > 48 hours | 3.1% (4/127) |
| GI complication requiring surgery | 0.8% (1/127) |
| New onset of permanent AF | 0 |
| Septicemia | 0 |
| Transfusion ≥ 2 units | 12.6% (16/127) |
| Totala | 18.9% (24/127) |
| Totala (Excluding Transfusions ≥ 2 units) | 9.4% (12/127) |
a Total number of patients may not equal the sum of patients in each row since one patient may experience multiple events.
Table 17: Prohibitive Risk DMR MitraClip Cohort - CEC Adjudicated Major Adverse Events at 12 Months
| Description of Event | Prohibitive Risk DMR MitraClip Patients % (n/N) (N = 127) |
| --- | --- |
| Death | 23.6% (30/127) |
| Myocardial infarction | 0.8% (1/127) |
| Re-operation for failed surgical repair or replacement | 0 |
| Non-elective cardiovascular surgery for adverse events | 0.8% (1/127) |
| Stroke | 2.4% (3/127) |
| Renal Failure | 3.9% (5/127) |
| Deep wound infection | 0.0% (0/127) |
| Ventilation > 48 hours | 4.7% (6/127) |
| GI complication requiring surgery | 2.4% (3/127) |
| New onset of permanent AF | 0.0% (0/127) |
| Septicemia | 4.7% (6/127) |
| Transfusion ≥ 2 units | 19.7% (25/127) |
| Totala | 35.4% (45/127) |
| Totala (Excluding Transfusions ≥ 2 units) | 26.0% (33/127) |
a Total number of patients may not equal the sum of patients in each row since one patient may experience multiple events.
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Other secondary safety endpoints occurred at a relatively low rate, consistent with access to the mitral valve achieved via the femoral vein and inferior vena cava. Major vascular complications occurred in $5.5\%$ of patients at 30 days and in $7.1\%$ of patients at 12 months. Major bleeding complications, defined as procedure-related bleeding requiring transfusions of at least 2 units or surgery, occurred at a rate of $12.6\%$ at 30 days. The majority of bleeding events required transfusions rather than surgery. Bleeding events that occurred after 30 days were unrelated to the MitraClip procedure. Clinically significant atrial septal defect requiring treatment occurred at a rate of $2.4\%$ at 12 months. A low rate $(2.4\%)$ of mitral stenosis was observed at 12 months, with a total of 3 patients reported to have experienced mitral stenosis defined as Echocardiography Core Laboratory assessed mitral valve area less than $1.5~\mathrm{cm}^2$ through 12 months. One additional patient is reported to have experienced mitral stenosis at 18 months. The site did not report mitral stenosis for these patients and none of these patients underwent mitral valve surgery for stenosis.
Table 18: Prohibitive Risk DMR MitraClip Cohort - Other Secondary Safety Events at 30 Days and 12 Months
| Description of Event | 30 Days % (n/N) | 12 Months % (n/N) |
| --- | --- | --- |
| Major Vascular Complications | 5.5% (7/127) | 7.1% (9/127) |
| Major Bleeding Complications | 12.6% (16/127) | 15.7% (20/127) |
| Non-Cerebral Thromboembolism | 1.6% (2/127) | 1.6% (2/127) |
| New Onset of Persistent Atrial Fibrillation | 3.9% (5/127) | 3.9% (5/127) |
| Heart Block/Other Arrhythmia requiring Permanent Pacemaker | 0.0% (0/127) | 1.6% (2/127) |
| Endocarditis | 0.0% (0/127) | 0.0% (0/127) |
| Thrombosis | 0.0% (0/127) | 0.0% (0/127) |
| Hemolysis | 0.0% (0/127) | 0.0% (0/127) |
| Atrial Septal Defect | 1.6% (2/127) | 2.4% (3/127) |
| Mitral Valve Stenosis | 0.0% (0/127) | 2.4% (3/127) |
There have been no reports of a MitraClip device embolization in the Prohibitive Risk DMR Cohort. A Single Leaflet Device Attachment (SLDA) is defined as the attachment of one mitral leaflet to the MitraClip device. Of the 121 patients with at least one MitraClip device implanted, no SLDAs have been reported.
A descriptive comparator for mortality comes from the Duke University Medical Center database, which consists of patient-level data with echocardiographic, medical history and follow-up data on a large number of patients with $\mathrm{MR} \geq 3+$ . This database allowed for characterization of survival in patients deemed high risk for surgery and managed nonsurgically at the Duke University Medical Center despite clear Class I indications for surgery according to the ACC/AHA Guidelines for the Management of Patients with Valvular Heart Disease. Nine hundred and fifty-three (953) patients in the Duke database with $3+$ or $4+$ MR were identified as too high risk for surgery based on the same high risk criteria as those in the EVEREST II HRR and REALISM studies (i.e. STS mortality risk $\geq 12\%$ or protocol-
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specified surgical risk factors) and managed non-surgically. This made up the Duke High Risk Cohort, of which 65 patients were identified as DMR.
Table 19 shows a comparison of baseline and demographic characteristics between the 127 Prohibitive Risk DMR patients and 65 Duke High Risk DMR patients. Both groups were comprised of elderly patients, with a majority of patients over the age of 75 years. The Duke High Risk DMR Cohort reported a lower LVEF at baseline and a higher proportion of female patients than the Prohibitive Risk DMR Cohort. The Prohibitive Risk DMR Cohort reported a higher proportion of patients with COPD and NYHA III/IV symptoms at baseline. Both groups had high rates of previous MI, atrial fibrillation and previous cardiovascular surgery.
Descriptive mortality comparisons were performed between the 127 Prohibitive Risk DMR patients and the 65 Duke High Risk DMR patients. Figure 2 displays Kaplan-Meier curves comparing survival in the Prohibitive Risk DMR patients to the Duke High Risk DMR patients. Based on these Kaplan-Meier curves, mortality in the Prohibitive Risk DMR Cohort was $6.4\%$ at 30 days and $24.8\%$ at 12 months compared to $10.9\%$ at 30 days and $30.6\%$ at 12 months in the Duke High Risk DMR patients. While these results are descriptive and limited by differences described above, they suggest that there is no elevated risk of mortality in Prohibitive Risk DMR patients who undergo the MitraClip procedure over non-surgical management. This is consistent with the observed safety of MitraClip in the EVEREST II RCT, the consensus of the FDA Advisory Panel that MitraClip is safe in high risk patients, and the commercial experience with the device.
Table 19: Baseline and Demographic Characteristics - Prohibitive Risk DMR MitraClip and Duke High Risk DMR Medical Therapy Cohorts
| Baseline Characteristic | Prohibitive Risk DMR MitraClip Cohort % (n/N) (N = 127) | Duke High Risk DMR Medical Therapy Cohort % (n/N) (N = 65) |
| --- | --- | --- |
| Age (years), Mean±SD (N) | 82.4±8.7 (127) | 76.8±11.3 (65) |
| Patients over 75 years of age | 83.5% (106/127) | 67.7% (44/65) |
| Male Gender | 55.1% (70/127) | 36.9% (24/65) |
| Body Mass Index (kg/m2), Mean±SD (N) | 25.0±5.7 (127) | 25.4±5.0(65) |
| Prior Myocardial Infarction | 24.4% (31/127) | 33.8% (22/65) |
| Atrial Fibrillation History | 70.5% (86/122) | 58.5% (38/65) |
| Prior Stroke | 10.2% (13/127) | 18.5% (12/65) |
| COPD with Home Oxygen | 13.4% (17/127) | 6.2% (4/65) |
| Hypertension | 88.2% (112/127) | 75.4% (49/65) |
| Diabetes | 29.9% (38/127) | 36.9% (24/65) |
| Moderate to Severe Renal Disease | 28.3% (36/127) | 20.0% (13/65) |
| Previous Cardiovascular Surgery | 48.0% (61/127) | 56.9% (37/65) |
| Previous Percutaneous Coronary Intervention | 33.3% (42/126) | 58.5% (38/65) |
| NYHA Functional Class III/IV | 86.6% (110/127) | 43.8% (28/65) |
| STS Predicted Mortality Risk | 13.2±7.3 (127) | 13.3±9.0 |
| LV Ejection Fraction (%), Mean±SD (N) | 60.6±9.5 (112) | 44.9±11.7 (65) |
| LV Internal Diameter, systole (cm), Mean±SD (N) | 3.4±0.8 (113) | 3.4±0.9 (65) |
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Figure 2: Kaplan-Meier Freedom from Mortality - Prohibitive Risk DMR MitraClip and Duke High Risk DMR Medical Therapy Patients
Number at Risk, Kaplan-Meier Estimates and $95\%$ CIs
| Time Post Index Procedure | Baseline | 30 Days | 6 Months | 12 Months |
| --- | --- | --- | --- | --- |
| Prohibitive Risk DMR MitraClip Patients (N = 127) | | | | |
| # At Risk | 127 | 117 | 106 | 85 |
| # Events | 0 | 8 | 19 | 31 |
| % Event Free | 100% | 93.6% | 84.8% | 75.2% |
| 95% CIa | - | [87.6%, 96.8%] | [77.2%, 90.0%] | [66.1%, 82.1%] |
| Duke High Risk DMR Medical Therapy Patients (N = 65) | | | | |
| # At Risk | 65 | 57 | 49 | 39 |
| # Events | 0 | 7 | 13 | 19 |
| % Event Free | 100% | 89.1% | 79.6% | 69.4% |
| 95% CIa | - | [78.5%, 94.7%] | [67.4%, 87.6%] | [56.3%, 79.3%] |
a Confidence intervals are provided to illustrate the variability of the corresponding summary statistic. They should not be used to draw statistical inference.
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Prohibitive Risk DMR MitraClip Patients – Effectiveness Analysis and Results
MR severity at baseline, discharge and 12 months are presented in Table 20 for patients with data available at each follow-up (Completers Analysis). Immediate improvement in MR severity was noted at discharge with 82.1% and 53.7% of surviving patients reporting MR severity ≤ 2+ and ≤ 1+, respectively. This improvement was sustained at 12 months, with the majority (83.3%) of surviving patients reporting MR severity ≤ 2+ and 36.9% reporting MR severity ≤ 1+. At 12 months, freedom from death and MR>2+ was 61.4% and freedom from death and MR > 1+ was 27.2% patients.
Table 20: Prohibitive Risk DMR MitraClip Cohort - MR Severity at Baseline and Follow-up Completers Analysis
| MR Severity | Baseline % (n/N) | Discharge^{a} % (n/N) | 12 Months % (n/N) |
| --- | --- | --- | --- |
| 0 : None | 0 | 1.6% (2/123) | 0 |
| 1+: Mild | 0 | 52.0% (64/123) | 36.9% (31/84) |
| 2+: Moderate | 9.7% (12/124) | 28.5% (35/123) | 46.4% (39/84) |
| 3+: Moderate-to-severe | 58.9% (73/124) | 13.0% (16/123) | 13.1% (11/84) |
| 4+: Severe | 31.5% (39/124) | 4.9% (6/123) | 3.6% (3/84) |
| Missing | 3 | 3 | 13 |
| Death | 0 | 1 | 30 |
| MR ≤ 2+ in surviving patients | 9.7% (12/124) | 82.1% (101/123) | 83.3% (70/84) |
| MR ≤ 1+ in surviving patients | 0.0% (0/124) | 53.7% (66/123) | 36.9% (31/84) |
| Freedom from Death and MR > 2+ | 9.7% (12/124) | 81.5% (101/124) | 61.4% (70/114) |
| Freedom from Death and MR > 1+ | 0.0% (0/124) | 53.2% (66/124) | 27.2% (31/114) |
*30-day MR severity was used if discharge MR was unavailable
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Reduced preload as a result of the reduction in MR severity achieved with the MitraClip device resulted in reverse left ventricular remodeling (Table 21), characterized largely by a clinically important decrease in diastolic volume (-16.6 ml) and dimension (-0.2cm).
Table 21: Prohibitive Risk DMR MitraClip Cohort - LV Measurements at Baseline and 12 Months Patients with Paired Dataᵃ
| LV Measurement | N | Baseline | 12-month | Difference (12-month - Baseline) | %Change (12-month - Baseline) |
| --- | --- | --- | --- | --- | --- |
| LVEDV, ml | | | | | |
| Mean±SD | 69 | 125.1±40.1 | 108.5±37.9 | -16.6±22.9 | -11.5±17.9 |
| Median | | 119.7 | 104.7 | -12.3 | -10.2 |
| 95% CIᵇ,ᶜ | | | | (-22.1, -11.1) | (-15.9, -7.2) |
| LVIDd, cm | | | | | |
| Mean±SD | 80 | 5.0±0.6 | 4.8±0.6 | -0.2±0.4 | -3.7±8.2 |
| Median | | 5.1 | 4.9 | -0.2 | -4.0 |
| 95% CIᵇ,ᶜ | | | | (-0.3, -0.1) | (-5.6, -1.9) |
| LVESV, ml | | | | | |
| Mean±SD | 69 | 49.1±24.5 | 46.1±21.4 | -3.0±13.7 | -1.3±27.0 |
| Median | | 45.7 | 41.0 | -1.5 | -2.7 |
| 95% CIᵇ,ᶜ | | | | (-6.3, 0.3) | (-7.7, 5.2) |
| LVIDs, cm | | | | | |
| Mean±SD | 75 | 3.4±0.7 | 3.3±0.7 | -0.1±0.5 | -0.2±16.4 |
| Median | | 3.2 | 3.3 | -0.1 | -2.3 |
| 95% CIᵇ,ᶜ | | | | (-0.2, 0.1) | (-4.0, 3.6) |
ᵃ Only patients who had a measurement at both Baseline and 12 months are included
ᵇ 95% CI is based on a t-distribution
ᶜ Confidence intervals are provided to illustrate the variability of the corresponding summary statistic.
They should not be used to draw statistical inference.
Improvement in LV function resulted in improvements in heart failure symptoms. NYHA Functional Class at baseline and follow-up are presented in Table 22 for patients with data available at each follow-up (Completers Analysis). Immediate improvement in NYHA Class was noted at 30 days with 82.3% of surviving patients reporting NYHA Class I or II symptoms. This improvement was sustained at 12 months, with the majority (86.9%) of surviving patients reporting NYHA Class I or II symptoms. At 12 months, freedom from death and NYHA Class III or IV symptoms was 64.0%. This improvement in NYHA Class symptoms is clinically important given that the majority of these patients (86.6%) were enrolled with NYHA Class III or IV symptoms.
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Table 22: Prohibitive Risk DMR MitraClip Cohort - NYHA Functional Class at Baseline and Follow-up
Completers Analysis
| NYHA Functional Class | Baseline % (n/N) | 30 Days % (n/N) | 12 Months % (n/N) |
| --- | --- | --- | --- |
| I | 2.4% (3/127) | 33.6% (38/113) | 40.5% (34/84) |
| II | 11.0% (14/127) | 48.7% (55/113) | 46.4% (39/84) |
| III | 63.8% (81/127) | 15.9% (18/113) | 10.7% (9/84) |
| IV | 22.8% (29/127) | 1.8% (2/113) | 2.4% (2/84) |
| Missing | 0 | 5 | 13 |
| Death | 0 | 9 | 30 |
| NYHA I/II in surviving patients | 13.4% (17/127) | 82.3% (93/113) | 86.9% (73/84) |
| Freedom from Death and NYHA Class III/IV | 13.4% (17/127) | 76.2% (93/122) | 64.0% (73/114) |
Table 23 shows the change in NYHA Class at 12 months from baseline. The table shows that 73 of 83 (88%) surviving patients improved by at least 1 class. More importantly, 30 of 83 (36.1%) surviving patients improved by at least 2 classes. Inclusion of deaths in the denominator results in 64.6% of patients alive and improved by at least 1 class and 26.5% alive and improved by at least 2 classes. The MIRACLE trial $^{17}$ , a randomized, double-blind trial randomizing patients between cardiac resynchronization therapy (CRT) to no CRT showed that only 6% of patients improved by 2 classes in the "no CRT" group and 16% improved by 2 classes in the CRT group.
Table 23: Prohibitive Risk DMR MitraClip Cohort - Change in NYHA Class at 12 Months from Baseline
| NYHA Class Change | Number of Patients |
| --- | --- |
| 3 Class Improvement | 4 |
| 2 Class Improvement | 26 |
| 1 Class Improvement | 43 |
| No Change | 9 |
| 1 Class Worsening | 2 |
| Death | 30 |
| Missing | 13 |
SF-36 quality of life (QOL) questionnaires were administered at baseline, 30 days and 12 months. Table 24 shows a paired analysis of the Physical Component Summary (PCS) and Mental Component Summary (MCS) mean scores at baseline and 12 months. The mean change of $+6.0$ points in the PCS score from baseline to 12 months after the MitraClip procedure is well above the 2-3 point minimally important difference (MID) threshold reported in the literature[18]. Analysis of a large sample of US Medicare patients showed that a 3-point PCS difference was associated with a $40\%$ higher risk of being unable to work and a $20\%$ increase in mortality rates at two years across a wide range of disease conditions[19]. The mean change of $+5.6$ points in the MCS score at 12 months is substantially above the 3 point mean threshold reported in the literature[18]. Anchor-based research has determined that a 3
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point MCS difference corresponds to a 30% increased risk of depression and use of mental health services¹⁹.
Table 24: Prohibitive Risk DMR MitraClip Cohort - SF-36 Quality of Life at Baseline and 12 Months
Completers Analysisᵃ
| Component | N | Baseline | 12-month | Difference (12-month - Baseline) |
| --- | --- | --- | --- | --- |
| Physical Component Summary Score | | | | |
| Mean±SD | 73 | 33.4±8.6 | 39.4±10.5 | 6.0±8.6 |
| Median | | 32.4 | 40.7 | 5.6 |
| 95% CIᵇ,ᶜ | | | | (4.0, 8.0) |
| Mental Component Summary Score | | | | |
| Mean±SD | 73 | 46.6±13.4 | 52.2±10.2 | 5.6±14.0 |
| Median | | 49.8 | 54.0 | 3.2 |
| 95% CIᵇ,ᶜ | | | | (2.3, 8.9) |
ᵃ Only patients who had a measurement at both Baseline and 12 months are included
ᵇ 95% CI is based on a t-distribution
ᶜ Confidence intervals are provided to illustrate the variability of the corresponding summary statistic. They should not be used to draw statistical inference.
Clinically important improvements in all components of physical score were noted at 12 months, with the exception of Bodily Pain, which would not be expected to improve by MR reduction (Figure 3). All components of the mental score showed consistent improvement at 12 months (Figure 4).
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Figure 3: Prohibitive Risk DMR MitraClip Cohort - Components of SF-36 Physical Score at Baseline and 12 Months
Patients with Paired Data $(N = 73)$
Figure 4: Prohibitive Risk DMR MitraClip Cohort - Components of SF-36 Mental Score at Baseline and 12 Months
Patients with Paired Data $(N = 73)$
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Analysis of individual responders was also performed for both the PCS and MCS scores using distribution-based methods recommended by the SF-36 authors (Significant Change Criteria, SCC) and the Standard Error of Measurement (SEM) method suggested by the FDA in its 2009 PRO Guidance. The SF-36 responder analysis evaluates the proportion of patients with paired data at baseline and 12 months who achieve an improvement in QOL score greater than the responder criteria using each method. The proportion of responders was 63-68% for PCS and 49-53% for MCS.
Table 25: Prohibitive Risk DMR MitraClip Cohort – SF-36 QOL Responder Rate
| Component | Minimally Important Difference | Completers Analysis |
| --- | --- | --- |
| Physical Component Summary Score | SCCa (3.1) | 63.0% (46/73) |
| | SEMb (2.2) | 68.5% (50/73) |
| Mental Component Summary Score | SCCa (3.8) | 49.3% (36/73) |
| | SEMb (2.7) | 53.4% (39/73) |
a SCC (Significant Change Criteria): Significant change assuming baseline-follow-up correlation of .4 and using a 80% CI.
b SEM (Standard Error of Measurement): One SEM equals 68% CI.
Heart failure hospitalizations 12 months pre-MitraClip procedure and 12 months post-MitraClip procedure were recorded and analyzed. In this analysis, deaths were censored. A clinically important decrease in the rate of hospitalization for heart failure was observed following discharge from the MitraClip procedure (0.67 to 0.18 per patient-year, a 73% reduction, Table 26) between the pre-enrollment and the post-discharge 12-month periods.
Table 26: Prohibitive Risk DMR MitraClip Cohort - Heart Failure Hospitalizations
| | 12 months Pre-enrollment | Post-discharge through 12 months |
| --- | --- | --- |
| # Patients for Analysis | 127 | 120 |
| # Patients with Events | 48 | 13 |
| # Events | 85 | 17 |
| Follow-up (Patient-Years) | 127 | 97 |
| Rate^{a} | 0.67 | 0.18 |
| (95% Two-sided CI^{a,b}) | (0.54, 0.83) | (0.11, 0.28) |
| # days hospitalized (Mean±SD) | 6.0±4.5 | 5.9±3.8 |
a CI is obtained from a Poisson regression model
b Confidence intervals are provided to illustrate the variability of the corresponding summary statistic. They should not be used to draw statistical inference.
Effectiveness results demonstrate that 82.1% (101/123) of completers experienced MR reduction from 3+ or 4+ to 2+ or less at discharge following the MitraClip procedure (Table 20). Reduction of MR at 12 (n=84) was sustained to ≤2+ in 83.3% (70/84), and ≤1+ in 36.9% (31/84) of patients for whom echocardiographic data was available. Reduction in MR severity was associated with reverse left ventricular remodeling characterized largely by clinically important decreases in diastolic volume and dimension. Patients also experienced clinically important improvement in NYHA Functional Class at 12 months; more than 80% of patients experienced NYHA Class III or Class IV symptoms at baseline, which reduced to
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less than $15\%$ at 12 months. Despite the elderly and highly co-morbid nature of the population, quality of life as measured by the SF-36 quality of life physical and mental component scores showed clinically important improvement. Sensitivity analyses showed that these effectiveness results are robust to missing data. Finally, heart failure hospitalizations showed clinically important reduction in the 12 months post-MitraClip procedure from the 12 months pre-MitraClip procedure, including in a sensitivity analysis where death is included in the analysis as a heart failure hospitalization.
Table 27: Effectiveness in Prohibitive Risk DMR MitraClip Cohort
| Effectiveness Measure$ | Prohibitive Risk DMR MitraClip Cohort (N=127) |
| --- | --- |
| Improvement in LVEDV at 1 year | -17±23 |
| Improvement in LVESV at 1 year | -3±14 |
| Improvement in SF-36 PCS at 1 year | 6.0±8.6 |
| Improvement in SF-36 MCS at 1 year | 5.6±14.0 |
| NYHA Class III or IV: Baseline → 1 year | 85% → 13% |
$^{\S}$ LVEDV, LVESV, SF-36 PCS and MCS results are in patients with paired data, and NYHA Class results are in Completers
Reduction in MR severity was assessed in patients who have 2-year follow-up available. Table 28 shows that MR reduction in surviving patients to $\leq 2+$ and $\leq 1+$ is $82.5\%$ (33/40) and $35.0\%$ (14/40), respectively, at 2 years. Therefore, there is no evidence of deterioration of MR severity from 12 months to 2 years in surviving patients.
Table 28: Prohibitive Risk DMR MitraClip Cohort - Durability of MR Reduction
| MR Severity | Baseline % (n/N) | 12 Months % (n/N) | 2 Years % (n/N) |
| --- | --- | --- | --- |
| 0 : None | 0 | 0 | 0 |
| 1+: Mild | 0 | 36.9% (31/84) | 35.0% (14/40) |
| 2+: Moderate | 9.7% (12/124) | 46.4% (39/84) | 47.5% (19/40) |
| 3+: Moderate-to-severe | 58.9% (73/124) | 13.1% (11/84) |…
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**Source:** [https://fda.innolitics.com/device/P100009](https://fda.innolitics.com/device/P100009)
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