ATRICURE SYNERGY ABLATION SYSTEM

P100046 · AtriCure, Inc. · OCM · Dec 14, 2011 · Cardiovascular

Device Facts

Record IDP100046
Device NameATRICURE SYNERGY ABLATION SYSTEM
ApplicantAtriCure, Inc.
Product CodeOCM · Cardiovascular
Decision DateDec 14, 2011
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic, Expedited Review

Intended Use

The AtriCure Synergy Ablation System is intended to ablate cardiac tissue for the treatment of persistent atrial fibrillation (sustained beyond seven days, or lasting less than seven days but necessitating pharmacologic or electrical cardioversion) or longstanding persistent atrial fibrillation (continuous atrial fibrillation of greater than one year duration) in patients who are undergoing open concomitant coronary artery bypass grafting and/or valve replacement or repair.

Device Story

The AtriCure Synergy Ablation System is a radiofrequency (RF) surgical device used during open concomitant cardiac surgery to ablate cardiac tissue. The system consists of Synergy Ablation Clamps (OLL2, OSL2), an Ablation and Sensing Unit (ASU2) RF generator, and an AtriCure Switch Box (ASB3). The surgeon controls the clamp, which features two pairs of opposing linear electrodes on its jaws. When activated via a footswitch, the ASU2 delivers bipolar RF energy to the clamped tissue to create transmural lesions. The ASB3 allows the surgeon to switch between multiple handpieces. The system is used by cardiac surgeons in the operating room to treat atrial fibrillation by isolating pulmonary veins and creating specific ablation lines (Maze IV procedure). By creating transmural lesions, the device aims to block abnormal electrical conduction in the heart, potentially restoring normal sinus rhythm and reducing AF burden, thereby benefiting patients with persistent or longstanding persistent atrial fibrillation.

Clinical Evidence

The pivotal ABLATE trial was a prospective, multi-center, one-arm, non-randomized study (n=55) using a Bayesian adaptive design. Primary safety endpoint (30-day MAE rate) was 9.1% (BCI 0.00-0.179). Primary effectiveness endpoint (freedom from AF off AADs at 6 months) was 74.0% (BCI 0.604-1.00). Secondary data from registries and institutional databases (n=164 total) supported these findings. Pacemaker implantation rate was 25% at 30 days and 33% at 12 months. No device-related adverse events were reported.

Technological Characteristics

The system uses bipolar radiofrequency energy for tissue ablation. Components include Synergy Ablation Clamps (OLL2, OSL2) with linear electrodes, an ASU2 RF generator, and an ASB3 switch box. The clamps are ethylene oxide sterilized. The system is designed for epicardial or endocardial use during open-heart surgery. It is a non-implantable, reusable generator system with single-use sterile clamps.

Indications for Use

Indicated for patients with persistent or longstanding persistent atrial fibrillation undergoing open concomitant coronary artery bypass grafting and/or valve replacement or repair. Contraindicated for contraceptive coagulation of fallopian tubes.

Regulatory Classification

Identification

Surgical cardiac ablation for the treatment of atrial fibrillation.

Predicate Devices

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Electrosurgical Device Device Trade Name: AtriCure Synergy Ablation System Applicant's Name and Address: AtriCure, Inc. 6217 Centre Park Drive West Chester, OH 45069 USA Date(s) of Panel Recommendation: October 26, 2011 Premarket Approval Application (PMA) Number: P100046 Date of FDA Notice of Approval: December 15, 2011 Expedited: Granted expedited review status on February 24, 2011 because we believe that this radio frequency ablation system for the treatment of patients with persistent or longstanding persistent atrial fibrillation who are undergoing open concomitant cardiac surgery may offer significant, clinically meaningful advantages over pharmacologic treatment or the open surgical Maze procedure. Also, the availability of the device may be in the best interest of patients. II. INDICATIONS FOR USE The AtriCure Synergy Ablation System is intended to ablate cardiac tissue for the treatment of persistent atrial fibrillation (sustained beyond seven days, or lasting less than seven days but necessitating pharmacologic or electrical cardioversion) or longstanding persistent atrial fibrillation (continuous atrial fibrillation of greater than one year duration) in patients who are undergoing open concomitant coronary artery bypass grafting and/or valve replacement or repair. III. CONTRAINDICATIONS The AtriCure Synergy Ablation System should not be used for contraceptive coagulation of the fallopian tubes. The device is not designed for safe and effective use for that purpose. IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the AtriCure Synergy Ablation System labeling. PMA P100046: FDA Summary of Safety and Effectiveness Data {1} # V. DEVICE DESCRIPTION The AtriCure Synergy Ablation System devices included in this PMA are: - AtriCure Synergy Ablation Clamps - Product Codes: OLL2, OSL2 - Ablation and Sensing Unit – ASU2 – RF Generator - AtriCure Switch Box – ASB3 – allows user to connect multiple AtriCure devices to ASU2 ## System Description The Synergy Ablation clamps are available in two models, the OLL2 (open long left curved) and OSL2 (open short left curved), to aid in accessing varying patient body habitus. The OLL2 and OSL2 are the same with the exception of jaw geometry and shaft length. The OSL2 jaws are slightly shorter than the OLL2’s to provide surgeons with different options for accessing patient anatomy. ## Synergy Ablation Clamp The Synergy Ablation Clamps resemble standard surgical clamps and are always under the direct control of the surgeon. The devices include a syringe type grip handle/actuator, cylindrical shaft of varying lengths; varying jaw curvatures, lengths, and apertures, rounded jaw tips, and a cable that plugs into the ASB switch matrix and ASU RF generator (Figure 1). The Clamp device handle is connected by a cylindrical shaft to a pair of grasping jaws with electrodes on each jaw. Each jaw contains two (2) linear electrodes located medially and axially on the centerline of each insulated jaw of the clamp type end effector (Figure 2). These directly opposing linear electrodes, two on each jaw, make up two electrode pairs. Within an electrode pair, energy flows from the electrode on the proximal or top jaw to the electrode on the distal or bottom jaw. To activate RF energy, the AtriCure Synergy Ablation Clamp is connected via an integral cable to the AtriCure Ablation and Sensing Unit (ASU2) and the AtriCure Switch Box (ASB3) (Figure 3). PMA P100046: FDA Summary of Safety and Effectiveness Data {2} ![img-0.jpeg](img-0.jpeg) Figure 1. AtriCure Synergy Ablation Clamp (OLL2) ![img-1.jpeg](img-1.jpeg) Figure 2. AtriCure Synergy Ablation Clamp End Effector ## Ablation and Sensing Unit The Ablation and Sensing Unit (ASU) is a radiofrequency (RF) generator used to power AtriCure Handpieces (Figure 3). The ASU is a portable reusable device that produces and delivers RF bipolar energy through the AtriCure Synergy Ablation Clamp to ablate cardiac tissue. The ASU limits the amount of voltage, current, and time for which the RF power is delivered to the Clamp. In addition, the ASU lights a visual indicator and sounds an audible tone signaling that the conditions for a complete ablation cycle have been satisfied. The footswitch is used to initiate (depress footswitch) and terminate (release footswitch) the RF energy delivery. PMA P100046: FDA Summary of Safety and Effectiveness Data page 3 {3} ![img-2.jpeg](img-2.jpeg) Figure 3. Generator- AtriCure Model ASU2/ASB3 ## AtriCure Switch Box The ASU2 is used in conjunction with the AtriCure Switch Box (ASB3). The AtriCure Switch Box (ASB3) is an accessory interface module allowing various AtriCure ablative devices to connect to the RF generator (ASU2) (Figure 3). The ASB3 also provides the RF switching mechanism for the two electrode pairs in the AtriCure Synergy Ablation Clamps. The ASU2 and ASB3 are connected via a short cable. These units (ASU2/ASB3) are always outside of the sterile field and function to provide the RF energy (ASU2) and to direct the energy delivery to the Handpieces. The ASB3 utilizes a mechanical switching system to allow the user to select a pathway for a specific source to communicate to a specific output. The operator can select which device will be activated via a rotating selection knob on the front of the ASB3. The operator is able to mechanically select and switch between ablation handpieces connected to the ASU2 RF generator. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction persistent or longstanding persistent AF: use of anti-arrhythmic and/or rate control medications and cardioversion (electrical and/or pharmacologic). Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The AtriCure Synergy Ablation System was cleared on January 26, 2007 (under a different trade name) via premarket notification K063630 for the following indication: The AtriCure Ablation System is intended to ablate soft tissues during general surgery PMA P100046: FDA Summary of Safety and Effectiveness Data {4} using radiofrequency energy. The indications for use for the AtriCure Synergy Ablation System was modified under K101174 (under a different trade name) to the following: The AtriCure Bipolar System including Isolator Synergy Dual Electrode Clamps is intended for the ablation of cardiac tissue during surgery. The AtriCure Synergy Ablation System first received the CE Mark in December 2005 for ablation of soft tissue, and thereby began commercial distribution in the European Union. In March 2009, the CE Mark approval was updated for the treatment of cardiac arrhythmias including atrial fibrillation. The list of countries where the AtriCure Synergy Ablation System is approved for commercial distribution is provided below: United States, European Union, Canada, Japan, Lebanon, Colombia, Panama, Ecuador, Peru, China, Hong Kong, Argentina, Chile, Brazil, Thailand, Australia, Mexico, Turkey, Georgia, Azerbaijan, Russia, Norway, Taiwan, Costa Rica, Korea, Lithuania, and Malaysia. The AtriCure Synergy Ablation System has not been withdrawn from marketing in any country for any reason ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH The AtriCure Synergy Ablation system is indicated to treat persistent or longstanding persistent AF using radiofrequency ablation in patients undergoing a concomitant surgical procedure (coronary artery bypass grafting and/or valve replacement or repair). Below is a list of the potential adverse effects (e.g., complications) associated with the combined procedure - Death - Excessive bleeding related to the procedure which may require reintervention, - Cardiac tamponade (if either open or catheter drainage is required), - Pulmonary vein stenosis, - Restrictive (constrictive) pericarditis, - Infection which may include Sepsis or Endocarditis, - Myocardial infarction (MI) per ACC guidelines, - Stroke or Transient Ischemic Attack (TIA), - Thromboembolism, - Diaphragmatic paralysis, - Esophageal-LA fistula or esophageal rupture, - Atrial perforation or rupture, - Ventricular perforation or rupture, - Atelectasis, - Pneumonia, - Congestive Heart Failure, - Cardiac Valve Injury, - Persistent Pneumothorax (requiring intervention), - Excessive Pain and Discomfort, - Deep Sternal Wound Infection, - Ventricular Arrhythmia (V. Tachycardia or V. Fibrillation), PMA P100046: FDA Summary of Safety and Effectiveness Data page 5 10 {5} - Drug Reaction, - Perioperative heart rhythm/conduction disturbance (atrial and/or ventricular), - Pericardial effusion or tamponade, - Injury to the great vessels, - Injury to unintended surrounding tissue structures, including tears and punctures, - Extension of cardiopulmonary bypass. For the specific adverse events that occurred in the clinical studies, please see Section X below. ## IX. SUMMARY OF PRECLINICAL STUDIES *In vitro* and *in vivo* testing was performed on the AtriCure Synergy Ablation System in bench and animal models and a summary is presented in this section. ## A. Laboratory Studies The following *in vitro* bench studies were performed to support the AtriCure Synergy Ablation System. Results for this testing was also submitted and reviewed in the 510k submissions under which the AtriCure Synergy Ablation System was cleared. Table 1: Summary of Pre-Clinical Bench Testing | In Vitro Test | Overall Purpose and Description | Acceptance Criterion | Results & Conclusions | | --- | --- | --- | --- | | Drop Testing | To verify that the OLL2 and OSL2 devices do not present a safety hazard as a result of a free fall drop from a height of 1 meter onto a hard surface per EN60601-1:1990. | All Handpiece components shall maintain electrical and mechanical integrity and not dislodge from the instrument during the free fall. | Pass. The OLL2 and OSL2 devices met the safety requirement were not considered a safety hazard as a result of a free fall drop from a height of 1 meter onto a hard surface per EN 60601-1:1990 Section 21.5. | | Strain Relief | To demonstrate the OLL2 and OSL2 cable meets the Cable Strain Relief Requirements as described in ANSI/AAMI HF 18:2001. | The handpiece cable must be capable of withstanding the mechanical stress of 40 N for 10 seconds and an impulse of 0.64 joules. | Pass. The OLL2 and OSL2 cable meets the Cable Strain Relief Requirements as described in ANSI/AAMI HF 18:2001 section 4.2.5.5. | PMA P100046: FDA Summary of Safety and Effectiveness Data {6} PMA P100046: FDA Summary of Safety and Effectiveness Data page 7 12 | In Vitro Test | Overall Purpose and Description | Acceptance Criterion | Results & Conclusions | | --- | --- | --- | --- | | Reliability Testing | To verify the reliability of the OLL2 and OSL2 Handpiece design per the product life profile using rate reliability testing and Weibull Analysis. | The OLL2 and OSL2 must demonstrate 99% reliability with 95% confidence. Failure of the device was defined as loss of mechanical function, loss of ability to create a transmural lesion, loss of mechanical integrity, loss or intermittent electrical power through the instrument, loss of electrical contact to the electrodes, insulation breakdown, adhesive failure, or EEPROM failure. | Pass. The OLL2 and OSL2 demonstrated 99% reliability with 95% confidence. The OLL2 meets the reliability target and lesion performance criteria. | | Bench Ablations Comparison | To investigate the ablation performance of the OLL2 and OSL2 on different types of tissue on bench testing. | OLL2: All ablated lesions must be transmural as evidenced by tissue sectioning and visual inspection and lesions must be wider than predicate device. OSL2: All lesions are transmural as evidenced by gross examination and average lesion width is no more than 5 mm. | Pass. The OLL2 and OSL2 successfully created lesions on bench tissue. All lesions were 100% transmural. No adverse tissue effects were observed with the OLL2 and OSL2. | | Dielectric Withstand | To verify the OLL2 and OSL2 meet electrical safety requirements specified in the product specification and IEC 60601-2-2 and AAMI HF-18. | The devices must meet electrical safety requirements specified in the product specification and IEC 60601-2-2 and AAMI HF-18. | Pass. The OLL2 and OSL2 met electrical safety requirements specified in the product specification and IEC 60601-2-2 and AAMI HF-18. | | Surface Temperature | To verify the handpieces meet the External Surface Temperature Requirements per EN 60601-1 Section 42. | The temperature of the shaft must be less than or equal to 60° C. | The handpieces meet the External Surface Temperature Requirements per EN 60601-1 Section 42. Thirty (30) instruments demonstrated 90% reliability with 95% confidence. | {7} PMA P100046: FDA Summary of Safety and Effectiveness Data page 8 13 | In Vitro Test | Overall Purpose and Description | Acceptance Criterion | Results & Conclusions | | --- | --- | --- | --- | | Closing Force | To verify the OLL2 and OSL2 (post 2x EtO Sterilization) meets the Closing Force requirements has a maximum force of 10 lbf and maximum momentary force spike of 25 lbf through the device range of motion. | The Handpiece maximum force is less than or equal to 10.0 lbf throughout the range device’s of motion and the Handpiece maximum momentary force spike is less than or equal to 25.0 lbf. | Pass. The OLL2 and OSL2 (2x EtO Sterilization) meet the Closing Force requirements. | | Closure Latch | To verify the OLL2 and OSL2 meet the Closure Latch unlatching requirement after exposure to 2x EtO sterilization. | Force to unlatch must be between 2.0 and 4.0 lbf. | Pass. The OLL2 and OSL2 meet the Closure Latch unlatching after exposure to 2x EtO sterilization. | | Tip Splay/ Lateral Alignment | To verify the OLL2 and OSL2 meet the lateral alignment requirement after 2x EtO sterilization. | The proximal jaw lateral motion is less than or equal to 0.60 inches (to the right and left, i.e. 0.120 inches total) and displacement less than or equal to 0.010 inches (both measurements at the midpoint of the jaw) when a load of 1.0±0.1 lbf is applied laterally at the midpoint of the jaw. | Pass. The OLL2 and OSL2 meet the lateral alignment requirement set forth in the product specification after 2x EtO sterilization. | | Shaft Stiffness | To verify that the OLL2 and OSL2 meet shaft stiffness as evidenced by retaining the ability to open and close under loading. | The jaws open to 1.00±0.2 inches and will be able to be closed and latched while under top and side loads of 4.0±0.2 lbf. | Pass. The OLL2 and OSL2 met shaft stiffness specifications. | | Force Testing | To verify that the OLL2 and OSL2 meet jaw force specifications. | OLL2: The instrument return spring rate must be 19.81±3.5 and the 2 mm differential must be ≤3.0 and the return force at 2 mm (2mm return stroke compression) must be 6.59±1.17. OSL2: The instrument spring rate must be 14.59±3.5 lbf/in. The maximum differential at 2 mm load must be 3.9 lbf. The 2 mm return force must be 4.85±0.78. | Pass. The OLL2 device met jaw force specifications. | {8} PMA P100046: FDA Summary of Safety and Effectiveness Data page 9 14 ## B. Animal Studies The AtriCure Synergy Ablation System was tested in acute and chronic animal studies. The studies were performed to verify cardiac ablation safety and performance in a clinically relevant *in vivo* environment. In all studies, device efficacy was assessed by gross examination of tissue after staining with 2,3,5,-triphenyl-tetrazolium chloride (TTC). The ablation was considered successful if the ablation was transmural (full thickness). All charring lesions were also examined for any signs of adverse tissue effects such as tissue charring, tissue perforation, and lateral thermal spread. One chronic (30 day) study was conducted in accordance with Good Laboratory Practices (GLP) per 21 CFR Part 58. The ablation lesions in this study were assessed for effectiveness by pacing and by histologic evaluation. All lesions were 100% transmural. The remaining five studies were non-GLP studies performed for product development in accordance with test facility standard operating procedures. Of these five studies, one was chronic (28 + 2 days) and four were acute studies. In addition to effectiveness, all studies were evaluated for safety by examining the lesions grossly for adverse tissue effects such as charring or perforation and monitoring the health of the animals over the duration of the two chronic studies. In both acute and chronic studies, the animals demonstrated no adverse effects specifically associated with ablation energy delivery. Although not formally assessed in the acute studies, there were no instances of thrombosis observed in any animal studied. In the chronic study, animals survived to the terminal surgery with no complications attributed to the ablation protocol. A summary of all animal studies is provided below in Table 2. {9} Table 2: Summary of In Vivo Animal Testing and Results | Chronic or Acute, # of Animals | Purpose and Description | Key Assessment Criteria | Key Outcomes | | --- | --- | --- | --- | | Study Title: Evaluation of the AtriCure Synergy Ablation Technology in the Porcine DCR-2538 | | | | | GLP, Chronic (30 d -2 ± 7 d) n=9 pigs: 1 control 7 studied 1 reserve | To evaluate the safety and performance of the AtriCure Synergy Ablation System in a porcine model 30 days post procedure, in compliance with Good Laboratory Practices (21CFR, Part 58). Following median sternotomy, the surgeon ablated the left atrial appendage (LAA), right atrial appendage (RAA), and left pulmonary vein (LPV); the control pig had sham surgery. | • Endpoints used to evaluate the safety of the devices included: 1) baseline and post-surgical CT scans; 2) gross pathology of heart, brain, liver, lung, kidneys, bowel, and spleen; and 3) histopathology of the tissue of the ablation site to assure no signs of thromboembolic events attributed to the devices. • The device performance was evaluated by verification of conduction block across the right atrial appendage, left atrial appendage, and left pulmonary vein ablations via pacing, and the assessment of clinical observations. | • Conduction block was achieved in all ablation lesions performed at time of surgery, and the electrical block was maintained at study endpoint (30 d-2, + 7) • The OLL2 ablations did not result in pulmonary vein stenosis, regurgitation at mitral/tricuspid valves, no decrease in LV ejection fraction, or endocardial thrombus as verified by CT scans. • Histopathology of the ablation lesions showed 100% transmurality at 1-month follow-up. • No clinical observations or events were attributed to ablation energy delivery. | PMA P100046: FDA Summary of Safety and Effectiveness Data {10} PMA P100046: FDA Summary of Safety and Effectiveness Data page 11 | Chronic or Acute, # of Animals | Purpose and Description | Key Assessment Criteria | Key Outcomes | | --- | --- | --- | --- | | Study Title: Performance Evaluation of the Dual Electrode System for Cardiac Ablation in a Chronic Porcine Model DCR-1181 | | | | | Non-GLP Performance Study Chronic (28 ± 2 d) n=6 pigs | To verify the performance of the AtriCure Synergy Ablation Clamp (model OLL2) for ablation of cardiac tissue using a Maze III surgical procedure. Cardiopulmonary bypass (CPB) was not used due to concerns regarding survivability post-CPB. Instead, RF lesions were created either by placing a purse-string incision at the targeted area or clamping the cardiac structure. The study also compared the AtriCure OLL2 Clamp to data from previous generation Handpieces for the following variables: RF time, energy delivered, lesion width. | • At necropsy the hearts were treated with a special stain (TTC) to allow visual examination and assessment of ablation line lesions for lesion transmurality, width (lateral thermal spread), presence or absence of thrombus, charring, and pulmonary vein stenosis. • Selected microscopic slides were sent to a veterinary pathologist for histological assessment of the ablation lesions and to confirm the gross visual assessment of lesion transmurality. • Engineering analysis of energy delivery: total energy delivery, duration of application. | • The OLL2 device can isolate cardiac tissue in one application but requires more time and energy. • The OLL2 device can create ablations that are discreet and visible to the naked eye via use of a special stain (TTC) without damaging adjacent structures. • Evidence of tissue charring, thrombus, or pulmonary vein stenosis was not observed. • A total of 63 slides with 244 cross-sections were examined; 212/244 cross-sections showed clearly demarcated ablation lesions. The remaining sections (35) were not reviewed for a variety of reasons including poor tissue staining and/or inability to locate the ablation lesion. All defined ablation lesions (209/209 sections) were 100% transmural from the epicardium to the endocardium at 28 days survival. | {11} | Chronic or Acute, # of Animals | Purpose and Description | Key Assessment Criteria | Key Outcomes | | --- | --- | --- | --- | | Study Title: OLL2 Acute Animal Lab DCR-1273 | | | | | Non-GLP Verification Study -- Acute n=2 pigs | To verify that the AtriCure Synergy Ablation Clamp (OLL2) functions as required in live tissue following EtO sterilization. Two OLL2 devices were used: one at maximum tissue pressure and one set at minimum tissue pressure. Assessment included: device must be atraumatic to tissue (i.e. free of pinch surfaces, sharp edges, snags) to prevent unintended damage during tissue interface; must be able to operate device with one hand; the device must be able to access and create transmural lesions on the porcine LAA, RAA, IVC, SVC. A comparison of the OSL2 device to previous AtriCure Handpieces (OLL1) was also performed to verify performance. | • At necropsy the hearts were treated with a special stain (TTC) to allow visual examination and assessment of ablation lesions: visual examination of lesions for transmurality, width (lateral thermal spread), presence or absence of thrombus, or charring. • Pacing to confirm electrical isolation following creation of ablation lesions. • Intraoperative device use was observed to determine whether the device was atraumatic to tissues. • A baseline ablation lesion was first created with the OLL1 device for lesion comparison. | • Blood was observed pooling between the jaws in the heel of both the OLL1 and OLL2 devices which extended the time of ablation. • The OLL2 devices created 100% transmural lesions as evidenced by gross examination and measurement. Lesions did not exhibit thrombus or charring. • The OLL2 devices appeared to be atraumatic to tissue as visual observation of tissue revealed no evident tissue damage following tissue interface. • The surgeon was able to operate the device with one hand. • The OLL2 device appeared to function as well as the previous generation OLL1AtriCure Handpiece. | PMA P100046: FDA Summary of Safety and Effectiveness Data {12} | Chronic or Acute, # of Animals | Purpose and Description | Key Assessment Criteria | Key Outcomes | | --- | --- | --- | --- | | Study Title: OLL2 Animal Lab DCR-1346 | | | | | Non-GLP Verification Study -- Acute n=2 pigs | To verify the ablation performance of the AtriCure Synergy Ablation Clamp (OLL2) device on various anatomical locations (IVC, small bowel, thigh muscle, diaphragm) in an in vivo porcine model. The study also compared the AtriCure OLL2 clamp to a previous generation AtriCure Handpiece (EML1) to verify performance. | • Assessment criteria included: Comparison of lesion width created with the OLL2 clamp to lesions created with the EML1 clamp and average maximum tissue temperature outside the insulated OLL2 jaw measured at thermo-couple position T4. • Ablation line visual assessment: 1) examination of lesions for transmurality, width (lateral thermal spread), and presence or absence of thrombus, or tissue charring. • Energy delivered per unit volume of tissue ablated and time to transmurality was also evaluated. | • Ablation times and energy delivered per unit volume to the tissue were comparable between the OLL2 and the previous generation EML1 AtriCure Handpiece. • All ablation lesions were 100% transmural with the exception of two (one for each device) per visual inspection post-mortem. • Lesions created with OLL2 Handpiece were wider compared to lesions created with the EML1 Handpiece. • Visual gross examination of ablation lesions did not exhibit thrombus or charring. No tissue damage beyond that intended by the ablation process was visible. • Tissue was not submitted for microscopic evaluation. • The average maximum temperature outside of the jaw was less than 50°C on all tissue types. | PMA P100046: FDA Summary of Safety and Effectiveness Data page 13 {13} | Chronic or Acute, # of Animals | Purpose and Description | Key Assessment Criteria | Key Outcomes | | --- | --- | --- | --- | | Study Title: OSL2 Animal Lab DCR-1579 | | | | | Non-GLP Verification Study -- Acute n=1 pig | To verify the ablation performance of the OSL2 Handpiece on cardiac tissue in an in vivo porcine model. Assessment included: 1) device must be atraumatic to tissue (i.e. free of pinch surfaces, sharp edges, snags) to prevent unintended damage during tissue interface; 2) must be able to operate device with one hand; 3) the device must be able to access and create as many transmural lesions on the LAA and RAA as possible. Evaluation of the study also compared the OSL2 Handpiece to a previous generation Handpiece (LHP2) for the following variables: RF time, energy delivered, lesion width. | • Ablation line gross visual examination and assessment of lesions for: 1) transmurality, 2) width (lateral thermal spread), and 3) presence or absence of thrombus, or charring. • Evaluation of energy delivered per unit volume of tissue ablation and time to achieve transmurality • Intraoperative device use was observed to determine whether the device was atraumatic to tissues. | • The OSL2 device can create ablations that are discreet and visible to the naked eye without visual evidence of damage to adjacent structures. • Neither charring nor thrombus was observed with the OSL2 ablations. • Gross visual examination of the lesions indicated 100% transmurality of the ablation lesions. • Tissue was not submitted for microscopic evaluation. • The OSL2 devices appeared to be atruamatic to tissue interface as visual observation of tissue post-mortem revealed no evident tissue damage. | ## C. Biocompatibility The biocompatibility of the patient contacting materials of the AtriCure Synergy Ablation Clamp have been assessed and tested according to ISO 10993-1:2003, Biological evaluation of medical devices, and the applicable subparts of Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices May 1, 1995 (FDA Bluebook Memorandum G95-1) with 100% passing results. The device is typically used epicardially on the perfused heart or epi/endocardially in an evacuated heart (on cardiopulmonary bypass). As such, the AtriCure Synergy Ablation Clamps (OLL2, OSL2) are categorized as externally communicating devices that are intended for bone/tissue contact for limited contact duration (less than 24 hours). Required testing was determined from ISO 10993 and with the independent contract biocompatibility test labs that AtriCure works with for biocompatibility testing. All test methods, sample sizes, and sample preparation are determined and performed by the contract laboratories that operate according to GLPs, ISO 10993, and other applicable standards. A summary of biocompatibility testing performed is included in Table 3. PMA P100046: FDA Summary of Safety and Effectiveness Data {14} Table 3: Summary of Biocompatibility Testing and Results | Biological effect category | Test Methods | Results | | --- | --- | --- | | Sensitization | Maximization Sensitization Test ISO 10993-10 | Pass | | Systemic Toxicity | Systemic Injection USP/ISO | Pass | | Cytotoxicity | ISO 10993-5 Elution Test (MEM Extract) | Pass | | Intracutaneous Reactivity | (Intradermal) Reactivity Test ISO 10993-10 | Pass | | Hemocompatibility | Hemolysis ISO 10993-4 ASTM Method Complement Activation C3a and Sc5b-9 | Pass | | Material Mediated Pyrogenicity | ISO 10993-11:2006 | Pass | | Genotoxicity | AMES reverse bacterial mutation | Pass | ## D. Sterilization The OLL2 and OSL2 are packaged at AtriCure Inc. and are ethylene oxide sterilized by a contract sterilizer in compliance with ISO 11135, EN550, and AAMI TIR 16. The AtriCure Synergy Ablation Clamps (models OLL2, OSL2) are the only devices in the AtriCure Synergy Ablation System that are provided sterile. The ASU generator and ASB switch box are used outside of the sterile field at all times. All validations follow ISO 11135, EN550 and AAMI TIR 16 regulations to ensure $10^{-6}$ SAL and include: bioburden analysis, a minimum of 3 half-cycles (including consideration for a half-cycle using a refrigerated truck to simulate cold shipping conditions and a minimum load half-cycle study), and a full cycle study to examine EtO residuals. ## E. Packaging Design and Shelf Life The OLL2 and OSL2 are packaged in a thermoformed tray and sealed with a Tyvek® lid. Qualification testing was performed for packaging design performance, packaging shelf-life, and device shelf-life for the OLL2 and OSL2. A three year shelf-life has been established for the OLL2 and OSL2. ## X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of radiofrequency ablation with the AtriCure Synergy Ablation System for the treatment of persistent and longstanding persistent AF in the US under IDE # G070080. Data from this clinical study were the primary basis for the PMA approval decision. In addition to the data collected under the pivotal IDE study, the applicant provided additional post-hoc data to support approval of their device. These included data PMA P100046: FDA Summary of Safety and Effectiveness Data {15} from a previous terminated IDE study (G020237), data from two institutional databases, and data from an ongoing registry. These are described briefly in Section XI. A summary of the clinical study is presented below. ## A. Study Design Patients were treated between February 8, 2008 and June 12, 2009. The database for this PMA/PMA supplement reflected data collected through November 17, 2010 and included 55 patients. There were 9 investigational sites. The ABLATE (“AtriCure Synergy Bipolar RF Energy Lesions for Permanent Atrial Fibrillation Treatment during Concomitant, On-Pump, Endo/Epicardial Cardiac Surgery”) trial was a prospective, multi-center, one-arm, non-randomized clinical study. The study was designed to evaluate the safety and effectiveness of the AtriCure Synergy Ablation System in the treatment of permanent¹ AF in the concomitant surgical setting. This pivotal study was based on a Bayesian adaptive design. The performance goal endpoints for the study were based on historical data reported in the clinical literature and the applicant’s data from a previous abandoned IDE study (G020237), the RESTORE trial discussed below. Therefore, control subjects were not used in this study. Candidates for treatment with the study device included subjects of both genders undergoing certain concomitant open-heart surgeries, such as coronary artery bypass grafting and/or valve repair or replacement. All subjects were followed through discharge, at 30 days, 3 months, 6 months, 12 months, 18 months, 2 years and annually for five years thereafter. ### Statistical Aspects of the ABLATE Study Statistical evaluation of primary outcomes was performed using Bayesian methodology for all analyses (interim, for sample size determination, and final). These are described briefly below. #### Primary Safety Analysis The primary safety endpoint was the rate of major adverse events (MAEs), which included death, stroke, myocardial infarction (MI), transient ischemic attack (TIA) or bleed, occurring within the initial 30 days post procedure or discharge (whichever was later). The statistical hypothesis for safety is $$ q_{T} &lt; 0.1895, $$ ¹ The ABLATE study protocol specified the target population to be those with “permanent” AF per the 2006 ACC/AHA/ESC Guidelines (Fuster, 2006). However, the definition of the AF classification “permanent” has changed with the publication of the 2007 HRS consensus statement (Calkins, 2007). Therefore, the current indication has translated this target population to those with “persistent” or “longstanding persistent” AF per the 2007 HRS consensus statement definitions. PMA P100046: FDA Summary of Safety and Effectiveness Data page 16 21 {16} where the treatment adverse event rate is labeled $q_{\mathrm{T}}$. The primary safety endpoint would be considered met if the posterior probability that $q_{\mathrm{T}}$ is less than 0.1895 exceeds 0.95, i.e. $$ \Pr(q_{\mathrm{T}} &lt; 0.1895 \mid \text{Trial Results}) \geq 0.95. $$ The prior distribution for the primary safety endpoint is Beta (1,1). The choice for the performance goal 0.1895 is discussed below. ## Primary Effectiveness Analysis The primary effectiveness endpoint is the rate of subjects that achieved successful obliteration of atrial fibrillation while off of any antiarrhythmic medication (Class I or III) evaluated at six months post procedure. The statistical hypothesis is $$ p_{\mathrm{T}} \geq 0.60, $$ where $p_{\mathrm{T}}$ is the probability of being a success for effectiveness. The primary effectiveness endpoint would be considered met if the posterior probability that $p_{\mathrm{T}}$ is greater than 0.60 exceeds 0.975, i.e., $$ \Pr(p_{\mathrm{T}} &gt; 0.60 \mid \text{Trial Results}) \geq 0.975. $$ A uniform prior distribution is assigned for the unknown probability of success, $p_{\mathrm{T}} \sim$ Beta(1,1). The choice for the performance goal 0.60 is discussed below in Section ## Interim Monitoring and Adaptive Design The Applicant used a Bayesian adaptive approach to sample size selection. The minimum total sample size was 50 patients and the maximum was 100. The first interim look was to be made when 50 patients had been enrolled in the study and 20 patients had reached their 6-month endpoint, whichever occurred later. This was to be repeated after every five patients were enrolled until the threshold for enrollment cessation was achieved, for a maximum of 10 interim analyses. At each interim analysis the Applicant was to calculate the predictive probability of meeting the primary safety and the primary effectiveness endpoint at the end of the trial. The predictive probability of meeting the effectiveness endpoint and the safety endpoint is calculated two ways: first assuming accrual stops and all currently enrolled patients are followed to six months, second assuming enrollment continues to the maximum sample size, 100 patients, and all are followed to six months. Because the final outcomes of some enrolled subjects were not yet known at the time of the interim look, they were predicted, using information from the subjects with known outcomes, in combination with a beta-binomial distribution for modeling the transition from either baseline or 3-month outcomes to the 6-month outcomes. The predictive probability was used to decide whether (1) to stop accruing patients, wait 6-months, and then do the final analysis, (2) to stop the trial for futility, or (3) to PMA P100046: FDA Summary of Safety and Effectiveness Data page 17 22 {17} continue enrolling subjects into the trial. The predictive probability thresholds for stopping enrollment began at 90%, and then decreased gradually to 80% as the maximum sample size was reached. The futility thresholds began at 5% and increased to 10%. Note that predictive probability is only used to decide whether to stop enrollment or stop for futility. It is not used for making a decision about the final analysis. The final analysis will use 6-month data from all enrolled patients, with no predicted patients. ## Study Oversight The ABLATE trial utilized an independent core laboratory to read all of the Holter, permanent pacemaker (PPM), and ECG results. In addition, an independent cardiac surgeon not involved with the clinical study reviewed all adverse events through one year. A Data and Safety Monitoring Board (DSMB) was established for the trial and reviewed data periodically to ensure safety of subjects. The DSMB is still being utilized for the active clinical registry study that is ongoing (ABLATE AF) to maintain their role of ensuring safety of subjects. ## 1. Clinical Inclusion and Exclusion Criteria Enrollment in the ABLATE study was limited to patients who met the following inclusion criteria: - Subject is greater than or equal to 18 years of age. - Subject has history of permanent atrial fibrillation (AF in which cardioversion (electrical and/or pharmacologic) has failed or has not been attempted) as defined by the 2006 ACC/AHA/ESC Guidelines. - Subject is scheduled to undergo elective cardiac surgical procedure(s) to be performed on cardiopulmonary bypass including open-heart surgery for one or more of the following: Mitral valve repair or replacement. Aortic valve repair or replacement. Tricuspid valve repair or replacement, and Coronary artery bypass procedures. - Left Ventricular Ejection Fraction &gt; 30% (determined by echocardiography performed within 60 days of enrollment as documented in patient medical history, or intra-operatively at the time of treatment). - Subject is willing and able to provide written informed consent. - Subject has a life expectancy of at least 1 year. - Subject is willing and able to return for scheduled follow-up visits. Patients were not permitted to enroll if they met any of the following exclusion criteria: - Stand alone AF without indication(s) for concomitant coronary artery bypass grafting (CABG) and/or valve surgery. - Previous atrial ablation, AV-nodal ablation, or surgical Maze procedure. - Wolff-Parkinson-White syndrome. - Prior cardiac surgery (Redo). PMA P100046: FDA Summary of Safety and Effectiveness Data {18} - Patients requiring surgery other than CABG and/or cardiac valve surgery and/or patent foramen ovale repair, and/or atrial septal defect repair. - Class IV NYHA heart failure symptoms. - Prior history of cerebrovascular accident within 6 months or at any time if there is residual neurological deficit. - Documented MI within the 6 weeks prior to study enrollment. - Need for emergent cardiac surgery (i.e. cardiogenic shock). - Known carotid artery stenosis greater than 80%. - LA size greater than or equal to 8 cm. - Current diagnosis of active systemic infection. - Severe peripheral arterial occlusive disease defined as claudication with minimal exertion. - Renal failure requiring dialysis or hepatic failure. - A known drug and/or alcohol addiction. - Mental impairment or other conditions which may not allow the subject to understand the nature, significance and scope of the study. - Pregnancy or desire to get pregnant within 12-months of the study treatment. - Preoperative need for an intra-aortic balloon pump or intravenous inotropes. - Requires anti-arrhythmic drug therapy for the treatment of a ventricular arrhythmia. - Patients who have been treated with thoracic radiation. - Patients in current chemotherapy. - Patients on long term treatment with oral or injected steroids (not including intermittent use of inhaled steroids for respiratory diseases). - Patients with known connective tissue disorders. 2. Study Treatment Along with their concomitant surgery, investigators were required to perform the Maze IV procedure using the investigational system. This procedure includes both right and left pulmonary vein isolation as well as a series of ablation lines to create “the box lesion” on the posterior left atrial free wall. Lesions to the mitral annulus and the left atrial appendage are also performed. On the right side of the heart lesions include a right atrial anterior free wall appendage lesion as well as a lesion from the appendage to the tricuspid annulus. Confirmation of pulmonary vein exit block was done to demonstrate effective isolation. The following table indicates which lesions required the use of the investigational device per the protocol. PMA P100046: FDA Summary of Safety and Effectiveness Data page 19 24 {19} Table 4: Protocol Required Device Use for Lesion Set Creation | Lesion | Device Recommended | | --- | --- | | Left-sided lesions | | | Right and Left Pulmonary Vein | Synergy Ablation Clamp only | | Roof Line | Synergy Ablation Clamp only | | Floor Line | Synergy Ablation Clamp only | | Mitral Valve Connecting | Initiated with Synergy Ablation Clamp, completed with AtriCure Transpolar Pen or cryo-surgical device | | Left Atrial Appendage to Pulmonary Vein | Synergy Ablation Clamp only | | Right-sided Lesions | | | Right Tricuspid Valve | Synergy Ablation Clamp, AtriCure Transpolar Pen, or a cryo-surgical device | | Superior Vena Cava (SVC) to Inferior Vena Cava (IVC) | Synergy Ablation Clamp only | | Free Wall Appendage | Synergy Ablation Clamp only | | Right Atrial Appendage to Tricuspid Annulus | Synergy Ablation Clamp, AtriCure Transpolar Pen or cryo-surgical device | | Septal Lesion (optional) | Any technique | After surgery, subjects were placed on either a Class I or Class III anti-arrhythmic drug (AAD) immediately. They received anti-coagulation according to the clinician's preference and clinical indications. 3. Follow-up Schedule Subjects were followed through discharge, at 30 days, 3 months, 6 months, 12 months, 18 months, 2 years and annually for five years thereafter. Follow-up at discharge was to be completed no more than 48 hours prior to hospital discharge. Other visits at or before 6 months had post-visit windows of 7 days (30 days and 2 months) or 14 days (3 months and 6 months) for completion of follow-up. The clinical assessments included a targeted history and physical exam as well as an assessment of medications and ECG. At two months an optional clinical assessment was encouraged as a means of evaluating the subject's AF status while on antiarrhythmic agents. All subjects were required to have a clinic visit at three and six months. At the 3-month visit, the subjects were to discontinue their antiarrhythmic medications in an effort to allow evaluation of treatment efficacy while off drugs at PMA P100046: FDA Summary of Safety and Effectiveness Data page 20 {20} 6 months (the primary efficacy time point). In an effort to wash out a drug at least five half-lives before the 6-month assessment, amiodarone was stopped 12 weeks earlier and other drugs four weeks earlier. Cardioversions were permitted up to the 6-month assessment and recommended by the protocol at any visit at which a subject was in AF or atrial flutter, if tolerated. At each clinic visit, subjects were evaluated for safety. Upon completion of the primary efficacy endpoint evaluation at 6 months post procedure, subjects are entered into a long-term surveillance phase. The study originally outlined a surveillance plan that consisted of a phone call assessment with the subjects at twelve months and then annually thereafter for a total of five years, with an allowed window of 28 days around each target visit date. A supplemental rhythm status at 12 months or greater was added to provide more insights on the durability of the procedure ABLATE study subjects. The key time points are shown below in the table summarizing the schedule of events. Table 5. Overall Schedule of Events | Assessment | Baseline | Procedure | Pre-Discharge | 30 days | 2 mo² | 3 mo | Interim Visit³ | 6 mo | 12 & 18 mo | Years 2 - 5 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Informed Consent | X | | | | | | | | | | | Medical History | X | | | | | | | | | | | Adverse Event Evaluation | | | X | X | X | X | X | X | | | | Physical Exam | X | | X | X | X | X | X | X | | | | NYHA Class | X | | | X | X | X | X | X | | | | Medications | X | | X | X | X | X | X | X | | | | AAD Adjustment | | | X | X | X | X | X | X | | | | 12 lead ECG | X | | X | X | X | X | X | X⁴ | | | | Holter Monitor 24hr/48 hr | | | | | | | | X | X^{xvii} | | | RBC, WBC, HGB, HCT, Platelets | X | | X | | | | | | | | | INR⁵ | X | | X | X | | X | X | X | | | | Pregnancy Test⁶ | X | | | | | | | | | | | Echocardiogram (transthoracic) | X⁷ | | | | | | | X⁸ | | | PMA P100046: FDA Summary of Safety and Effectiveness Data page 21 {21} | Echocardiogram (transesophageal) | | X^{9} | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | AtriCure lesion set | | X | | | | | | | | | | Pacing Study^{10} | | X | | | | | | | | | | Concomitant Surgical Procedure | | X | | | | | | | | | | Cardioversion^{11} | | | X | X | X | X | X | | | | | Telephone FU | | | | | | | | | X | X | ## 4. Clinical Endpoints ### Primary Safety Endpoint With regards to safety, the primary safety endpoint was the rate of Major Adverse Events (MAEs) occurring within the initial 30 days post procedure or discharge (whichever was later). The MAEs consisted of: death, excessive bleeding (defined as &gt; 2 units of RBCs with reoperation), stroke, TIA or MI. The Applicant derived a historical safety rate of 13.95% from the reported experience with the “cut and sew” Cox Maze III procedure. A performance goal of 18.95% was used for hypothesis testing. The primary safety endpoint would be considered met if the Bayesian posterior probability that the rate of MAE is less than 18.95% exceeded 0.95. ### Secondary Safety Endpoints The following secondary safety endpoints were evaluated: - Composite six month post procedure major adverse event rate - Overall adverse event rate at six months ### Primary Effectiveness Endpoint With regard to effectiveness, the primary effectiveness endpoint was defined as the rate of subjects that are free of AF while off of any antiarrhythmic medication (Class I or III) evaluated at six months post procedure via 24-hour Holter monitor assessment (or permanent pacemaker interrogation in the case of those subjects that have a pacemaker implanted). The Applicant identified a reference rate of 70% based on surgical ablation procedures performed using RF ablation technology in the setting of concomitant surgery as found in historical literature, as well as its own RESTORE IDE study. A performance goal of 60% was used for hypothesis testing. The primary effectiveness endpoint would be considered met if the Bayesian posterior probability that the six-month success rate is greater than 60% exceeded 0.975. Freedom from AF was defined as episodes &lt; 5 minutes duration and no more than 1 hour total AF duration in 24 hours. PMA P100046: FDA Summary of Safety and Effectiveness Data page 22 {22} # Secondary Effectiveness Endpoints The following secondary effectiveness endpoints were prospectively defined: - The proportion of patients who are free of atrial fibrillation (episodes &lt; 5 min. duration and no more than 1 hr total AF duration in 24 hrs monitoring) independent of the need for anti-arrhythmic drugs (Class I and Class III) as determined by a 24-hour Holter recording at 6 months - Effectiveness of pulmonary vein isolation to produce acute electrical conduction block - Reduction of overall AF burden as measured on 24 hour Holter at 6 months In addition, the following secondary endpoints were added to the investigational plan after enrollment was completed based on discussions with FDA: - The proportion of patients in who are free of atrial fibrillation (episodes &lt; 5 min. duration and no more than 1 hr total AF duration in a 24 hr timeframe) independent of the need for anti-arrhythmic drugs (Class I and Class III) as assessed by a 48-hour Holter recording performed at a minimum of 12 months post procedure. - The proportion of patients in the treatment group who are free of atrial fibrillation (episodes &lt; 5 min. duration and no more than 1 hr total AF duration in a 24 hr timeframe) and off Class I and III antiarrhythmic drugs as assessed by a 48-hour Holter recording performed at a minimum of 12 months post procedure. - Overall atrial fibrillation burden measured on a 48 hour Holter recording at 12 months or after. ## B. Accountability of PMA Cohort ### 1. Interim Analysis The Applicant conducted the first interim look when 55 patients had been enrolled and all had provided the 30-day safety outcome. The pre-specified safety performance goal was met; therefore, the predictive probability of meeting the safety endpoint with the current sample size was 100%. There were 50 patients for the effectiveness interim analysis, and there were 24 effectiveness successes out of 29 patients providing 6-month data. After calculation, the predictive probability of meeting the effectiveness endpoint with the current sample size was 98.8%, which exceeded the stopping boundary. Thus the trial accrual was stopped per the pre-specified stopping rules. ### 2. Patient Disposition At the time of database lock, of 55 patients enrolled and treated in the PMA study, 50 patients are available for analysis at the 6-month post-operative visit. The following chart presents patient accountability. PMA P100046: FDA Summary of Safety and Effectiveness Data page 23 28 {23} ![img-3.jpeg](img-3.jpeg) Figure 4: ABLATE Subject Accountability ## C. Study Population Demographics and Baseline Parameters The study inclusion criteria specified the target population as subjects with "permanent" AF per the 2006 ACC/AHA/ESC guidelines as shown below. As the definition for "permanent AF" has changed with the publication of the 2007 HRS Consensus Statement, subjects were reclassified during FDA review of the PMA by PMA P100046: FDA Summary of Safety and Effectiveness Data page 24 29 {24} two expert independent reviewers according to current AF classification definitions, which are given here. Table 6: AF Classification per 2006 ACC/AHA/ESC Guidelines and 2007 HRS Statement | AF Classification | 2006 ACC/AHA/ESC Guidelines | 2007 HRS Statement | | --- | --- | --- | | Paroxysmal | AF is self-terminating within 7 days of recognized onset | Recurrent AF (>2 episodes) that terminates spontaneously within 7 days | | Persistent | AF is not self-terminating within 7 days, or is terminated electrically or pharmacologically | AF which is sustained beyond 7 days, or lasting less than 7 days but necessitating pharmacologic or electrical cardioversion | | Longstanding Persistent | | Continuous AF of greater than one-year duration | | Permanent | AF in which cardioversion (electrical and/or pharmacologic) has failed or has not been attempted | Patients where a decision has been made not to pursue restoration of sinus rhythm by any means | Upon reclassification, the subjects were categorized as having paroxysmal AF, persistent AF or longstanding persistent AF with the following distribution. Table 7: Number of Subjects in ABLATE by AF Classification | AF Classification | Number of Subjects Enrolled | | --- | --- | | Paroxysmal | 4 | | Persistent | 22 | | Longstanding persistent | 29 | During review of the PMA data, FDA and the applicant agreed that the target population for the PMA should only be patients with persistent or longstanding persistent AF. For completeness, results are presented for all treated subjects as well as for non-paroxysmal (persistent and longstanding persistent) AF subjects only. The demographics of the study population are typical for patients undergoing the mix of concomitant surgeries that were performed. Table 9 provide a summary of the significant baseline comorbidities. Table 8: Subject Demographics | Parameter | Treated Subjects N=55 | Non-Paroxysmal Subjects N=51 | | --- | --- | --- | | Age [years] | | | | Mean +/- SD (N) | 70.5 +/- 9.3 (55) | 70.8 +/- 9.6 (51) | | Median | 72.0 | 73.0 | PMA P100046: FDA Summary of Safety and Effectiveness Data page 25 30 {25} | Parameter | Treated Subjects N=55 | Non-Paroxysmal Subjects N=51 | | --- | --- | --- | | Min, Max | 45.0, 88.0 | 45.0, 88.0 | | Gender [% (n/N)] | | | | Male | 58.2% (32/55) | 60.8% (31/51) | | Female | 41.8% (23/55) | 39.2% (20/51) | | Ethnic Group [% (n/N)] | | | | Caucasian | 90.9% (50/55) | 90.2% (46/51) | | Black | 3.6% (2/55) | 3.9% (2/51) | | Asian | 1.8% (1/55) | 2.0% (1/51) | | Hispanic | 3.6% (2/55) | 3.9% (2/51) | | Height [in] | | | | Mean +/- SD (N) | 68.0 +/- 5.0 (55) | 68.0 +/- 5.1 (51) | | Median | 68.0 | 68.0 | | Min, Max | 54.9, 79.0 | 54.9, 79.0 | | Weight [lbs] | | | | Mean +/- SD (N) | 199.6 +/- 56.2 (55) | 200.0 +/- 55.2 (51) | | Median | 185.0 | 185.0 | | Min, Max | 113.0, 349.8 | 113.0, 349.8 | | BMI | | | | Mean +/- SD (N) | 30.1 +/- 6.9 (55) | 30.1 +/- 6.6 (51) | | Median | 28.5 | 28.6 | | Min, Max | 20.4, 47.4 | 20.4, 47.4 | Table 9: Significant Baseline Comorbidities | | Treated Subjects N=55 | Non-Paroxysmal Subjects N=51 | | --- | --- | --- | | Parameter | % (n/N) | % (n/N) | | Cardiomyopathy | 9.1% (5/55) | 7.8% (4/51) | | Congestive Heart Failure | 34.5% (19/55) | 37.3% (19/51) | | Coronary Artery Disease | 54.5% (30/55) | 56.9% (29/51) | | Chronic Obstructive Pulmonary Disease (COPD) | 14.5% (8/55) | 15.7% (8/51) | | Diabetes | 20.0% (11/55) | 21.6% (11/51) | | Hyperlipidemia | 65.5% (36/55) | 68.6% (35/51) | | Hypertension | 70.9% (39/55) | 76.5% (39/51) | | Myocardial Infarction | 7.3% (4/55) | 7.8% (4/51) | | Obesity | 23.6% (13/55) | 23.5% (12/51) | PMA P100046: FDA Summary of Safety and Effectiveness Data {26} | | Treated Subjects N=55 | Non-Paroxysmal Subjects N=51 | | --- | --- | --- | | Parameter | % (n/N) | % (n/N) | | Smoking | 5.5% (3/55) | 3.9% (2/51) | | Cerebral Vascular Accident (CVA)/Stroke | 5.5% (3/55) | 3.9% (2/51) | | Transient Ischemic Attack (TIA) | 7.3% (4/55) | 7.8% (4/51) | | Valvular Heart Disease | 85.5% (47/55) | 84.3% (43/51) | | EF (%) | | | | Mean +/-SD (n) | 50.0 +/- 10.3 (54) | 49.6 +/- 10.6 (50) | | Median (Min, Max) | 50.0 (20.0, 70.0) | 50.0 (20.0, 70.0) | | LA Size (cm) | | | | Mean +/-SD (n) | 5.9 +/- 1.0 (50) | 6.0 +/- 1.0 (46) | | Median (Min, Max) | 6.0 (3.9, 7.7) | 6.0 (3.9, 7.7) | | NYHA Classification [% (n/N)] | | | | I | 16.4% (9/55) | 17.6% (9/51) | | II | 41.8% (23/55) | 41.2% (21/51) | | III | 40.0% (22/55) | 39.2% (20/51) | | IV | 1.8% (1/55) | 2.0% (1/51) | | Missing | 0% (0/55) | 0% (0/51) | Concomitant procedures were performed on all 55 subjects who were treated with the device. As detailed in the table below, valve surgery was performed in the majority of subjects, either alone (56.4%) or in combination with coronary artery bypass grafting (25.5%). Isolated coronary bypass made up an appreciable minority of procedures (18.2%). Mitral surgery in any form was undertaken in 54.5% of subjects. PMA P100046: FDA Summary of Safety and Effectiveness Data page 27 32 {27} Table 10: Concomitant Procedures Performed | Concomitant Procedure Performed | Treated Subjects (N=55) Percentage | Non-Paroxysmal Subjects (N=51) Percentage | | --- | --- | --- | | CABG only | 18.2% | 19.6% | | Valve Surgery | 40.0% | 37.2% | | Mitral | 18.2% | 17.6% | | Aortic | 21.8% | 19.6% | | Double Valve Surgery | 16.4% | 17.6% | | Aortic & Mitral | 7.3% | 7.8% | | Mitral & Tricuspid | 9.1% | 9.8% | | CABG and Valve Surgery | 16.4% | 15.7% | | CABG + Mitral | 10.9% | 9.8% | | CABG + Aortic | 5.5% | 5.9% | | CABG + Double Valve Surgery | 9.1% | 9.8% | | Aortic & Mitral | 5.5% | 5.9% | | Mitral & Tricuspid | 3.6% | 3.9% | ## D. Safety and Effectiveness Results ### 1. Control of Type I Error Rate The type I error rate may be inflated in a statistical design that incorporates interim monitoring. For the ABLATE study, the Applicant calculated the type I error rate jointly for the primary safety endpoint and the primary effectiveness endpoint. However, FDA currently believes that the type I error rate should be controlled independently at a desired level for the primary safety endpoint (5% for this study) and for the effectiveness endpoint (2.5% for this study). Therefore FDA conducted its own simulations to calculate the type I error rate for each primary endpoint (safety and effectiveness) independent of the other primary endpoint. The results showed that the type I error rate for the primary safety endpoint was inflated from 5% to 6.1% and the type I error for the primary effectiveness endpoint was inflated from 2.5% to 2.6%. Given the current design scheme, if the type I error rate for the primary endpoints were controlled at 5% and 2.5% for safety and effectiveness, respectively, the corresponding posterior probability criteria for the primary endpoints at the final analysis would be increased. However, this result would not change the study conclusions. ### 2. Safety Results The analysis of safety was based on the cohort of 55 patients treated with the AtriCure Synergy Ablation System available for the 30-day evaluation. The key safety outcomes for this study are presented below in Tables 10 to 12. Adverse effects are reported in Tables 14 to 16. The primary safety endpoint was evaluated for all 55 subjects enrolled and treated. There were five safety failures: two deaths, two excessive bleeds and one stroke. Only one of the 5 MAEs, a death, was attributed to the Maze procedure by PMA P100046: FDA Summary of Safety and Effectiveness Data page 28 33 {28} the independent physician adjudicator. None of the MAEs was found to be device related. The safety results are detailed in the table below, along with the one-sided 95% Bayesian credible intervals (BCI) for the composite. Table 11: Primary Safety Endpoint Results for Treated and Non-Paroxysmal Subjects | Primary Safety Endpoint | Treated | Non-Paroxysmal | | --- | --- | --- | | | % (n/N) | % (n/N) | | Composite MAE within 30 days | 9.1% (5/55) BCI (0.00, 0.179) | 9.8% (5/51) BCI (0.00, 0.192) | | Death | 3.6% (2/55) | 3.9% (2/51) | | <=30 days | 3.6% (2/55) | 3.9% (2/51) | | >30 days, procedure related | 0.0% (0/55) | 0.0% (0/51) | | Stroke/TIA | 1.8% (1/55) | 2.0% (1/51) | | Stroke (with significant permanent disability) | 1.8% (1/55) | 2.0% (1/51) | | TIA | 0.0% (0/55) | 0.0% (0/51) | | MI | 0.0% (0/55) | 0.0% (0/51) | | Excessive Bleeding (>2 units blood and surgical intervention) | 3.6% (2/55) | 3.9% (2/51) | | Posterior probability that the safety rate is less than 0.1895 Pr($q_T < 0.1895 | \text{Trial Results}$) | 0.967 | 0.946 | Based on the results presented in the table above, the primary safety endpoint is met for the Treated population, but not for the Non-Paroxysmal subgroup. The secondary safety endpoints of composite 6-month major adverse event rate and overall 6-month adverse event rate are given in the following table for the Treated and Non-Paroxysmal populations. PMA P100046: FDA Summary of Safety and Effectiveness Data page 29 34 {29} Table 12: Secondary Safety Endpoints for Treated and Non-Paroxysmal Subjects | Secondary Safety Endpoints | Treated | Non-Paroxysmal | | --- | --- | --- | | | % (n/N) | % (n/N) | | MAE through 6 months | 10.9% (6/55) | 11.8% (6/51) | | Death | 7.3% (4/55) | 7.8% (4/51) | | Stroke (with significant permanent disability) | 1.8% (1/55) | 2.0% (1/51) | | TIA | 0.0% (0/55) | 0.0% (0/51) | | MI | 0.0% (0/55) | 0.0% (0/51) | | Excessive Bleeding (>2 units blood and surgical intervention) | 3.6% (2/55) | 3.9% (2/51) | | Any Adverse Event through 6 months | 90.9% (50/55) | 94.1% (48/51) | | Any Serious Event | 74.5% (41/55) | 76.5% (39/51) | | Any Device Related Event | 0.0% (0/55) | 0.0% (0/51) | | Any AF-Procedure Related Event | 14.5% (8/55) | 15.6% (8/51) | | Any Serious Device Related Event | 0.0% (0/55) | 0.0% (0/51) | | Any Serious AF-Procedure Related Event | 12.7% (7/55) | 13.7% (7/51) | Permanent Pacemaker Implantation Ablation may have an effect on the cardiac conduction system. Damage to the sinoatrial and/or atrioventricular nodes may result in pacemaker implantation after treatment. Seven of the 55 subjects who presented for treatment already had pacemakers implanted. In the remaining 48 subjects, 12 pacemakers were implanted within 30-days after ablation (25%): 4 for A-V nodal dysfunction, and 8 for sinus node dysfunction. Four more pacemakers were implanted later, bringing the cumulative total to 33%. All of the later implants were for sinus node dysfunction, and all occurred between 30-days and 6-months. This is detailed in the table below. Table 13: Rates of Pacemaker Implantation | | In Hospital | Cumulative to 30 days | Cumulative to 6 months | Cumulative to 12 months | | --- | --- | --- | --- | --- | | | % [n/N] | % [n/N] | % [n/N] | % [n/N] | | Permanent Pacemaker Implantation | 25.0% (12/48) | 25.0% (12/48) | 33.3% (16/48) | 33.3% (16/48) | | AV node dysfunction | 8.3% (4/48) | 8.3% (4/48) | 8.3% (4/48) | 8.3% (4/48) | | Sinus node dysfunction | 16.7% (8/48) | 16.7% (8/48) | 25.0% (12/48) | 25.0% (12/48) | Adverse effects that occurred in the PMA clinical study: A summary of the adjudicated clinical events based on attribution is provided in Table 14. PMA P100046: FDA Summary of Safety and Effectiveness Data page 30 {30} Table 14: Summary of Adverse Events Through 6 Months | | ABLATE Cumulative to 30 Days N=55 | | ABLATE Cumulative to 6 Months N=55 | | ABLATE Non-paroxysmal Cumulative to 30 Days N=51 | | ABLATE Non-paroxysmal Cumulative to 6 Months N=51 | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Parameter [1][2] | # of Evts | % (n/N) of Pts with Event | # of Evts | % (n/N) of Pts with Event | # of Evts | % (n/N) of Pts with Event | # of Evts | % (n/N) of Pts with Event | | Any Adverse Event | 166 | 89.1% (49/55) | 198 | 90.9% (50/55) | 160 | 92.2% (47/51) | 188 | 94.1% (48/51) | | Investigational Device | 0 | 0.0% (0/55) | 0 | 0.0% (0/55) | 0 | 0.0% (0/51) | 0 | 0.0% (0/51) | | AF Procedure | 8 | 14.5% (8/55) | 8 | 14.5% (8/55) | 8 | 15.7% (8/51) | 8 | 15.7% (8/51) | | Ancillary Device | 1 | 1.8% (1/55) | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | 1 | 2.0% (1/51) | | General Surgical Procedure | 140 | 87.3% (48/55) | 144 | 87.3% (48/55) | 134 | 90.2% (46/51) | 138 | 90.2% (46/51) | | Other Relationship | 17 | 20.0% (11/55) | 45 | 41.8% (23/55) | 17 | 21.6% (11/51) | 41 | 43.1% (22/51) | | Serious Adverse Event | 84 | 63.6% (35/55) | 106 | 74.5% (41/55) | 80 | 64.7% (33/51) | 99 | 76.5% (39/51) | | Investigational Device | 0 | 0.0% (0/55) | 0 | 0.0% (0/55) | 0 | 0.0% (0/51) | 0 | 0.0% (0/51) | | AF Procedure | 7 | 12.7% (7/55) | 7 | 12.7% (7/55) | 7 | 13.7% (7/51) | 7 | 13.7% (7/51) | | Ancillary Device | 1 | 1.8% (1/55) | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | 1 | 2.0% (1/51) | | General Surgical Procedure | 67 | 60.0% (33/55) | 70 | 61.8% (34/55) | 63 | 60.8% (31/51) | 66 | 62.7% (32/51) | | Other Relationship | 9 | 14.5% (8/55) | 28 | 32.7% (18/55) | 9 | 15.7% (8/51) | 25 | 33.3% (17/51) | | [1] As Adjudicated or site reported if not yet adjudicated. [2] Relationship presented hierarchally as listed in table. | | | | | | | | | ## Device- and Ablation-Procedure Related Adverse Events The following table presents rates for adverse events related to the device and AF ablation procedure. All of these events occurred prior to discharge for the index procedure. There were no adverse events adjudicated as related to the device. Of the 8 adverse events related to the AF procedure, 7 were serious. In addition to those listed in the table, one serious adverse event (ischemia requiring coronary bypass) was attributed to the ancillary AtriCure pen used to complete the lesion to the tricuspid annulus. PMA P100046: FDA Summary of Safety and Effectiveness Data page 31 36 {31} Table 15: Rates of Adjudicated Device- and AF Procedure-Related Adverse Events | Parameter | # of Events | % (n/N) of Pts with Event | # of Evts | % (n/N) of Pts with Event | | --- | --- | --- | --- | --- | | Device Related Adverse Event | 0 | 0.0% (0/55) | 0 | 0.0% (0/51) | | AF Procedure Related Adverse Event | 8 | 14.5% (8/55) | 8 | 15.7% (8/51) | | Cardiac disorders | 6 | 10.9% (6/55) | 6 | 11.8% (6/51) | | Atrial rupture | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | | Atrioventricular block | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | | Atrioventricular block first degree | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | | Atrioventricular block second degree | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | | Bradycardia | 2 | 3.6% (2/55) | 2 | 3.9% (2/51) | | Injury, poisoning and procedural complications | 2 | 3.6% (2/55) | 2 | 3.9% (2/51) | | Vena cava injury | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | | Venous injury | 1 | 1.8% (1/55) | 1 | 2.0% (1/51) | A summary of the adjudicated clinical events specifically associated with the AF ablation procedure is provided in Table 16. Of the nine events associated with the AF ablation procedure, one event met the criteria of a primary safety event. These events are described further below. Table 16: Adverse Events Adjudicated as Associated to the AF Ablation Procedure or Ancillary Device Use | Subject | Event Name | Adjudication | Relationship | Treatment | Primary Safety Endpoint | | --- | --- | --- | --- | --- | --- | | 11-04-GKE | Atrioventricular Block First Degree | Non-Serious AE | AF Ablation Procedure | Recovery | NO | | 05-03-LRG | A-V Node Dysfunction | Serious AE | AF Ablation Procedure | PPM | NO | | 11-10-ECW | A-V Node Dysfunction | Serious AE | AF Ablation Procedure | PPM | NO | | 13-06-JDH | A-V Node Dysfunction | Serious AE | AF Ablation Procedure | PPM | NO | | 19-01-EEE | A-V Node Dysfunction | Serious AE | AF Ablation Procedure | PPM | NO | PMA P100046: FDA Summary of Safety and Effectiveness Data {32} | Subject | Event Name | Adjudication | Relationship | Treatment | Primary Safety Endpoint | | --- | --- | --- | --- | --- | --- | | 11-08-NTW | Cardiac Akinesis | Serious AE | Ancillary Device Related | CAB x2 | NO | | 11-01-HPH | Pulmonary Vein Tear (LPV) | Serious AE | AF Ablation Procedure | Suture | NO | | 13-02-JCM | Torn IVC Cannulation Site | Serious AE | AF Ablation Procedure | Patch | NO | | 13-04-PJP | Left Atrial Tear | Serious AE | AF Ablation Procedure | Suture | DEATH | As previously stated, a death occurred in subject 13-04 who had a significant bleeding event caused during dissection of the pulmonary veins prior to placing the clamp in position. This was attributed to the Maze IV procedure. The other six serious adverse events (SAEs) that were attributed to the ablation procedure included four cases of AV nodal dysfunction that required placement of a permanent pacemaker, one pulmonary vein tear after the left pulmonary vein was retracted, and one tear at the IVC cannulation site for cardiopulmonary bypass. There was one episode of AV block that was deemed non-serious because the subject was treated with medication and no permanent pacemaker was implanted. There was one serious adverse event attributed to an ancillary device. After an RF ablation pen was used to complete the lesion line to the tricuspid annulus, the lateral and inferior wall of the left ventricle became akinetic. This was successfully treated by placing bypass grafts on the circumflex and distal right coronary arteries. ## 3. Effectiveness Results The analysis of effectiveness was based on the 50 evaluable subjects at the 6-month time point. Key effectiveness outcomes are presented in Tables 17 to 20. The primary effectiveness endpoint was evaluated for 50 evaluable subjects out of 55 treated subjects. This excludes 4 deaths and 1 withdrawal. The following table presents the primary effectiveness results along with the one-sided 97.5% Bayesian credible intervals (BCIs). PMA P100046: FDA Summary of Safety and Effectiveness Data page 33 38 {33} Table 17: Primary Effectiveness Endpoint Results for Treated and Non-Paroxysmal Subjects | | Treated N=50 | Non-Paroxysmal N=46 | | --- | --- | --- | | Primary Effectiveness Endpoint | % (n/N) | % (n/N) | | Primary Success at 6 months^{12} | 74.0% (37/50) BCI (0.604, 1.00) | 73.9% (34/46) BCI (0.597, 1.00) | | Failure by AAD | 10.0% (5/50) | 8.7% (4/46) | | Failure by Rhythm | 16.0% (8/50) | 17.4% (8/46) | | Posterior probability that the effectiveness rate is greater than 60% Pr(p_{T} > 0.60 | Trial Results) | 0.978 | 0.972 | The primary effectiveness endpoint is met for the Treated population but not met for the Non-Paroxysmal subpopulation. Freedom from AF, whether on or off AADs, is shown in the table below. The table also shows the AF burden in a 24-hour period measured either with a 24-hour Holter (44 Treated, 40 Non-Paroxysmal) or pacemaker interrogation (6 Treated, 6 Non-Paroxysmal). Table 18: Secondary Effectiveness Endpoints for Treated and Non-Paroxysmal Subjects | Secondary Effectiveness Endpoint | All Treated N=50 | Non-Paroxysmal N=46 | | --- | --- | --- | | | % (n/N) | % (n/N) | | Free of AF, Regardless of AADs^{13} | 84.0% (42/50) | 82.6% (38/46) | | AF Burden | | | | = 0 min | 82.0% (41/50) | 82.6% (38/46) | | <= 5 min | 2.0% (1/50) | 0% (0/46) | | > 5 min - 1 hr | 2.0% (1/50) | 0% (1/46) | | > 1 hr | 14.0% (7/50) | 15.2% (7/46) | ## Acute Pulmonary Vein Isolation Exit block was assessed by pacing from the pulmonary veins after ablation. This was technically possible in 23 subjects. Complete block was demonstrated in all of them. PMA P100046: FDA Summary of Safety and Effectiveness Data page 34 {34} Table 19: Pulmonary Vein Isolation | Secondary Effectiveness Endpoint | % (n/N) | | --- | --- | | Both Right & Left Pulmonary Vein Isolation | | | Isolation Confirmed (Of 23 evaluable subjects) | 100.0% (23/23) | Freedom from AF at 12 or More Months Late follow-up was obtained for subjects at least one year after treatment in order to assess effectiveness over time. The additional endpoints to be studied were: (1) Freedom from AF, off AADs; (2) Freedom from AF, regardless of AADs; and (3) AF burden. This data collection was not prospectively specified was data collection for this effort began after many subjects had already completed one year of follow-up. The median follow-up was 658 days (range 365 - 952 days). The data shown below are divided according to the populations of interest; the exact number of subjects varies because of the retrospective collection without all subjects being available. Table 20: Additional Effectiveness Endpoints for Treated and Non-Paroxysmal Subjects | | All Treated | Non-Paroxysmal | | --- | --- | --- | | Additional Effectiveness Endpoints | % (n/N) | % (n/N) | | Effectiveness Evaluable at 12 month Follow-up or greater | N=48 | N=45 | | Free of AF^{14} at 12+ months | 75.0% (36/48) | 73.3% (33/45) | | Free of AF and off AAD at 12+ months | 62.5% (30/48) | 62.2% (28/45) | | Time to Evaluation (days) | | | | Mean +/- SD (N) | 640.9 +/- 147.3 | 641.7 +/- 151.7 | | Min, Max | 365.0, 952.0 | 365.0, 952.0 | | Method of Evaluation | | | | Holter | 81.3% (39/48) | 82.2% (37/45) | | Pacemaker Interrogation (PMI) | 2.1% (1/48) | 2.2% (1/45) | | ECG | 6.3% (3/48) | 4.4% (2/45) | | Other/Telephone Assessment | 10.4% (5/48) | 11.1% (5/45) | | AF Burden (initial 24 hrs or >24 - 48 hrs) at 12+ months | | | | = 0 min | 77.5% (31/40) | 76.3% (29/38) | | <= 5 min | 0.0% (0/40) | 0.0% (0/38) | | > 5 min - 1 hr | 0.0% (0/40) | 0.0% (0/38) | | > 1 hr | 22.5% (9/40) | 23.7% (9/38) | 4. Additional Analyses Lesion Set Deviations According to the study protocol, 6 of 9 of the ablative lesions were to be created only with the Synergy Ablation Clamp. Several deviations from the lesion set protocol were observed in the ABLATE study. Although only 4% of all lesions PMA P100046: FDA Summary of Safety and Effectiveness Data 40 {35} (24/550 lesions in 55 subjects) were performed with device(s) or techniques other than the Synergy Ablation Clamp or not performed at all, this occurred in about 25% of subjects (14/55 treated subjects and 13/51 non-paroxysmal subjects). An accounting of these deviations is shown in the tables below on a per-lesion and per-patient basis, respectively. These results demonstrate the extent to which the AtriCure Synergy Ablation System was used in achieving the reported effectiveness results. Table 21: Lesion Set Deviations Presented by Lesion | Lesion | Deviations | Alternative Method Used | Lesion not Performed | | --- | --- | --- | --- | | Pulmonary veins | 0 | 0 | 0 | | Box lesion - Floor | 8 | Cut & Sew (6) RF Pen (1) | 1 | | Box lesion – Roof | 2 | RF Pen (1) | 1 | | Mitral valve annulus* | 2 | Cryoablation alone used (1) | 1 | | LA appendage | 3 | Cryoablation (2) | 1 | | Tricuspid valve** | 1 | 0 | 1 | | SVC-to-IVC line | 1 | 0 | 1 | | Free wall | 5 | 0 | 5 | | RA appendage** | 2 | 0 | 2 | | *lesion must be initiated with the clamp but can be completed by another modality **lesion can be performed by any method | | | | Table 22: Lesion Set Deviations Per Patient | Number of deviations per patient | Number of patients | Note | | --- | --- | --- | | Patients with only 1 deviation | 12 | 9 subjects had a lesion performed with an alternative method 3 subjects had a lesion omitted | | Patients with > 1 deviation | | | | 4 deviations | 1 | In this patient 2 lesions (Roof and Floor) were performed with an alternative method (RF pen) and 2 were omitted (Free wall and RA appendage) | | 8 deviations | 1 | This subject was classified has having paroxysmal AF. Only pulmonary vein isolation was performed on this patient. | Additional per-lesion detail is outlined in the following tables. PMA P100046: FDA Summary of Safety and Effectiveness Data page 36 {36} Table 23: Biatrial Lesion Details - Right Atrial Lesions | | ABLATE N=55 | ABLATE Non-paroxysmal N=51 | | --- | --- | --- | | Parameter | % (n/N) | % (n/N) | | Left Sided Lesions [1] | | | | I. Mitral Valve Connecting Lesion [2] | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 33.3% (18/54) | 29.4% (15/51) | | Cryothermy | 1.9% (1/54) | 2.0% (1/51) | | AtriCure Clamp and AtriCure Pen | 27.8% (15/54) | 29.4% (15/51) | | AtriCure Clamp and Cryothermy | 29.6% (16/54) | 31.4% (16/51) | | AtriCure Clamp and Surgical (cut and sew) | 7.4% (4/54) | 7.8% (4/51) | | II. Floor Line Lesion | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 87.0% (47/54) | 86.3% (44/51) | | AtriCure Pen | 1.9% (1/54) | 2.0% (1/51) | | Surgical (cut and sew) | 11.1% (6/54) | 11.8% (6/51) | | III. Roof Line Lesion | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 98.1% (53/54) | 98.0% (50/51) | | AtriCure Pen | 1.9% (1/54) | 2.0% (1/51) | | IV. LAA Appendage to Pulmonary Vein | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 96.3% (52/54) | 96.1% (49/51) | | Cryothermy | 3.7% (2/54) | 3.9% (2/51) | | [1] One subject did not undergo the Maze 4 procedure. [2] Mitral valve connecting lesion includes the full complement of the mitral valve annular lesion (lesion taken from the atriotomy to the mitral valve annulus and lesion completed on the posterior mitral valve annulus). | | | PMA P100046: FDA Summary of Safety and Effectiveness Data page 37 42 {37} Table 24: Biatrial Lesion Details - Right Atrial Lesions | | ABLATE N=55 | ABLATE Non-paroxysmal N=51 | | --- | --- | --- | | Parameter | | % (n/N) | | Right Sided Lesions [1] | | | | I. Tricuspid Valve Annulus lesion | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 46.3% (25/54) | 43.1% (22/51) | | AtriCure Pen | 14.8% (8/54) | 15.7% (8/51) | | Surgical (cut and sew) | 1.9% (1/54) | 2.0% (1/51) | | Cryothermy | 14.8% (8/54) | 15.7% (8/51) | | AtriCure Clamp and AtriCure Pen | 9.3% (5/54) | 9.8% (5/51) | | AtriCure Clamp and Cryothermy | 11.1% (6/54) | 11.8% (6/51) | | AtriCure Clamp and Surgical (cut and sew) | 1.9% (1/54) | 2.0% (1/51) | | II. Ablation of SVC / IVC | 100.0% (54/54) | 100.0% (51/51) | | AtriCure Clamp | 100.0% (54/54) | 100.0% (51/51) | | III. Free wall Appendage Lesion | 92.6% (50/54) | 92.2% (47/51) | | AtriCure Clamp | 100.0% (50/50) | 100.0% (47/47) | | IV. Right Atrial Appendage Lesion | 98.1% (53/54) | 98.0% (50/51) | | AtriCure Clamp | 54.7% (29/53) | 52.0% (26/50) | | AtriCure Pen | 9.4% (5/53) | 10.0% (5/50) | | Cryothermy | 18.9% (10/53) | 20.0% (10/50) | | AtriCure Clamp and AtriCure Pen | 7.5% (4/53) | 8.0% (4/50) | | AtriCure Clamp and Cryothermy | 5.7% (3/53) | 6.0% (3/50) | | AtriCure Clamp and Surgical (cut and sew) | 1.9% (1/53) | 2.0% (1/50) | | Surgical (cut and sew) and Cryothermy | 1.9% (1/53) | 2.0% (1/50) | | [1] One subject did not undergo the Maze 4 procedure. | | | Modified Effectiveness Analysis In addition to the information presented above, FDA believes the effectiveness results should be presented considering contemporary definitions for AF treatment success. In the ABLATE study, freedom from AF was defined as freedom from episodes &lt; 5 minutes in duration and no more than 1 hour total AF PMA P100046: FDA Summary of Safety and Effectiveness Data page 38 43 {38} duration in 24 hours. Current guidelines consider recurrence of AF to include any episode of AF, atrial flutter, or atrial tachycardia lasting longer than 30 seconds. Ideally, rhythm status is measured with a 24-48 hour Holter monitor. In the ABLATE study, the 6 month evaluation was primarily performed with a 24 hour Holter recording. The 12 month (or greater) evaluation was primarily performed with a 48 hour Holter recording. The results in the table below include 2 cases of atrial flutter greater than 5 minutes (non-paroxysmal subjects) and 1 case of AF between 30 seconds and 5 minutes (paroxysmal subject) at the 6 month evaluation. At 12+ months, the results in the table include one additional case of atrial flutter and one additional case of atrial tachycardia (counting these cases as failures), compared to results using the original ABLATE definitions. Current guidelines also consider cardioversion performed after a 3 month blanking period to be effectiveness failures. According to the study protocol, DC cardioversions were permitted at any time during the follow-up period, up to the 6-month assessment. In the ABLATE study, 12 subjects underwent cardioversion during their 6 month follow-up period. Of these, four (4) were cardioverted after 3 months. All four were classified as having longstanding persistent AF prior to treatment. In the primary effectiveness analysis, one was considered a primary effectiveness success, one a secondary effectiveness success, and two were effectiveness failures. In addition, one subject underwent cardioversion between 6 and 12 months after treatment that resulted in the patient'…
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