Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Russo RJ, Costa HS, Silva PD, et al. Assessing the risks associated with MRI in patients with a pacemaker or defibrillator. N Engl J Med 2017;376: DOI: /NEJMoa

2 M AGNAS AFE R EGISTRY F INAL R ESULTS This supplement contains the following items: 1. The original research protocol submitted and approved by the FDA as part of the IDE application process (FINAL FDA MagnaSafe Registry ) 2. The most recent version of the protocol which includes all protocol amendments (MagnaSafe Registry Full Protocol ) 3. A protocol amendment that changed the requirements for a Supervising Physician (FDA Cover Letter ) 4. FDA acknowledgement of the requested protocol change (FDA Acknowledgement ) 5. A protocol amendment that changed the requirements for medical personnel present at the time of the MRI examination (FDA Protocol Modification Request ) 6. FDA acknowledgement of the requested protocol change (FDA Approval MagnaSafe Protocol version ) 7. Notification to the contributing sites of a protocol modification that excluded enrollment of MRIconditional pacemakers (Site notification MRI-conditional devices ) 8. A protocol amendment that increased the potential maximum study enrollment from 1500 to 2500 cases to allow for ICD enrollment of 500 cases (Extension Request Letter for MagnaSafe ) 9. Acknowledgement by FDA of the protocol change requested (FDA Approval 2500) 10. A summary of changes is presented within FDA Protocol Modification Request There was no separate statistical analysis plan. The plan for data analysis is contained in the original protocol, final protocol, and study design paper (Russo RJ, Am Heart J 2013;165: ). The plan for data analysis was not changed or amended during the conduct of the study. 1

3 The MagnaSafe Registry: Determining the Risks of Clinically-Indicated MRI for Patients with Pacemakers and Implantable Cardioverter Defibrillators Principal Investigator: Robert J. Russo, MD, PhD, FACC V ERSION 03/25/09 1 ROBERT J. RUSSO, MD, PHD

4 REGISTRY SYNOPSIS... 6 ABBREVIATIONS INTRODUCTION Specific Aim Background and Significance MRI in Patients with Cardiac Devices Preliminary Data Capability of the Principal Investigator INVESTIGATIONAL PLAN Study Design Baseline Data on Device Parameter Changes Clinical experience: device parameter changes in subjects undergoing MRI Sub-study: device parameter changes in subjects without MRI Anticipated Observations Device failure Temporary and permanent device reprogramming Anticipated rates of clinically significant events Inclusion Criteria Exclusion Criteria Conditions which do not require exclusion from the present protocol Transdermal drug patches with metallic backing STUDY PROTOCOL Overview V ERSION 03/25/09 2 ROBERT J. RUSSO, MD, PHD

5 3.2 MRI Protocol Specific MRI Precautionary Procedures During the Performance of Clinically-Indicated Scanning Protocol for the Performance of MRI Pacemaker Device Interrogation Protocol Pacemaker pre-scan interrogation Pacemaker programming during the scan Pacemaker post-scan interrogation ICD Device Interrogation Protocol ICD pre-scan interrogation ICD post-scan interrogation Monitoring During the Scan Follow-up Interrogations Subjects requiring multiple follow-up visits Subjects requiring single follow-up visits Variables to be Collected Patient Medical Record MRI Study Procedure Record Device Interrogation Primary Outcomes Secondary Outcomes Reporting Events Reporting Adverse Events V ERSION 03/25/09 3 ROBERT J. RUSSO, MD, PHD

6 Reporting Protocol Deviations DATA MANAGEMENT Data Collection Data Monitoring STATISTICAL CONSIDERATIONS Data Analysis Sample Size RISK ANALYSIS Justification for Investigation Risks Risk Management Procedures DESCRIPTION OF THE DEVICE STUDY MONITORING Name and Address of Monitor: Overview of Study Monitoring Plan Site visits Remote monitoring Registry Reports MANUFACTURING INFORMATION I N V E S T I G A T O R I N F O R M A T I O N Site Selection and Training Qualifications for the participating clinical site Principal Investigator Clinical Study Agreement IRB INFORMATION V ERSION 03/25/09 4 ROBERT J. RUSSO, MD, PHD

7 12. SALES INFORMATION INVESTIGATIONAL LABELING INFORMED CONSENT MATERIALS DATA SAFETY MONITORING BOARD (DSMB) T I M E L I N E REFERENCES V ERSION 03/25/09 5 ROBERT J. RUSSO, MD, PHD

8 REGISTRY SYNOPSIS Study Title Princpal investigator Determining the Risks of Clinically-Indicated MRI for Patients with Pacemakers and Implantable Cardioverter Defibrillators: The MagnaSafe Registry Robert J. Russo, MD, PhD, La Jolla, CA Purpose To create a multicenter registry designed to prospectively document the safety of Clinically-Indicated Magnetic Resonance Imaging (MRI) studies at 1.5 Tesla performed in patients with pacemakers or implantable cardioverter defibrillators (ICDs). Study design This study will be a multicenter, prospective registry of patients with implanted cardiac devices who undergo MRI for clinical purposes. The incidence of device parameter changes or adverse events will be recorded. Number of subjects 1500 subjects (1000 with pacemakers and 500 with ICDs) Number of sites Up to 35 sites Duration of patient participation Variable; 6 months or less Duration of study Approximately 5 years Study Coordinator Heather Costa, PhD Study Biostatistician Patricia Silva, MA V ERSION 03/25/09 6 ROBERT J. RUSSO, MD, PHD

9 ABBREVIATIONS ACLS bpm DOO DSMB ECG ICD MRI RF RV SAR SVC VOO Advanced cardiac life support Beats per minute Asynchronous pacing mode using both atrial and ventricular leads Data Safety Monitoring Board Electrocardiogram Implantable cardioverter defibrillator Magnetic resonance imaging Radiofrequency Right ventricle Specific adsorption rate Superior vena cava Asynchronous pacing mode using only the ventricular lead V ERSION 03/25/09 7 ROBERT J. RUSSO, MD, PHD

10 1. INTRODUCTION 1.1 Specific Aim Specific Aim: Create a multi-center registry designed to prospectively document the safety of non-thoracic magnetic resonance imaging (MRI) studies for patients with pacemakers or implantable cardioverter defibrillators (ICDs). Until recently, the presence of a permanent pacemaker or an implantable cardioverter defibrillator (ICD) has been an absolute contraindication for the performance of magnetic resonance imaging (MRI). A number of small studies, with a total of 350 patients, have shown that MRI can be performed with minimal risk in patients with pacemakers or ICD s implanted after However, controversy persists as to the routine performance of MRI for patients with implanted cardiac devices, 1, 2 and the safety of current pre and post-imaging device interrogation protocols have not been sufficiently evaluated to allow routine clinical use. To determine the risk of non-cardiac/non-thoracic MRI for patients with implanted cardiac devices, prospective studies documenting the outcome of a large number of cases are needed 3, 4 The aim of the present protocol is to prospectively determine the adverse event rate of non-thoracic MRI for patients with implanted cardiac devices by collecting pre- and post-mri device interrogations in a multi-center registry. The results of this registry may be used to change the recommendations of the American Heart Association and the American College of Cardiology and to establish a clinical protocol for the performance of clinically-indicated MR imaging for patients with implanted cardiac devices. 1.2 Background and Significance Magnetic resonance is the imaging modality of choice for the diagnosis of many diseases of the brain, spinal cord, and musculoskeletal system. For some disease states, no acceptable alternative diagnostic imaging method is available. The advantages of MR imaging include the lack of exposure to ionizing radiation (x-rays), and the use of gadolinium which is a non-nephrotoxic contrast agent. Allergic reactions to gadolinium-based contrast are very rare. In addition, patients do not have to abstain from food prior to MRI; a concern for elderly patients and those with diabetes mellitus. 300, , , , ,000 50, Pacemaker AICD Figure 1. National estimates of cardiac device implantation (data from Zhan et al. 2008) V ERSION 03/25/09 8 ROBERT J. RUSSO, MD, PHD

11 The number of patients living with permanent pacemakers or ICD devices in the United States is increasing dramatically as a result of expanded indications (Figure 1). Between 1990 and 2005, an estimated 2.8 million pacemakers and 690,000 ICDs were implanted in the United States. 5-7 The number of implanted devices continues to increase without an apparent plateau. As the number of implanted cardiac devices is increasing, the clinical indications for MRI are expanding as well (Figure 2). Marketing research estimates that approximately 27.5 million MRI procedures were completed in 2007 (The Medical Information Division of IMV, LTD). It is predicted that there is a 50-75% probability that a patient with a pacemaker or ICD will have the need for an MRI over the lifetime of the device. 8 Most physicians consider the presence of a pacemaker or ICD to be an absolute contraindication to an MRI study. Patients are denied the examination, even when MR is clearly the superior diagnostic modality or when there is no acceptable alternative imaging test available. To provide optimal care to the increasing number of patients with an implanted cardiac device, health care professionals must have the capability to perform MR imaging with minimal risk and full knowledge of the possible complications. Number of Scan (millions) Figure 2 Estimate of total domestic MRI scan procedure volume in millions (data from Kalin and Stanton 2005, Roguin et al ). The present study will create a registry of patients with pacemakers and ICDs who will undergo clinically indicated MRI and will document any adverse event or change in device parameters that may be associated with the imaging procedure. The results of this registry will provide the medical community with an accurate documentation of risk to patients and will establish a protocol of patient screening and device reprogramming for the purpose of maximizing the safe performance of MRI as a diagnostic tool in patients with implantable cardiac devices when indicated. This protocol will also benefit the community by providing more patients with implantable devices access to the best and most appropriate diagnostic imaging available. 1.3 MRI in Patients with Cardiac Devices Recent studies have suggested that MRI can be performed with minimal risk in patients who have pacemakers or ICDs as long as the patients are monitored by a cardiologist and the device output is modified appropriately pre and post scan. However, there is controversy related to the V ERSION 03/25/09 9 ROBERT J. RUSSO, MD, PHD

12 risk of performing MR studies in patients with cardiac devices, 1, 2 and current protocols have not been sufficiently evaluated to allow routine imaging at every facility. 1, 9 Published studies examining the safety of MRI in patients with cardiac devices have been relatively small (1-82 patients), and primarily involved patients with pacemakers. 2 These studies have reported varying effects of MRI on pacemakers including impedance changes, battery depletion and an increase in pacing thresholds (Table 1). Shellock et al. 10 tested both pacemakers and ICDs in a phantom system and reported that magnetic field interactions do not create a hazard. There was no significant temperature change in the device. No memory corruption, hardware changes, or changes in device parameters were seen. Martin et al. 11 studied 54 patients with pacemakers undergoing MRIs. A total of 107 leads and 61 pulse generators were evaluated with no severe adverse events reported. Two leads required reprogramming due to increased pacing thresholds. Sommer et al. 12 studied 82 patients undergoing 115 extra-thoracic MRIs. No serious adverse events were observed and none of the leads required a change in programmed output. Nazarian et al. 13 studied 31 pacemaker and 24 ICD patients who underwent a total of 68 MRI studies. No serious adverse events and no significant changes in device parameters were observed. V ERSION 03/25/09 10 ROBERT J. RUSSO, MD, PHD

13 Table 1. Previous Studies of MR in Patients with Pacemakers (P) or ICDs. a) Case Reports and Retrospective Studies Author Year Devic e #Patients/ #Studies Condition Findings Iberer et al P 1/1 No adverse effect Alagona et al P 1/1 Inbar et al P 1/1 Gimbel et al P Garcia-Boloa et al P 1/2 Fontaine et al P 1/1 Anfinsen et al ICD 5/5 Retrospective 1/1 Inadvertent 1.5 T Brain 1.5 T Brain T Cardiac Brain C-Spine 1.0 T Brain 1.5 T Brain C-Spine 0.5 T Brain No adverse effect No adverse effect Two second pause No adverse effect Rapid pacing Inappropriate sensing, battery voltage transient change to EOL. Fiek et al ICD 1/1 Inadvertent 0.5 T Brain Unable to communicate with device. Rozner et al PM 2/2 Roguin et al ICD 1/1 Wollmann et al ICD 1/3 Naehle et al ICD 1/1 Mikolich & Martin P 1/1 1.5 T Thorax Lumbar 1.5 T Cardiac 1.5 T Brain 1.5 T Brain 1.5 T Cardiac Transient change to ERI in 1 patient. No adverse effect. No adverse effect. No adverse effect. No adverse effect V ERSION 03/25/09 11 ROBERT J. RUSSO, MD, PHD

14 Table 1. (continued) Previous Studies of MR in Patients with Pacemakers (P) or ICDs. b) Prospective Studies at 0.5 Tesla Field Strength Author Year Device #Patients/ #Studies Sommer et al P 18/18 Condition 0.5 T Brain Cardiac Vascular Findings Asynchronous mode due to activation of the reed switch in all patients Sommer et al P 45/ T Multiple No adverse effect Valhaus et al P 32/ T Multiple Heatlie et al P 5/6 Non-pacing dependent 0.5 T Cardiac Decrease in battery voltage recovered at 3 months Pacing at maximum voltage at a fixed rate of 100 beats/ minute in 1 patient. c) Prospective Studies at 1.5 or Greater Tesla Field Strength #Patients/ Author Year Device Condition #Studies Findings Martin et al P 54/ T Multiple Significant change in pacing threshold in 9.4% of leads, and 1.9% of leads requiring an increase in output. Coman et al. 31 (abstract) 2004 ICD 11/ T Cardiac General Brief asymptomatic pause in 1patient. Unable to interrogate device in 1 patient. Del Ojo et al P 13/13 Gimbel et al P Gimbel et al ICD 7/8 10/11 All pacingdependent 2.0 T Multiple 1.5 T Brain C-Spine 1.5 T Brain L-Spine No adverse effect. Small variances in pacing threshold were seen in four patients. Power on reset requiring reprogramming in 1 patient. Nazarian et al P 31 ICD 24 Sommer et al P 55/ T No adverse effect. 82/115 All nonpacemaker dependent 1.5 T Extra-thoracic Significant increase in pacing threshold, decreased lead impedance, and battery voltage. No inhibition of pacing and no leads which required an increase in pacing output. Table modified from Shinbane et al. 2 V ERSION 03/25/09 12 ROBERT J. RUSSO, MD, PHD

15 Although no pacemaker or ICD is presently labeled as safe for MRI scanning, 4 the FDA recognizes that on a case-by-case basis, the diagnostic benefit from MRI may outweigh the presumed risks for some pacemaker and ICD patients. 3 The FDA has stated that it is committed to working with manufactures to pursue studies that would allow the modification or removal of device warning and contraindications on the device label. 3,4 The American College of Radiology considers a the presence of a permanent pacemaker or ICD to be a relative contraindication for MRI, and that imaging should be assessed on a case-by-case as well as a site-by-site basis. 35 A Scientific Statement from the American Heart Association providing recommendations for the performance of MR examinations in patients with pacemakers or ICDs includes guidelines for pre- and post-scanning procedures for device setting, monitoring and emergency equipment, and appropriate personnel that should be present at the site (Appendix F) Preliminary Data To our knowledge, Green Hospital, La Jolla, CA, is presently the only facility in the western United States routinely performing MRI on patients with implanted cardiac devices. At this facility, patients with a history of permanent pacemaker or ICD placement have successfully undergone MR imaging after pre-procedure evaluation by a cardiologist. The most common types of scans ordered are for the evaluation of the brain or spine, where the benefits of superior imaging by MRI clearly outweigh the risks. Since January 2006, more than 125 scans in 100 patients with implanted devices have been performed at the Green MRI facility with no serious adverse events observed. In 2 cases, minor changes in pacing threshold were observed that did not require reprogramming of any device parameters. Appropriate requests for MRI scans involving patients with cardiac devices have increased at Green Hospital, and are now averaging 3-4 cases per week. Results of retrospective clinical observations were presented at the American Heart Association 2008 Scientific Sessions 37 (See sections 2.2 and 2.3). 1.5 Capability of the Principal Investigator The Principal Investigator for this study is well-suited to conduct the research. His research laboratory includes an Advanced Cardiovascular Imaging fellow, a research coordinator, and a biostatistician. The research facilities of the Cardiac MRI Program have 3 computers workstations connected to a server, with redundant file architecture and off site backup. In addition, the laboratory is equipped the appropriate support hardware including printers, copier, and fax machine. The facilities are secure with limited keyed access. The Principal Investigator has a successful track record of conducting two investigator-initiated, multicenter studies: (1) a 23- center, 800-patient, randomized clinical trial with one-year follow-up (Angiography Vs Intravascular ultrasound-direct stent placement The AVID Trial) and (2) a 20-center, 252- patient, prospective cohort with one-year follow-up The Left Main IVUS Registry ). V ERSION 03/25/09 13 ROBERT J. RUSSO, MD, PHD

16 2. INVESTIGATIONAL PLAN 2.1 Study Design This is a prospective, multicenter registry of cases where Magnetic Resonance Imaging (MRI) studies are performed on patients with pacemakers or implantable cardioverter defibrillators. Clinical care Patient with cardiac device and MRI clinically indicated Research Subjects enrolls in study Device parameters recorded Magnetic resonance imaging Clinical Care Device parameters recorded Restore or Adjust settings Parameter Change? Yes No Follow-up interrogation within 7 days Research Follow-up Interrogation at 3 months Follow-up interrogation at 3-6 months when clinically indicated Follow-up Interrogation at 6 months Figure 3. The sequence of steps that precede and follow subject enrollment into the MagnaSafe Registry. V ERSION 03/25/09 14 ROBERT J. RUSSO, MD, PHD

17 2.2 Baseline Data on Device Parameter Changes Clinical experience: device parameter changes in subjects undergoing MRI To date, more than 120 patients with cardiac devices have undergone a clinically indicated MRI at Green Hospital. Results from pre- and post-scan interrogations were used to standardize the interrogation protocol, including the pacing rate and pulse width duration for threshold measurements. The magnitude of changes in device parameter measurements anticipated for patients undergoing MRI are based on published research data 11-13, 36 and clinical data collected at Green Hospital. 37 The average battery voltage, pacing lead impedance, shock lead impedance, pacing threshold, and P and R wave amplitude changes in patients undergoing MRI at Green Hospital were 0 ± 0.02 V, -4.8 ± 28 ohms, 0.9 ± 0.8 ohms, 0.03 ± 0.15 V, ± 0.45 mv, and ± 0.82 mv respectively. These findings also highlighted the need to use a relative change for the P and R wave amplitudes. Based on our observed measurements, a significant P and R wave amplitude change will be defined as a decrease by 50% and 25%, respectively Sub-study: device parameter changes in subjects without MRI Published studies do not provide adequate data on short-term variability of measured values in patients not undergoing MRI with which to compare our research results. To provide further reference values, a sub-study conducted at Green Hospital will examine 100 patients not undergoing an MRI that will have 2 sequential interrogations one hour apart to simulate the duration of an MRI scan. The same protocol that is used for interrogation of devices immediately prior to and following the MRI will be used and is described below. Battery voltage, lead impedances, and P and R wave amplitudes were recorded. Pacing thresholds were measured at a fixed pulse width of 0.4 ms and the same pacing rate. The range and variance of the device measurements (including pacing thresholds and battery voltage) will be used as a basis for comparison with our research values. To date, 30 patients have been enrolled in this sub-study. In subjects that did not undergo MRI, 6.7% of generators had a battery voltage decrease of 0.02V, 3.6% of pacing leads had an impedance change of 50 ohms and 17.6% of defibrillator leads had lead impedance changes of 2 ohms. There were no P wave decreases of 1.0 V and no R wave decreases 2.0 V. None of the pacing leads had a threshold increase 0.5 mv. In this control group, the mean battery voltage change was ± V and the mean lead impedance change was 5.1 ± 24.2 ohms. The mean change in pacing lead threshold measurements was 0.00 ± 0.14 V. Most importantly, there were essentially equal numbers of lead threshold increases as there were decreases. When these parameters were compared with patients who underwent MRI in our retrospective chart review, the changes in measurements were similar in both groups. V ERSION 03/25/09 15 ROBERT J. RUSSO, MD, PHD

18 2.2.3 Defining a Significant Parameter Change Based on a comparison of the retrospective clinically-performed MRI group with the control group described above in section 2.2, published literature and standard-of care medical judgment, the following are defined as a significant parameter change after an MR scanning: 1) A battery voltage change 0.04 V. 2) Pacing lead impedance change 50 ohms. 3) A shock lead impedance change 3 ohms 4) A P wave decrease of 50% (instead of an absolute decrease of 1.0 V). 5) An R wave decrease of 25% (instead of an absolute decrease of 2.0 V). 6) A pacing lead threshold increase 0.5 V, at fixed pacing rate and pulse width duration of 0.4 msec. 2.3 Anticipated Observations The general hypothesis of this study is that the risk of magnetic resonance imaging (MRI) in patients with implanted cardiac devices can be minimized by adherence to a protocol of preprocedure and post-procedure device interrogation and reprogramming. A minimal risk MRI examination is defined for the purpose of this protocol as: (a) an imaging study performed with up to a 0.5% risk of generator or lead failure requiring immediate replacement in pacemaker patients and up to a 2% risk in ICD patients; (b) up to a 5% risk of requiring permanent reprogramming of the implanted device; and (c) up to a 10% risk of requiring temporary reprogramming of the implanted device Device failure To determine the background rate of device failure requiring lead or generator replacement (pacemakers and ICD s), post-market approval annual reports submitted to the US Food and Drug Administration (FDA) by manufacturers of pacemakers and ICDs were reviewed. 5 During the period , 2.25 million pacemakers and 415,780 ICDs were implanted in the United States. Overall, 17,323 devices or 0.65% (8834 pacemakers and 8489 ICDs) were explanted due to confirmed malfunction. In other words, the annual combined device malfunction replacement rate was 6.5 per 1000 implants. The device specific replacement rate per 1000 implants was 3.9 for pacemakers and 20.4 for ICDs. Battery/capacitor abnormalities (4085 malfunctions [23.6%]) and electrical issues (4708 malfunctions [27.1%]) accounted for half of the total device failures. The annual pacemaker malfunction replacement rate per 1000 implants decreased significantly during the study, from a peak of 9.0 in 1993 to a low of 1.4 in 2002 (P=.006 for trend). In contrast, the ICD malfunction replacement rate per 1000 implants, after decreasing from 38.6 in 1993 to 7.9 in 1996, increased markedly during the latter half of the study, peaking in 2001 at 36.4 (P=.04 for trend). More than half of the reported ICD V ERSION 03/25/09 16 ROBERT J. RUSSO, MD, PHD

19 malfunctions occurred in the last 3 years of the study. Overall, the annual ICD malfunction replacement rate was significantly higher than the pacemaker malfunction replacement rate (20.7 versus 4.6 replacements per 1000 implants) Temporary and permanent device reprogramming The need for temporary and permanent reprogramming is based on maintaining adequate safety margins for pacing threshold outputs and P and R wave sensing. Anticipated rates of temporary and permanent reprogramming of the implanted devices are based on the frequency of these events that were observed in published research data 11-13, 36 and clinical data collected at Green Hospital 37. A change of 0.5 V was considered to represent the need for temporary or permanent reprogramming of the threshold output. In our study, the rate of these events was 1.2% in pacemakers and 0% in ICDs. A significant P and R wave change was defined as a decrease in amplitude of 1.0 mv and 2.0 mv, respectively. This could require reprogramming of the lead sensitivity. In our study, the rate of these events was 5.8% in pacemakers and 3.3% in ICDs. Since arrhythmia detection and treatment in ICDs requires anesthesia and a delivered shock, the decision was made that it is unwarranted to require patients to undergo follow up defibrillator threshold testing Anticipated rates of clinically significant events Based on these findings, the following rates of clinically relevant events are anticipated: Anticipated Observation #1: The observed percentage of patients undergoing MRI for clinical care who then require immediate generator or lead replacement will be 0.5% for pacemakers and 2% for ICDs. Anticipated Observation #2: The observed percentage of patients undergoing MRI for clinical care who then require permanent reprogramming of the pacemaker or ICD device will be 5%. Anticipated Observation #3: The observed percentage of patients undergoing MRI for clinical care who then require temporary reprogramming of the pacemaker or ICD device will be 10%. V ERSION 03/25/09 17 ROBERT J. RUSSO, MD, PHD

20 2.4 Inclusion Criteria 1. Male or female 18 years or older 2. Able to provide informed consent 3. Permanent implanted pacemaker or ICD 4. Strong clinical indication for MRI; in the clinical setting where MRI is the diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology as determined by the ordering physician. 5. Patient is scheduled for non-thoracic MRI (joint, extremity, brain, pelvis, cervical, and lumbar or sacral spine) 2.5 Exclusion Criteria 1. Metallic objects that represent a contraindication to MR imaging, including: intra-orbital or intra-ocular retained metal fragments, and intracranial vascular clips and coils 2. Claustrophobia unresponsive to oral pre-procedure sedatives provided by the ordering physician 3. Morbid obesity (abdominal diameter >60 cm) which results in contact with the magnet facade 4. ICD or pacemaker generator placement prior to ICD and pacing dependent 6. Pregnancy 7. Device generator battery voltage at elective replacement index (ERI) 8. Presence of active implantable medical device (other than pacemaker or ICD) 9. Presence of abandoned leads (with the exception of post CABG temporary epicardial pacing wires) 10. Presence of implanted cardiac device in the abdominal position 2.6 Conditions which do not require exclusion from the present protocol 1. Prior MRI with pacemaker or ICD in place (patients may undergo repeat scanning) 2. Coronary stent placement (without minimum time from stent implant exclusion) 3. Non-coronary stent placement (including aortic stent grafts) 4. Vascular shunts 5. Mechanical heart valves 6. Prior coronary artery bypass surgery (including the associated sternal wires) 7. Prior joint replacement surgery V ERSION 03/25/09 18 ROBERT J. RUSSO, MD, PHD

21 2.7 Transdermal drug patches with metallic backing The FDA recommends that healthcare professionals referring patients to have an MRI scan identify those patients who are wearing a patch before the patients have the MRI. The healthcare professional should advise these patients about the procedures for removing and disposing of the patch before the MRI scan, and replacing the patch after the MRI scan. The MRI facilities should follow published safe practice recommendations concerning patients who are wearing patches. V ERSION 03/25/09 19 ROBERT J. RUSSO, MD, PHD

22 3. STUDY PROTOCOL 3.1 Overview The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. MR examination of patients with permanent implanted cardiac devices will only be performed if there are highly compelling circumstances and when the benefits clearly outweigh the risks in the opinion of the ordering physician. Completion of the study Inclusion/Exclusion form by the participating physician will document that the ordering physician has requested the present non-thoracic MRI study as the clinically indicated diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and has been selected independent of this research protocol. Enrolling in the study will not add any additional physical risk to the patient. Patients with a pacemaker or ICD who are scheduled for a clinically-indicated MRI will be invited to enroll in the study. Enrollment will be open to patients with either pacemakers or ICDs until the target enrollment of either 1000 pacemakers or 500 ICDs is reached, then enrollment will be limited to the type of device that has not yet reached the target enrollment. At this time, Green Hospital is the only heath care facility in San Diego performing MR on patients with implanted cardiac devices. The MRI suite is equipped to provide the necessary monitoring and emergency care, and a cardiologist with expertise in device interrogation and programming will be available for each scan. All patients with a pacemaker or ICD scheduled for an MRI at Green Hospital will be asked to enroll in the study. The Green Torrey Pines campus alone performed more than 8,000 MRI scans in In the entire system, 18,000 MRI scans were performed in In this study, up to 34 additional sites will be recruited to participate in the registry (see Section 10). MRI compatible equipment will be required to monitor vital signs (non-invasive blood pressure monitoring, pulse oximeter, and single lead cardiac rhythm monitor) while performing scans on patients with implanted devices. Recommendations from the American Heart Association for performance of MR examination in patients with pacemakers or ICDs will be followed (Appendix F). 1 V ERSION 03/25/09 20 ROBERT J. RUSSO, MD, PHD

23 3.2 MRI Protocol Specific MRI Precautionary Procedures During the Performance of Clinically-Indicated Scanning 1. Initiate each study in a standard fashion using Normal Operating Mode 2. The patient will be weighed and the technologist will enter an accurate weight for the purpose of determining SAR levels during the examination. 3. If the patient cannot be weighed, then a weight obtained during inpatient status may be used or the patient s best estimate of a recent weight. 4. If a SAR limit is reached during an examination, parameters should be changed as needed to maintain Normal Operating Mode (TR, number of slices, or flip angle). These changes should be documented and it should also be documented whether this led to a successful diagnostic scan. 5. If it is clinically necessary to change to First Level Controlled Operating Mode, a study deviation form should be filled out explaining the reason Protocol for the Performance of MRI a) A cardiologist will review the medical record to determine suitability for the imaging study. b) A signed written informed consent will be obtained. c) The radiology technical staff will use the standard screening form to evaluate the patient for MRI contraindications: aneurysm clips or coils, infusion pumps, nerve stimulators, metal shavings in the eye, ferrous metal implants, transdermal drug patches with metallic backing, cochlear implants, an allergy to gadolinium, morbid obesity, pregnancy and severe claustrophobia. d) ACLS trained personnel and a crash cart, including a non-mri compatible defibrillator and transcutaneous pacemaker, will be available throughout the procedure to respond to an adverse clinical event. e) All patients will be monitored throughout the procedure with continuous cardiac rhythm recording and pulse oximetry. In addition, a blood pressure will be obtained at 5 minute intervals. f) All patients will undergo device interrogation in the MRI suite, but outside of the magnet room immediately prior to and following the scan. The results of the device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. V ERSION 03/25/09 21 ROBERT J. RUSSO, MD, PHD

24 3.3 Pacemaker Device Interrogation Protocol Patient with a Cardiac Device Patient with an ICD Patient with a Pacemaker Yes Pacemaker dependent? Pacemaker dependent? Yes No No Disable antitachycardia therapy and Disable pacing and sensing functions (OVO/ODO) Disable pacing and sensing functions (OVO/ODO) Reprogram to asynchronous pacing mode (VOO/DOO) and Disable magnet response No MRI MRI MRI MRI Figure 4. Device reprogramming prior to MRI. V ERSION 03/25/09 22 ROBERT J. RUSSO, MD, PHD

25 3.3.1 Pacemaker pre-scan interrogation Pre-scan interrogation will include the following: Baseline device parameter settings, determination of the patient s underlying rhythm and full interrogation of the device. a) Interrogation of the device will include: battery voltage measurement; measurement of the P and R wave amplitudes (if present at a pacing rate of 40 bpm); measurement of the lead impedance for all leads (atrial when present, right ventricular, and left ventricular when present); and pacing threshold measurements of all leads. b) Pacing threshold measurements will be performed at 10 bpm above the programmed pacing rate or the patient s intrinsic rate. The pacing rate for testing can be increased by increments of 10 bpm if there is insufficient suppression of the patient s underlying rhythm. c) Pacing threshold measurements will measure the pacing amplitude and will be performed with a fixed pulse width of 0.4 ms, regardless of the permanent pacing output. If the pulse width cannot be safely decreased to 0.4 ms to test a lead, the amplitude threshold test should be performed at the programmed pulse width Pacemaker programming during the scan a) The pacing rate will gradually be decreased to 40 bpm. If the patient has an intrinsic rhythm, the device will be programmed to no pacing (ODO or OVO). The patient will be observed for 5 minutes prior to the scan. If symptoms of presyncope are noted, the pacing function will be reprogrammed to an asynchronous pacing mode (DOO or VOO). b) If the patient has a Boston Scientific/Guidant pacemaker which does not allow permanent reprogramming to an ODO or OVO mode, the patient will be reprogrammed to an asynchronous mode (DOO or VOO). c) If there is no intrinsic rhythm when the device is reprogrammed to 40 bpm, the patient will be considered dependent and the device programmed to an asynchronous pacing mode (DOO or VOO). The patient will be observed for 5 minutes prior to the scan to ensure that the asynchronous pacing is well-tolerated. If not, the original pacing parameters will be restored and the scan will not be performed. These patients will remain enrolled in the study and the results recorded. d) Immediately following the scan, initial pacemaker parameters will be restored. V ERSION 03/25/09 23 ROBERT J. RUSSO, MD, PHD

26 3.3.3 Pacemaker post-scan interrogation a) Post-scan interrogation will include: Battery voltage measurement; measurement of the P and R wave amplitudes (if present at a pacing rate of 40 bpm); measurement of the lead impedance for all leads; and pacing threshold measurements of all leads. b) All threshold measurements will be performed at the same pacing rate and pulse width amplitude as the pre-scan interrogation. c) If there is a significant increase in pacing threshold ( ms or any increase at a wider pulse width) after the scan compared with before the scan, the pacing output will be increased to maintain a amplitude safety margin. d) If there is a significant decrease in the P and R wave amplitudes, the sensitivities will be adjusted to maintain adequate atrial and ventricular electrogram detection. 3.4 ICD Device Interrogation Protocol ICD pre-scan interrogation a) ICD pre-scan interrogation will include: Baseline device parameter settings, determination of the patient s underlying rhythm and full interrogation of the device. b) If there is no intrinsic rhythm when the device is reprogrammed to pace at 40 bpm, the patient will be considered dependent and will be excluded from the study. c) Interrogation of the pacing functions (thresholds, impedances, and P and R waves) will be performed as described for the pacemaker patients above. Additionally, the shock impedance of the SVC and RV coils will be determined (RV only when an SVC coil is not present). d) All tachycardia therapy functions will be disabled. e) Immediately following the scan, initial parameters will be restored ICD post-scan interrogation a) Post-scan interrogation will include: all pacing functions and shock impedances as described above. b) All threshold measurements will be performed at the same pacing rate and pulse width amplitude as the pre-scan interrogation. c) If there is a significant increase in pacing threshold ( ms or any increase at a wider pulse width) after the scan compared with before the scan, the pacing output will be increased to maintain a amplitude safety margin. d) If there is a significant decrease in the P and R wave amplitudes, the sensitivities will be adjusted to maintain adequate atrial and ventricular electrogram detection. V ERSION 03/25/09 24 ROBERT J. RUSSO, MD, PHD

27 3.5 Monitoring During the Scan a) A cardiologist who is trained in ACLS and has pacemaker/icd expertise will be in attendance for the study and will be able to visualize and hear the subject throughout the procedure. b) The patient will be instructed to alert the MR system operator to any unusual sensations or problems. c) Blood pressure, pulse oximetry and electrocardiogram will be monitored throughout the procedure. d) If a magnet response occurs when the patient enters the scanner, they will be removed and the device will be reprogrammed with the magnet response disabled. If the magnet response function is not programmable, the physician monitoring the scan will determine if the patient can tolerate the procedure at the magnet heart rate. If they can, the scan will be completed. If they cannot, the scan will not be performed, the patient will remain enrolled in the study, and the results recorded. e) If the patient experiences new onset atrial fibrillation, bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation, the scan will be stopped immediately, the patient will be removed from the scanner into the holding area, initial device parameters will be restored immediately, and all further treatment will be performed as per ACLS protocol or the discretion of the monitoring physician. 3.6 Follow-up Interrogations Parameter changes requiring multiple follow-up visits Parameter changes that will require multiple follow-up visits to ensure patient safety and/or determine if the change is temporary or permanent: 1) A battery voltage change 0.04 V. 2) Pacing lead impedance change 50 ohms. 3) A shock lead impedance change 3 ohms 4) A P wave decrease of 50% 5) An R wave decrease of 25% 6) A pacing lead threshold increase 0.5 V, at fixed pacing rate and pulse width duration of 0.4 msec Subjects requiring multiple follow-up visits a) If patients had a parameter change as listed in section above, the patient will be asked to return for three follow-up interrogations. Follow-up interrogations will be scheduled: 1. Between 2-7 days after the procedure. V ERSION 03/25/09 25 ROBERT J. RUSSO, MD, PHD

28 2. Three months (± 30 days) after the MRI procedure. 3. Six months (± 30 days) after the MRI procedure. b) Device reprogramming will be based on clinical judgment of the interrogating clinician. c) The results of each follow-up device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. d) Subjects with a significant parameter change who have medical conditions that preclude them from completing multiple follow-up visits will not be required to complete research follow-up interrogations Subjects requiring single follow-up visits a) If no parameter changes requiring multiple follow-up visits occur (see 3.7.1), the patient will be required to return for a single device interrogation between 2-7 months after the MRI procedure. b) Device reprogramming will be based on clinical judgment of the interrogating clinician. c) The results of the 2-7 months device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. d) If the patient returns for a 2-7 month device interrogation at another institution, then the coordinating center will obtain the data from the medical record as previously outlined in the informed consent/release of medical records. 3.7 Variables to be Collected Patient Medical Record 1. Demographics (age, sex, height, weight) 2. Make and model of device and leads 3. Date of device and lead implant 4. Presence of mechanical heart valve 5. Reason for MRI scan 6. History of coronary artery disease 7. History of cardiomyopathy 8. History of diabetes 9. Use of beta blockers/antiarrhythmic medications 10. Ejection fraction 11. History of previous MRI scans in the presence of a pacemaker or ICD V ERSION 03/25/09 26 ROBERT J. RUSSO, MD, PHD

29 3.7.2 MRI Study Procedure Record 1. Date of MRI 2. Body region scanned (Brain, Spine, etc.), coil used 3. Duration of scan (Estimate of RF/SAR exposure) 4. Device setting during scan 5. Loss of capture during scan Device Interrogation 1. Lead Impedance a. Measurement must be performed using the programmed lead polarity (bipolar versus unipolar). b. For all pacing leads c. Shock impedance for ICD leads including SVC and RV coils when present 2. Lead Threshold a. Capture management algorithms must be disabled. b. Threshold measurements must be performed using the programmed lead polarity (bipolar versus unipolar). c. Measured amplitude at the fixed pulse width of 0.4 ms for each lead d. If the pulse width cannot be safely decreased to 0.4 ms for testing, the amplitude threshold test will be performed at the programmed pulse width both pre and postscan. 3. Battery Voltage 4. P/R Wave Amplitude measured at a pacing rate of 40 bpm if there is an intrinsic rhythm 5. Induced arrhythmia (new onset atrial fibrillation, bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation) 3.8 Primary Outcomes Significant Parameter Changes during or immediately after MRI Scan, or at clinical follow-up: 1. Change in Lead Impedance a. Increase or decrease in pacing lead impedance 50 Ω b. Increase or decrease in shock lead impedance 3 Ω. 2. Change in Lead Threshold a. Increase in pacing threshold ms b. Any increase at a wider pulse width. 3. Change in P/R Wave Amplitude a. Decrease in P wave measurement 50%. b. Decrease in R wave measurement 25%. 4. Loss of capture during scan V ERSION 03/25/09 27 ROBERT J. RUSSO, MD, PHD

30 5. Induced Arrhythmia (new onset atrial fibrillation, bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation) 6. Device failure requiring generator replacement 7. Lead failure requiring replacement 3.9 Secondary Outcomes Significant Parameter Changes during or immediately after MRI Scan, or at clinical follow-up: 1. Any increase or decrease in Lead Threshold 2. Any increase or decrease in Battery Voltage 0.04V 3. Any inability to perform the scan because the patient did not tolerate reprogramming the pacing functions of the device to VOO/DOO 3.10 Reporting Events Reporting Adverse Events The following outcomes will be considered adverse events, and a description of the event will be reported to the Coordinating Center at Green Hospital within 48 hours of the event. 1. Death 2. Electrical reset-to-on 3. Loss of pacemaker capture for patients programmed to an asynchronous mode (VOO, DOO). 4. New onset atrial fibrillation 5. Ventricular fibrillation 6. Syncope 7. Device failure requiring immediate generator or lead replacement. Any Unexpected Adverse Device Effects (UADE) observed as a result of the MRI will be reported by the site investigator to the reviewing IRB and the coordinating center as soon as possible but no later than 10 working days after the investigator first learns of the effect Reporting Protocol Deviations Protocol limitations or follow-up visits that establish continued safety of a research procedure that are not performed as scheduled or as described will be reported to the reviewing IRB and to the Coordinating Center, within five (5) working days of their occurrence or within five (5) working days of the investigator becoming aware of their occurrence. V ERSION 03/25/09 28 ROBERT J. RUSSO, MD, PHD

31 The following procedures not performed will be considered reportable safety protocol deviations and will be reported to the reviewing IRB and to the coordinating center: 1. Subject eligibility for enrollment. 2. Monitoring vital signs during the MRI scan. 3. Interrogating the device before and after the MRI scan. 4. Setting device functions appropriately for the scan: a. Disable tachycardia therapy functions in ICDs. b. Program pacemaker dependent subjects to DOO/VOO. c. Program pacemaker non-dependent subjects to ODO/OVO. 5. Maintenance of normal operating mode during performance of the MRI scan. 6. One week follow-up interrogation of a device that had a significant parameter change. 4. DATA MANAGEMENT 4.1 Data Collection Electronic case report forms will be developed on a secure, 21 CFR PART 11 compliant, webbased site. Electronic Data Capture will be managed by KIKA Medical Inc. (Boston, MA) using their Veracity web-based software platform. KIKA Medical is ISO 9001:2000 and ISO 13485:2003 certified since October Investigators at participating registry sites will complete an electronic Inclusion/Exclusion, Initial Case Report Forms and any applicable followup forms for each subject visit. The software can identify values that are out of range by flagging the field of entry, and can generate a list of errors. The remote-entry database for this registry will incorporate password-protection and encryption design features such that each site will only be able to view data that they will enter. Investigators will not be able to access data entered by any of the other sites. The Coordinating Center will have access to all submitted data and patient related information required to complete the analysis. 4.2 Data Monitoring Central statistical trial monitoring by the Coordinating Center will be used to check for missing or invalid data. 38 Range checks will be built into the registry database to identify unlikely or implausible values. The Veracity software system provides the coordinating center with the ability to download and monitor data at any time, and can generate reports for data overview to identify issues with data entry. The software will also generate reports of number enrolled at each site, data values, and monitoring reports. V ERSION 03/25/09 29 ROBERT J. RUSSO, MD, PHD

32 5. STATISTICAL CONSIDERATIONS 5.1 Data Analysis Data will be summarized in table form separately for the 1000 pacemaker patients and for the 500 ICD patients. For each patient with a significant parameter change, summary information regarding clinical, device, and MRI descriptors will be provided. Estimated proportions of each type of significant parameter change event will be accompanied by 95% confidence interval upper bounds based on the Score method with continuity correction. 39, 40 Table 2 shows the upper bounds of the 95 percent confidence intervals for possible observed event rates. For example, if there are no observed events in 500 patients, we can be 95% certain that the population event rate is not more than 1%. If there are no observed events in 1000 patients, then we can be 95% certain that the population event rate is not more than 0.5%. The association between the frequency of parameter changes and the following variables will be examined: type of scan, length of time in scanner, single versus multiple scans, type of lead (A, RV, LV, shock), type of device (ICD, Pacemaker), pacing-dependence, time from implant. A control group (see section 2.2.2) will be used to compare the relative frequency of parameter changes in patients with cardiac devices undergoing MRI to patients with cardiac devices not undergoing MRI. Table 2. Upper bound of the 95% confidence interval for possible observed event rates. Upper bound of the 95% confidence interval Observed event rate Based on 500 patients Based on 1000 patients 0% 1.0% 0.5% 1% 2.5% 1.9% 2% 3.8% 3.1% 3% 5.0% 4.3% 4% 6.2% 5.5% 5% 7.4% 6.6% 6% 8.6% 7.7% 7% 9.7% 8.8% 8% 10.8% 9.9% 9% 11.9% 11.0% 10% 13.1% 12.1% V ERSION 03/25/09 30 ROBERT J. RUSSO, MD, PHD

33 5.2 Sample Size A recent FDA post-market approval report ( ) estimated that the mean annual cardiac device replacement rate due to malfunction was 4.6 (±2.2) per 1000 implants for pacemakers, and 20.7 (±11.6) per 1000 pacemakers for ICDs. The estimate of background device failure without an MRI study was used as a guideline to determine an acceptable level of device failure during or after an MRI. If the observed primary outcome event rate of device failure is 0%, we want the upper bound of the 95% confidence interval to be within one percentage point of our estimate for ICDs and within a half-percentage point of our estimate for pacemakers. The minimum sample size needed to do this is 500 patients in the ICD group and 1000 patients in the pacemaker group. In 1000 pacemaker studies, if the observed device failure rate is 0%, the upper bound of the 95% CI will be 0.5%. In 500 ICD studies, if the observed failure rate is 0%, the 95% upper bound will be 1%. Based on the number of MRI studies on patients with cardiac devices that are presently performed at Green Hospital, we expect to enroll 200 subjects at this site in 18 months. By recruiting up to 34 additional sites that are equipped to perform these studies, we expect to enroll a total of 1500 subjects (1000 with pacemakers and 500 with ICDs) during the enrollment period. If a patient returns on a subsequent day for repeat MRI, then the data will be entered as a unique case. 6. RISK ANALYSIS 6.1 Justification for Investigation The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. MR examination of patients with permanent implanted cardiac devices will only be performed if there are highly compelling circumstances and when the benefits clearly outweigh the risks in the opinion of the ordering physician. Completion of the study Inclusion/Exclusion form by the participating physician will document that the ordering physician has requested the present non-thoracic MRI study as the clinically indicated diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and has been selected independent of this research protocol. Enrolling in the study will not add any additional physical risk to the patient. V ERSION 03/25/09 31 ROBERT J. RUSSO, MD, PHD

34 The results of this registry will provide the medical community with an accurate assessment of risk to patients and provide a protocol allowing the safe utilization of MRI as a diagnostic tool in patients with implantable cardiac devices when indicated. It will benefit the community by providing more patients with implantable devices access to the best diagnostic tools available. 6.2 Risks a) Risks associated with MRI with cardiac devices: 1. Pacemaker or ICD dysfunction 2. Pacemaker or ICD damage 3. Arrhythmia 4. Death b) Serious adverse events associated with MRI in patients with cardiac devices are rare, and the majority of cases that have been reported resulted from failure to follow established safety guidelines. 1, 9 No deaths have been reported in studies in which patients were deliberately scanned and properly monitored 1, and occurrence of arrhythmia is very infrequent. c) Changes in device parameters such as pacing thresholds, battery voltage, and lead impedance are not considered serious risk to the subject. Limited data is available on the incidence of such parameter changes, and it is the purpose of this study to generate this data. Previous studies have reported the incidence of significant changes in pacing threshold after MRI scans to be between 3-10% (See section 2.2 and 2.3). d) Device interrogations do not pose any risk to the subject. e) The risk of confidentiality breach is extremely low as the investigators are the only ones with access to the data, and the data will be secured in a password-protected computer. 6.3 Risk Management Procedures The American Heart Association Recommendations for the Performance of Magnetic Resonance Examinations in Patients with Pacemaker of Implantable Cardioverter-Defibrillators will be followed (Appendix F). 1 a) ACLS trained personnel and a crash cart, including a non-mri compatible defibrillator and transcutaneous pacemaker, will be available throughout the procedure to respond to an adverse clinical event. b) All patients will be monitored throughout the procedure with continuous cardiac rhythm recording and pulse oximetry. In addition, a blood pressure will be obtained at 10 minute intervals. c) To limit the risk of MR imaging: Examinations will be limited to non-thoracic studies, using normal, normal operating mode and gradient switching speeds. V ERSION 03/25/09 32 ROBERT J. RUSSO, MD, PHD

35 d) A physicist with knowledge of clinical magnetic resonance imaging will not be in attendance during the examination. While the presence of a physicist is recommended in the ACC/AHA guidelines, the number of persons with this skill set is severely limited and would not be feasible for a large scale multicenter protocol. In addition, the present protocol is meant to represent real world medical practice where technical staff would not be available at all but a few institutions. e) To minimize the risk of dysfunction and arrhythmia associated with the MRI scan: 1. Pacemaker output will be turned off or set to pace continually and not to respond to external input. 2. For subjects with ICDs, defibrillation (shock) function will be disabled. 3. MRI scans will be limited to non-thoracic studies to minimize RF exposure to device. 4. The subject s vital signs will be monitored during the scan, and an external defibrillator is available in the MRI suite. A physician trained in ACLS and pacemaker/icd expertise will be in attendance for the study and will be able to visualize and hear the subject the entire time. A blood pressure cuff, pulse oximeter, and ECG electrodes will be placed. 5. Device parameters will be measured at the post-scan device interrogation, and the device will be reprogrammed to adjust to any changes. f) To prevent breach of confidentiality, data will be kept in a password-protected computer in a locked research office. No personal identifiers will be released. The results of the research may be published or presented, but subjects will remain anonymous. The effectiveness of these measures is high. g) Any Unexpected Adverse Device Effects (UADE) observed as a result of the MRI will be reported by the site investigator to the reviewing IRB and the coordinating center as soon as possible but no later than 10 working days after the investigator first learns of the effect. The coordinating center will evaluate the event (See Appendix A2). to determine if any modifications are needed to the protocol or if the investigation should be terminated. The results of the evaluation will be reported to the FDA, all reviewing IRBs, participating investigators, and cardiac device vendors, within 10 working days after the coordinating first receives notice of the effect. 7. DESCRIPTION OF THE DEVICE Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. V ERSION 03/25/09 33 ROBERT J. RUSSO, MD, PHD

36 8. STUDY MONITORING 8.1 Name and Address of Monitor: Robert J. Russo, MD Division of Cardiovascular Diseases North Torrey Pines Road La Jolla, CA Overview of Study Monitoring Plan This monitoring schedule may be revised based on accrual rate, history of protocol deviations or non-compliance with GCPs, magnitude of data corrections required and/or IRB request. See APPENDIX A1: Study Monitoring Plan for details Site visits Site visits may be conducted and will be limited to one visit during the course of the study that will be generally scheduled within one month of enrollment of the 10 th patient at that site, or prior to one year of initiation of the study whichever occurs first. At each site visit: a) The protocol will be reviewed with MRI technical staff, and the performing cardiologist to: 1. Verify the clinical site has followed the approved protocol 2. Ensure the trial staff is adequately informed about the trial and has not delegated responsibilities to unauthorized individuals. b) Medical records will be reviewed to: 1. Verify that only eligible subjects are enrolled. 2. Determine whether all unanticipated adverse device effects are reported appropriately. c) Study records will be reviewed to: 1. Determine all essential documents are maintained. 2. Verify trial records are accurate, complete, and current Remote monitoring Remote study monitoring will conducted from the Coordinating Center. Data entry will be monitored monthly. We feel that remote monitoring is sufficient for this study for the following reasons: a) This is an observational study and the data generated from this trial will be used for scientific purposes and not for product labeling changes. V ERSION 03/25/09 34 ROBERT J. RUSSO, MD, PHD

37 b) The pacemakers and ICD devices in this study were previously implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant c) The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. Enrolling in the study will not add any additional physical risk to the patient. Completion of the Inclusion/Exclusion form by the participating study physician will document that the ordering physician has requested a non-thoracic MRI study as the diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and that the imaging study has been selected independent of this research protocol. d) Source documents will be forwarded by the participating sites to the coordinating center: 1. Signed investigator agreement 2. A copy of a CV of each investigator 3. Copy of each site IRB approved protocol and informed consent 4. Hard copies of device interrogation print-outs for each subject 5. Copy of signed consent forms for each subject e) Detailed written instructions of the protocol to be used to acquire complete interrogation data during the MRI procedure will be provided to investigators. All primary outcomes of the study are recorded on the printed interrogation outputs that will be forwarded to the coordinating center. Thus, the source documents needed to verify the primary outcome variables will be available for review at the Coordinating Center. f) Remote monitoring of electronic data entry will be conducted via a password protected data base that allows remote monitoring of subject enrollment, data entry, and subject follow-up tracking. Electronic Data Capture will be managed by KIKA Medical Inc. (Boston, MA) using their Veracity web-based software platform. KIKA Medical is ISO 9001:2000 and ISO 13485:2003 certified since October Using the Veracity software, electronic entries can be compared to these source documents, and any entries that differ from the source documents will be marked for inquiry. The program will be used to generate monitoring reports. 8.3 Registry Reports a) Monthly Registry Report. The study Statistician will prepare monthly trial reports for review by the Lead Investigator, and the Data Safety Monitoring Board. b) Annual Registry Report. The study Statistician will prepare yearly summary reports that will be sent to the site investigators summarizing numbers of patients enrolled, reasons for MRI scans, and any adverse events noted. V ERSION 03/25/09 35 ROBERT J. RUSSO, MD, PHD

38 c) Final Registry Report and Publications. A final report will be sent to the site investigators with the results of the registry. The Lead Investigator will submit a manuscript on behalf of the investigators at the participating centers with the registry final results. 9. MANUFACTURING INFORMATION Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 10. INVESTIGATOR INFORMATION 10.1 Site Selection and Training Sites will be selected for participation in the registry based on: 1) Experienced clinical/academic centers with expertise in MR imaging and electrophysiology 2) Sufficient MRI volume to enroll cases in a one-year period 3) Availability of competent clinical support staff 4) Cardiologist with working knowledge of pacemaker and ICD function and willingness to participate in the study. A detailed Investigator s Manual will be supplied to all enrolling institutions. The manual will include a set of step-by-step instruction for the pre- and post-procedure interrogation of the pacemaker or ICD Qualifications for the participating clinical site Principal Investigator 1) Board certified general cardiologist or a cardiologist with subspecialty training in cardiac electrophysiology 2) Able to interrogate an implanted cardiac device with the assistance of an industry device representative 3) Able to program/reprogram implanted cardiac device parameters with the assistance of an industry device representative 4) Able to place and utilize a temporary external cardiac pacemaker 5) Hospital privileges to place a temporary transvenous cardiac pacemaker V ERSION 03/25/09 36 ROBERT J. RUSSO, MD, PHD

39 10.3 Clinical Study Agreement No investigator will be added to the study until the agreement is signed. See Appendix C: Sample Clinical Study Agreement. 11. IRB INFORMATION Institutional Review Board approval will be required of all sites prior to enrolling any patients in the registry. Patient information collected for the registry will be protected in accordance with the standards sets forth by the Health Insurance Portability and Accountability Act (HIPAA). 12. SALES INFORMATION Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 13. INVESTIGATIONAL LABELING Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 14. INFORMED CONSENT MATERIALS The informed consent includes all risks specified by the American Heart Association in the Recommendations for the Performance of MR Examinations in Patients with Pacemakers and ICDs. 1 See Appendix B: Sample Consent V ERSION 03/25/09 37 ROBERT J. RUSSO, MD, PHD

40 15. DATA SAFETY MONITORING BOARD (DSMB) A Data Safety Monitoring Board (DSMB) composed of three Green Hospital cardiologists with expertise in electrophysiology will review the accumulated data monthly to determine if any trends are noted regarding adverse events. The DSMB will be established following the FDA Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees (2006). The DSMB will meet quarterly and will review the data stripped of any personal identifiers. If, in the opinion of the DSMB, information becomes known that could benefit subgroups of patients undergoing MRI, that information will be shared with the site investigators. 16. TIMELINE It is anticipated that clinical site selection will begin in February Patient enrollment is expected to begin in March The initial abstract submission of preliminary results will be in October 2010, for presentation at the American College of Cardiology Annual Scientific Sessions March Additional presentations will be made at the American Heart Association Scientific Sessions November 2010 and the American College of Cardiology Scientific Sessions March Presentation of final results is anticipated at American Heart Association, Annual Scientific Session in November V ERSION 03/25/09 38 ROBERT J. RUSSO, MD, PHD

41 17. REFERENCES 1. Levine GN, Gomes AS, Arai AE, Bluemke DA, Flamm SD, Kanal E, Manning WJ, Martin ET, Smith JM, Wilke N, Shellock FS. Safety of magnetic resonance imaging in patients with cardiovascular devices: an American Heart Association scientific statement from the Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Council on Cardiovascular Radiology and Intervention: endorsed by the American College of Cardiology Foundation, the North American Society for Cardiac Imaging, and the Society for Cardiovascular Magnetic Resonance. Circulation. 2007;116(24): Shinbane JS, Colletti PM, Shellock FG. MR in patients with pacemakers and ICDs: Defining the issues. J Cardiovasc Magn Reson. 2007;9(1): Faris OP, Shein M. Food and Drug Administration perspective: Magnetic resonance imaging of pacemaker and implantable cardioverter-defibrillator patients.[comment]. Circulation. 2006;114(12): Faris OP, Shein MJ. Government viewpoint: U.S. Food & Drug Administration: Pacemakers, ICDs and MRI.[comment]. Pacing & Clinical Electrophysiology. 2005;28(4): Maisel WH, Moynahan M, Zuckerman BD, Gross TP, Tovar OH, Tillman D-B, Schultz DB. Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports.[see comment]. JAMA. 2006;295(16): Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y, American Heart Association Statistics Committee and Stroke Statistics S. Heart disease and stroke statistics update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e Zhan C, Baine WB, Sedrakyan A, Steiner C. Cardiac device implantation in the United States from 1997 through 2004: a population-based analysis. Journal of General Internal Medicine. 2008;23 Suppl 1: Kalin R, Stanton MS. Current clinical issues for MRI scanning of pacemaker and defibrillator patients. Pacing & Clinical Electrophysiology. 2005;28(4): Roguin A, Schwitter J, Vahlhaus C, Lombardi M, Brugada J, Vardas P, Auricchio A, Priori S, Sommer T. Magnetic resonance imaging in individuals with cardiovascular implantable electronic devices. Europace. 2008;10(3): Shellock FG, Fischer L, Fieno DS. Cardiac pacemakers and implantable cardioverter defibrillators: in vitro magnetic resonance imaging evaluation at 1.5-tesla. Journal of Cardiovascular Magnetic Resonance. 2007;9(1): Martin ET, Coman JA, Shellock FG, Pulling CC, Fair R, Jenkins K. Magnetic resonance imaging and cardiac pacemaker safety at 1.5-Tesla. J Am Coll Cardiol. 2004;43(7 (Print)): V ERSION 03/25/09 39 ROBERT J. RUSSO, MD, PHD

42 12. Sommer T, Naehle CP, Yang A, Zeijlemaker V, Hackenbroch M, Schmiedel A, Meyer C, Strach K, Skowasch D, Vahlhaus C, Litt H, Schild H. Strategy for safe performance of extrathoracic magnetic resonance imaging at 1.5 tesla in the presence of cardiac pacemakers in non-pacemaker-dependent patients: a prospective study with 115 examinations.[see comment]. Circulation. 2006;114(12): Nazarian S, Roguin A, Zviman MM, Lardo AC, Dickfeld TL, Calkins H, Weiss RG, Berger RD, Bluemke DA, Halperin HR. Clinical utility and safety of a protocol for noncardiac and cardiac magnetic resonance imaging of patients with permanent pacemakers and implantable-cardioverter defibrillators at 1.5 tesla. Circulation. 2006;114(12): Iberer F, Justich E, Stenzl W, Tscheliessnig KH, Kapeller J. Nuclear magnetic resonance imaging of a patient with implanted transvenous pacemaker. Herz. 1987;7: Alagona P, Jr., Toole JC, Maniscalco BS, Glover MU, Abernathy GT, Prida XE. Nuclear magnetic resonance imaging in a patient with a DDD Pacemaker. Pacing & Clinical Electrophysiology. 1989;12(4 Pt 1): Inbar S, Larson J, Burt T, Mafee M, Ezri MD. Case report: nuclear magnetic resonance imaging in a patient with a pacemaker. American Journal of the Medical Sciences. 1993;305(3): Gimbel JR, Johnson D, Levine PA, Wilkoff BL. Safe performance of magnetic resonance imaging on five patients with permanent cardiac pacemakers. Pacing Clin Electrophysiol. 1996;19(6 (Print)): Garcia-Bolao I, Albaladejo V, Benito A, Alegria E, Zubieta JL. Magnetic resonance imaging in a patient with a dual-chamber pacemaker. Acta Cardiologica. 1998;53(1): Fontaine JM, Mohamed FB, Gottlieb C, Callans DJ, Marchlinski FE. Rapid ventricular pacing in a pacemaker patient undergoing magnetic resonance imaging. Pacing & Clinical Electrophysiology. 1998;21(6): Anfinsen O-G, Berntsen RF, Aass H, Kongsgaard E, Amlie JP. Implantable cardioverter defibrillator dysfunction during and after magnetic resonance imaging. Pacing & Clinical Electrophysiology. 2002;25(9): Fiek M, Remp T, Reithmann C, Steinbeck G. Complete loss of ICD programmability after magnetic resonance imaging.[see comment]. Pacing & Clinical Electrophysiology. 2004;27(7): Rozner MA, Burton AW, Kumar A. Pacemaker complication during magnetic resonance imaging.[comment]. J Am Coll Cardiol. 2005;45(1): ; reply Roguin A, Donahue JK, Bomma CS, Bluemke DA, Halperin HR. Cardiac magnetic resonance imaging in a patient with implantable cardioverter-defibrillator. Pacing Clin Electrophysiol. 2005;28(4 (Print)): Wollmann C, Grude M, Tombach B, Kugel H, Heindel W, Breithardt G, Bocker D, Vahlhaus C. Safe performance of magnetic resonance imaging on a patient with an ICD. Pacing & Clinical Electrophysiology. 2005;28(4): V ERSION 03/25/09 40 ROBERT J. RUSSO, MD, PHD

43 25. Naehle CP, Sommer T, Meyer C, Strach K, Kreuz J, Litt H, Lewalter T, Schild H, Schwab JO. Strategy for safe performance of magnetic resonance imaging on a patient with implantable cardioverter defibrillator. Pacing & Clinical Electrophysiology. 2006;29(1): Mikolich JR, Martin ET. Images in cardiovascular medicine. Constrictive pericarditis diagnosed by cardiac magnetic resonance imaging in a pacemaker patient. Circulation. 2007;115(7):e Sommer T, Lauck G, Schimpf R, von Smekal A, Wolke S, Block W, Gieseke J, Schneider C, Funke HD, Schild H. [MRI in patients with cardiac pacemakers: in vitro and in vivo evaluation at 0.5 tesla].[see comment]. Rofo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 1998;168(1): Sommer T, Vahlhaus C, Lauck G, von Smekal A, Reinke M, Hofer U, Block W, Traber F, Schneider C, Gieseke J, Jung W, Schild H. MR imaging and cardiac pacemakers: in-vitro evaluation and in-vivo studies in 51 patients at 0.5 T.[see comment]. Radiology. 2000;215(3): Vahlhaus C, Sommer T, Lewalter T, Schimpf R, Schumacher B, Jung W, Luderitz B. Interference with cardiac pacemakers by magnetic resonance imaging: are there irreversible changes at 0.5 Tesla?[see comment]. Pacing & Clinical Electrophysiology. 2001;24(4 Pt 1): Heatlie G, Pennell DJ. Cardiovascular magnetic resonance at 0.5T in five patients with permanent pacemakers. Journal of Cardiovascular Magnetic Resonance. 2007;9(1): Coman JA, Martin ET, Sandler DA, Thomas JR. Implantable Cardiac Defibrillator Interactions with Magnetic Resonance Imaging at 1.5 Tesla. J Am Coll Cardiol. 2004;43:138A. 32. Del Ojo JL, Moya F, Villalba J, Sanz O, Pavon R, Garcia D, Pastor L. Is magnetic resonance imaging safe in cardiac pacemaker recipients? Pacing & Clinical Electrophysiology. 2005;28(4): Gimbel JR, Bailey SM, Tchou PJ, Ruggieri PM, Wilkoff BL. Strategies for the safe magnetic resonance imaging of pacemaker-dependent patients. Pacing Clin Electrophysiol. 2005;28(10 (Print)): Gimbel JR, Kanal E, Schwartz KM, Wilkoff BL. Outcome of magnetic resonance imaging (MRI) in selected patients with implantable cardioverter defibrillators (ICDs). Pacing Clin Electrophysiol. 2005;28(4 (Print)): Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Jr., Froelich JW, Gilk T, Gimbel JR, Gosbee J, Kuhni-Kaminski E, Lester JW, Jr., Nyenhuis J, Parag Y, Schaefer DJ, Sebek- Scoumis EA, Weinreb J, Zaremba LA, Wilcox P, Lucey L, Sass N, Safety ACRBRPoM. ACR guidance document for safe MR practices: 2007.[see comment]. AJR. 2007;American Journal of Roentgenology. 188(6): Nazarian S, Hansford R, Roguin A, Zviman MM, Lardo AC, Calkins H, Berger RD, Bluemke DA, Halperin HR. Abstract 2803: Clinical Utility of Magnetic Resonance V ERSION 03/25/09 41 ROBERT J. RUSSO, MD, PHD

44 Imaging of Patients with Permanent Pacemakers and Implantable-Cardioverter Defibrillators at 1.5 Tesla. Circulation. 2008;118(18_MeetingAbstracts):S_ Cohen JD, Costa HS, Russo RJ. Abstract 2804: Pacemaker and Implantable Cardioverter Defibrillator Safety for Patients Undergoing Magnetic Resonance Imaging (The MagnaSafe Registry). Circulation. 2008;118(18_MeetingAbstracts):S_ Baigent C, Harrell FE, Buyse M, Emberson JR, Altman DG. Ensuring trial validity by data quality assurance and diversification of monitoring methods. Clin Trials. 2008;5(1): Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods.[see comment]. Statistics in Medicine. 1998;17(8): Tobi H, van den Berg PB, de Jong-van den Berg LT. Small proportions: what to report for confidence intervals? Pharmacoepidemiol Drug Saf. 2005;14(4): V ERSION 03/25/09 42 ROBERT J. RUSSO, MD, PHD

45 Protocol for Pre- and Post-MRI Interrogations 1) Press Interrogate. for initial interrogation ( Quick Start / Interrogate ) a) PRINT programmed settings and patient data from the programmer. 2) Generate NEW interrogation values created at the time of interrogation (not from stored values) for the following parameters: a) Battery Voltage. For BSC/Guidant a value of Good or ERT is given. b) PRINT screen of battery voltage measurement from programmer. c) PACING LEAD IMPEDANCE. d) SHOCK LEAD IMPEDANCE. Perform NEW shock lead impedance measurements if this can be done without a low voltage shock being delivered. e) PRINT screen of impedance measurements from programmer. 3) Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm emerges. a) The patient is dependent if they do not have a stable heart rate when the device is reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic b) PRINT strip of the underlying rhythm from the programmer. 4) For the non-dependent patients only, measure an intrinsic P-WAVE AND R-WAVE. You may use either automatic or manual sensing programmer protocol. a) PRINT strip of the P and R wave electrograms with the measurements. 5) THRESHOLD MEASUREMENTS. IMPORTANT: Use the same pacing rate, pulse width, lead polarity and mode Pre- and Post. a) Perform threshold measurements at 10 beats above the patient s intrinsic rate (if not paced) or 10 beats above the pacing lower rate limit (if paced). Record at what rate the threshold is tested. Testing can be performed in DDD, AAI or VVI mode. If the patient has a competing rhythm, test rate can be increased by 10 bpm until the underlying rhythm is suppressed. b) Test threshold using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased (but this must be recorded on CRF). c) If auto-capture is programmed on, turn the auto-capture off and perform the threshold testing using the routine amplitude decrement mode. When disabling auto-capture, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. d) Record whether the threshold is being tested in a unipolar or bipolar mode. e) PRINT electrograms demonstrating the loss of capture for each lead. 6) PRINT the summary of all of the recorded measurements. 7) Note any reprogramming of device. MagnaSafe Multicenter Registry V ERSION 03/25/09 43 ROBERT J. RUSSO, MD, PHD

46 M AGNAS AFE R EGISTRY D ETAILED P ROCEDURE M ANUAL Before the Scan: Patient is scheduled for a clinically-indicated MRI without acceptable alternative imaging available for a compelling reason by a referring physician. Investigator is notified of potential patient for enrollment. Patient has a permanent pacemaker/icd. If patient has an ICD, they are NOT pacer dependent. Patient is scheduled for a non-thoracic MRI Patient does not have abandoned leads or an abdominal implant. (Optional) Obtain a signed note for the patient chart from the ordering physician indicating: the reason for the MRI is compelling; there is no alternative test available; and the risks and benefits have been preliminarily discussed with the patient. (See Ordering Physician Authorization Letter ) Patient presents 30 minutes prior to MRI to the MRI suite. Patient is screened by MRI staff, routine clinical screening. Clinical informed consent obtained (use site clinical consent for MRI form). Research project described. Inclusion/Exclusion criteria form completed. Patient agrees to be enrolled and is consented for the research project. Research consent signed. Make 3 copies of the signed original. (One copy given to patient, one copy placed in patient chart, one copy to be mailed to coordinating center, and the original placed in research file.) Patient is hooked up to the noninvasive monitor, ECG (3 lead ok), pulse oximetry, BP. Obtain demographic information (top of case report form). Need accurate height and weight to enter into the scanner prior to MRI for accurate SAR calculations. The patient is considered enrolled in the MagnaSafe Registry once they enter the scanner room (when the device is exposed to the magnet). If the patient enters the MRI scanner room, and the scan is not completed for some reason, the protocol and CRFs should still be completed as usual. The patient should be treated as if they completed a scan (the device was exposed to the magnet and the patient is enrolled ). If the patient was consented, but did NOT enter the MRI scanner room for some reason (the device was not exposed to the magnet), they will be considered consented, not enrolled. V ERSION 03/25/09 44 ROBERT J. RUSSO, MD, PHD

47 Pre-Scan Device Interrogation: 1. Interrogate. Press for initial interrogation ( Quick Start / Interrogate ) PRINT programmed settings and patient data from the programmer. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Please note that if the battery voltage reading is ERI, the scan should not be performed. The patient will be considered consented, not enrolled. Note: For Boston Scientific/Guidant pacemakers a value of Good is given. PRINT screen of battery voltage measurement from programmer if possible. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. PRINT screen of impedance measurements from programmer. 5. Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm recovers. 6. The patient is deemed dependent if they do not have a stable intrinsic heart rate when the device is temporarily reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic with a pacing rate less than their programmed lower rate limit. 7. The patient is deemed not dependent if they have a stable intrinsic heart rate and are asymptomatic when the device is temporarily reprogrammed to a lower rate limit of 40 ppm. PRINT strip of the underlying rhythm from the programmer. 8. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). If patient has atrial fibrillation, you do not need to record a P wave even if available. No calculation of a decrease in P V ERSION 03/25/09 45 ROBERT J. RUSSO, MD, PHD

48 wave amplitude should be performed if the patient is in atrial fibrillation even if the programmer is able to measure a P wave. 9. For recording purposes, use the lower value of the range reported for the P and R waves (ie. R wave measures mv, please record 10 ) PRINT strip of the P and R wave electrograms with the measurements if available. If the electrograms are not available, then print the screen of the measurement values. 10. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. It is important that the threshold testing after the MRI is performed at the same rate. Testing can be performed in the DDD, AAI or VVI mode. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Please note that if there is ANY change in the threshold when tested at a pulse width other than 0.4 ms, this will be an event and the patient will be required to return for multiple follow ups. Also record whether the threshold is being tested in a unipolar or bipolar mode. If at all possible, test the threshold using the same polarity programmed for the lead. If Autocapture/Capture Management is programmed on, turn the Autocapture/Capture Management off and perform the threshold testing using the routine amplitude decrement mode. When disabling Autocapture/Capture Management, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. Record on the Case Report Form whether the lead was tested in unipolar or bipolar mode. It is important that the post-scan threshold measurement is performed with the same lead polarity. PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 11. PRINT the summary of all of the recorded measurements. V ERSION 03/25/09 46 ROBERT J. RUSSO, MD, PHD

49 Programming during the MRI: For non-dependent pacemaker patients: 1. Program the device to ODO or OVO. Monitor patient for 5 minutes to ensure that they are not symptomatic. If the patient is symptomatic, they will be considered dependent and you must follow the instructions for dependent pacemaker patients. 2. Turn the magnet response OFF. In some devices, when the pacing is programmed off (ODO/OVO), the magnet response cannot be disabled. The patient should not have a magnet response since pacing is turned off. However, when at all possible, the magnet response should be disabled regardless. If the magnet response cannot be programmed OFF, note this on the case report form. PRINT from the programmer the screen displaying the new programming settings. Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. For dependent pacemaker patients: 1. Program the device to DOO or VOO at the previously programmed lower rate limit. Monitor the patient for 5 minutes to ensure that these settings are tolerated. The pacing rate may be increased in 10 ppm intervals if necessary for suppression of any ectopy. 2. Turn the magnet response off. If the magnet response cannot be disabled, the observing physician must determine if the patient can tolerate the magnet pacing rate for the duration of the MRI examination. If the patient cannot tolerate the magnet pacing rate, they will not enter the scanner and will be considered consented, not enrolled. PRINT from the programmer the screen displaying the new programming settings. Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. For ICD patients: If an ICD patient is determined at this point to be pacing dependent in the setting of having an ICD, they cannot be enrolled in the study and will be considered consented, not enrolled. The patient cannot enter the magnet. For non-dependent ICD patients: 1. Program the pacing to OFF (ODO or OVO). 2. Turn all tachycardia therapies to off. PRINT from the programmer the screen displaying the new programming settings. V ERSION 03/25/09 47 ROBERT J. RUSSO, MD, PHD

50 Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. It is also helpful to print a summary page of the changes made if available (usually found under the Reports menu). This will ensure that you have noted all of the programming changes made during the scan and all of the original parameters are restored following the scan.be sure the Demographics information and MRI scanner information is filled out on the Case Report Form. Device information from the interrogation can be filled out on the Case Report form. The MRI Scanner: 1. Patient enters the MRI scanner and is positioned for the scan. Ensure that the monitor is displaying the ECG, pulse oximetry and blood pressure when the table moves into the tube. 2. Please note the time when the patient enters the scanner room. 3. Blood pressure, oxygen level saturation, and pulse should be monitored throughout the exam and values recorded at the beginning, middle and end of the exam on the Case Report Form. 4. Take initial heart rate, pulse ox, and blood pressure readings and enter on the case report form. 5. Complete other information on the Case Report Form: MRI Procedure Body region scanned, contrast used, reason for the scan. 6. Initiate scan. 7. Many sequences will cause interference on the ECG. Therefore, it is important that the pulse oximeter is in place at all times and a sufficient wave form is present to monitor the patient s pulse. 8. Monitor the patient for: death, electrical reset to on, loss of pacemaker capture for patients programmed VOO or DOO, a new episode of atrial fibrillation that occurs after the patient enters the MRI scanner room, ventricular tachycardia or ventricular fibrillation after the patient enters the MRI scanner room, and syncope. Immediate intervention or ACLS protocols should be followed as necessary. If any of these events occur, the Adverse Event Form must be filled out and filed with the coordinating center and your institutional IRB. 9. There is a risk that the magnet will cause the device to undergo a hard reset and enter backup mode. In patients who are dependent and reprogrammed to VOO, this will result in a reversion to VVI mode. The magnet can then inhibit pacing and the patient V ERSION 03/25/09 48 ROBERT J. RUSSO, MD, PHD

51 will be asystolic. This must be recognized immediately and the patient removed from the scanner. The device should no longer be inhibited when the patient is removed from the scanner room. The procedure should be aborted at this point and the device reprogrammed to initial values. A full follow up interrogation should be performed as described below and the patient will be followed according to the multiple follow up schedule. If this occurs, the Adverse Event Form must be filled out and filed with the coordinating center and your institutional IRB. Please note that St. Jude Medical devices will require engineering assistance to reprogram the device. Please place a call immediately to bradycardia technical services and they will guide you through the reset process. 10. Monitor the patient for pre-syncope, a heart rate <40 bpm with symptoms of bradycardia, and other patient symptoms and complaints. These should be noted on the Case Report Form if they occur. 11. Note on the Case Report Form the scan sequences used. 12. Instruct your technicians that normal operating mode should be maintained if at all possible. Note if the SAR limit is reached on any scan. Note which scan sequence was being performed when SAR limit was reached. If normal operating mode is maintained, note the parameter that is changed. If it is necessary to change to First Level Controlled Operating Mode, this should be recorded. If SAR is reached on multiple sequences, please record each one and the steps taken regarding Normal Operating Mode or First Level Controlled Operating Mode. Note: If it is necessary to change to First Level Controlled Operating Mode, a Study Deviation form must be filled out. 13. Take mid-scan readings of heart rate, pulse ox, and blood pressure and enter on the case report form. 14. Take end-of-scan readings of heart rate, pulse ox, and blood pressure and enter on the case report form. 15. Once the scan is completed, the patient is removed from the MRI scanner room and the follow up interrogation is performed immediately. 16. All of the following events are considered adverse events if they occur during the MRI scan: a. Death b. Electrical reset-to-on c. Loss of pacemaker capture for patients programmed to an asynchronous mode (VOO, DOO) d. New onset atrial fibrillation occurring during the MRI scan e. Ventricular tachycardia V ERSION 03/25/09 49 ROBERT J. RUSSO, MD, PHD

52 f. Ventricular fibrillation g. Device failure requiring immediate generator or lead replacement. Note: If any of these Adverse Event events occur, an Adverse Event Form must be completed, and the event reported to the Coordinating Center within 48 hours of the event. Report to the reviewing IRB according to site policy. These patients will require multiple follow-up visits. Note: If any UADE (unanticipated adverse device effects) occur (any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity or degree of incidence in the investigational plan or application) then an Adverse Event Form must be filled out and filed as soon as possible, but no later than 10 business days after the investigator first learns of the effect. Report to the reviewing IRB according to site policy. These patients will require multiple follow-up visits. V ERSION 03/25/09 50 ROBERT J. RUSSO, MD, PHD

53 Post-Scan Device Interrogation: 1. Restore initial parameters. Ensure that tachycardia therapies are all turned on and restored to initial detection criteria. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: If the battery voltage decreased by 0.04 V, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. Note: For Boston Scientific/Guidant pacemakers a value of Good is given. A repeat measurement will either be listed as Good or ERT. If ERT is noted after the scan, please mark this as a battery voltage change of 0.04 V and schedule the patient for multiple follow up visits. PRINT screen of battery voltage measurement from programmer. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: If the pacing lead impedance in any lead changed by 50 Ω, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. Note: If the shock lead impedance changed by 3 Ω, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT screen of impedance measurements from programmer. 5. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). V ERSION 03/25/09 51 ROBERT J. RUSSO, MD, PHD

54 6. For recording purposes, use the lower range of the reported P and R waves (ie. R wave measures mv, please record 10 ). If patient has atrial fibrillation, you do not need to record a P wave even if available. No calculation of a decrease in P wave amplitude should be performed if the patient is in atrial fibrillation even if the programmer is able to measure a P wave. Note: If the P wave measurement decreased by 50%, this is a significant event. If the R wave measurement decreased by 25%, this is a significant event. These must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT strip of the P and R wave electrograms with the measurements. 7. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. Testing can be performed in the DDD, AAI or VVI mode. It is important that the threshold testing after the MRI is performed at the same rate, with the same pulse width, and in the same mode as before the MRI, if at all possible. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Also record whether the threshold is being tested in a unipolar or bipolar mode. The threshold should be tested using the same polarity as used in the pre-mri interrogation. If Autocapture/Capture Management is programmed on, turn the Autocapture/Capture Management off and perform the threshold testing using the routine amplitude decrement mode. When disabling Autocapture/Capture Management, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. It is important to duplicate the pre-scan threshold testing (pacing rate, pulse width, and lead polarity). V ERSION 03/25/09 52 ROBERT J. RUSSO, MD, PHD

55 Note: If both the pre-mri and post-mri threshold tests are performed at a pulse width of 0.4 ms and there is a decrease in the threshold in any lead by 0.5 V, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. If the pre-mri and post-mri threshold tests are performed at a pulse width other than 0.4 ms and there is any decrease in the threshold in any lead, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 8. PRINT the summary of all of the recorded measurements. 9. PRINT a summary of the current programmed parameters. If there were any changes made to the programming of the device, this must be listed on the Case Report Form under Other Outcomes. 10. Determine if there were any changes to the device parameters that require multiple follow-up visits: A pacing lead threshold increase 0.5 V when measured at 0.4 ms. (If the threshold had to be tested at a pulse width other than 0.4 ms, then ANY increase in the threshold will require multiple follow-up visits.) Decrease in battery voltage 0.04 V A pacing lead impedance change of 50 ohms A shock lead impedance change of 3 ohms A P wave decrease of 50% An R wave decrease of 25% 11. Schedule single or multiple follow-up visits as needed. 12. Record CRF data in online data base entry system within 2 days. 13. Report any Adverse Events or UADE to the Coordinating Center and reviewing IRB. 14. Report Protocol Deviations that might affect the safety of subjects to the Coordinating Center and reviewing IRB 15. Mail hard copies of consents and interrogation reports to the coordinating center by FedEx. V ERSION 03/25/09 53 ROBERT J. RUSSO, MD, PHD

56 Follow-up Visit Interrogation: 1. Interrogate. Press for initial interrogation ( Quick Start / Interrogate ) PRINT programmed settings and patient data from the programmer. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: For Boston Scientific/Guidant pacemakers a value of Good or ERT is given. PRINT screen of battery voltage measurement from programmer if possible. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. PRINT screen of impedance measurements from programmer. 5. Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm recovers. 6. The patient is deemed dependent if they do not have a stable intrinsic heart rate when the device is temporarily reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic with a pacing rate less than their programmed lower rate limit. 7. The patient is deemed not dependent if they have a stable intrinsic heart rate and are asymptomatic when the device is temporarily reprogrammed to a lower rate limit of 40 ppm. PRINT strip of the underlying rhythm from the programmer. 8. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). If patient has atrial fibrillation, you do not need to record a P wave even if available. 9. For recording purposes, use the lower value of the range reported for the P and R waves (ie. R wave measures mv, please record 10 ) V ERSION 03/25/09 54 ROBERT J. RUSSO, MD, PHD

57 PRINT strip of the P and R wave electrograms with the measurements if available. If the electrograms are not available, then print the screen. 10. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. Testing can be performed in the DDD, AAI or VVI mode. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Also record whether the threshold is being tested in a unipolar or bipolar mode. If autocapture is programmed on, turn the autocapture off and perform the threshold testing using the routine amplitude decrement mode. When disabling autocapture, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. Whenever possible, try to duplicate the threshold testing performed at the time of the MRI (pacing rate, pulse width, and lead polarity). PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 11. PRINT the summary of all of the recorded measurements. 12. Confirm any follow-up visits that were required. 13. Record CRF data in remote data base entry system within 2 days. 14. Report any Adverse Events or UADE to the Coordinating Center and reviewing IRB. 15. Report Protocol Deviations that might affect the safety of subjects to the Coordinating Center and reviewing IRB 16. Mail hard copies of consents and interrogation reports to the coordinating center by FedEx. V ERSION 03/25/09 55 ROBERT J. RUSSO, MD, PHD

58 The MagnaSafe Registry: Determining the Risks of Clinically-Indicated MRI for Patients with Pacemakers and Implantable Cardioverter Defibrillators Protocol Version: February 2012 Principal Investigator: Robert J. Russo, MD, PhD, FACC VERSION R OBERT J. R USSO, MD

59 R E G I S T R Y S Y N O P S I S... 5 A B B R E V I A T I O N S I N T R O D U C T I O N Specific Aim Background and Significance MRI in Patients with Cardiac Devices Preliminary Data Capability of the Principal Investigator I N V E S T I G A T I O N A L P L A N Study Design Baseline Data on Device Parameter Changes Clinical experience: device parameter changes in subjects undergoing MRI Sub-study: device parameter changes in subjects without MRI Anticipated Observations Device failure Temporary and permanent device reprogramming Anticipated rates of clinically significant events Inclusion Criteria Exclusion Criteria Conditions which do not require exclusion from the present protocol Transdermal drug patches with metallic backing STUDY PROTOCOL Overview MRI Protocol Specific MRI Precautionary Procedures During the Performance of Clinically- Indicated Scanning Protocol for the Performance of MRI VERSION R OBERT J. R USSO, MD

60 3.3 Pacemaker Device Interrogation Protocol Pacemaker pre-scan interrogation Pacemaker programming during the scan Pacemaker post-scan interrogation ICD Device Interrogation Protocol ICD pre-scan interrogation ICD post-scan interrogation Monitoring During the Scan Follow-up Interrogations Subjects requiring multiple follow-up visits Subjects requiring single follow-up visits Variables to be Collected Patient Medical Record MRI Study Procedure Record Device Interrogation Primary Outcomes Secondary Outcomes Reporting Events Reporting Adverse Events Reporting Protocol Deviations D A T A M A N A G E M E N T Data Collection Data Monitoring STATISTICAL CONSIDERATIONS Data Analysis Sample Size VERSION R OBERT J. R USSO, MD

61 6. R I S K A N A L Y S I S Justification for Investigation Risks Risk Management Procedures D E S C R I P T I O N O F T H E D E V I C E S T U D Y M O N I T O R I N G Name and Address of Monitor: Overview of Study Monitoring Plan Site visits Remote monitoring Registry Reports M A N U F A C T U R I N G I N F O R M A T I O N I N V E S T I G A T O R I N F O R M A T I O N Site Selection and Training Qualifications for the participating clinical site Principal Investigator Clinical Study Agreement I N S T I T U T I O N A L R E V I E W B O A R D I N F O R M A T I O N S A L E S I N F O R M A T I O N I N V E S T I G A T I O N A L L A B E L I N G I N F O R M E D C O N S E N T M A T E R I A L S D A T A S A F E T Y M O N I T O R I N G B O A R D T I M E L I N E R E F E R E N C E S VERSION R OBERT J. R USSO, MD

62 REGISTRY SYNOPSIS Study Title Princpal investigator Determining the Risks of Clinically-Indicated MRI for Patients with Pacemakers and Implantable Cardioverter Defibrillators: The MagnaSafe Registry Robert J. Russo, MD, PhD, La Jolla, CA Purpose To create a multicenter registry designed to prospectively document the safety of Clinically-Indicated Magnetic Resonance Imaging (MRI) studies at 1.5 Tesla performed in patients with pacemakers or implantable cardioverter defibrillators (ICDs). Study design This study will be a multicenter, prospective registry of patients with implanted cardiac devices who undergo MRI for clinical purposes. The incidence of device parameter changes or adverse events will be recorded. Number of subjects 1500 subjects (1000 with pacemakers and 500 with ICDs) Number of sites Up to 35 sites Duration of patient participation Variable; 6 months or less Duration of study Approximately 5 years Study Coordinator Heather Costa, PhD Study Biostatistician Patricia Silva, MA VERSION R OBERT J. R USSO, MD

63 ABBREVIATIONS ACLS bpm DOO DSMB ECG ICD MRI RF RV SAR SVC VOO Advanced cardiac life support Beats per minute Asynchronous pacing mode using both atrial and ventricular leads Data Safety Monitoring Board Electrocardiogram Implantable cardioverter defibrillator Magnetic resonance imaging Radiofrequency Right ventricle Specific adsorption rate Superior vena cava Asynchronous pacing mode using only the ventricular lead VERSION R OBERT J. R USSO, MD

64 1. INTRODUCTION 1.1 Specific Aim Specific Aim: To create a multi-center registry designed to prospectively document the safety of non-thoracic magnetic resonance imaging (MRI) studies for patients with pacemakers or implantable cardioverter defibrillators (ICDs). Until recently, the presence of a permanent pacemaker or an implantable cardioverter defibrillator (ICD) has been an absolute contraindication for the performance of magnetic resonance imaging (MRI). A number of small studies, with a total of 350 patients, have shown that MRI can be performed with minimal risk in patients with pacemakers or ICD s implanted after However, controversy persists as to the routine performance of MRI for patients with implanted cardiac devices, 1, 2 and the safety of current pre and post-imaging device interrogation protocols have not been sufficiently evaluated to allow routine clinical use. To determine the risk of non-cardiac/non-thoracic MRI for patients with implanted cardiac devices, prospective studies documenting the outcome of a large number of cases are needed 3, 4 The aim of the present protocol is to prospectively determine the adverse event rate of non-thoracic MRI for patients with implanted cardiac devices by collecting pre- and post-mri device interrogations in a multi-center registry. The results of this registry may be used to change the recommendations of the American Heart Association and the American College of Cardiology and to establish a clinical protocol for the performance of clinically-indicated MR imaging for patients with implanted cardiac devices. 1.2 Background and Significance Magnetic resonance is the imaging modality of choice for the diagnosis of many diseases of the brain, spinal cord, and musculoskeletal system. For some disease states, no acceptable alternative diagnostic imaging method is available. The advantages of MR imaging include the lack of exposure to ionizing radiation (x-rays), and the use of gadolinium which is a non-nephrotoxic contrast agent. Allergic reactions to gadolinium-based contrast are very rare. In addition, patients do not have to abstain from food prior to MRI; a concern for elderly patients and those with diabetes mellitus. 300, , , , ,000 50, Pacemaker AICD Figure 1. National estimates of cardiac device implantation (data from Zhan et al. 2008) VERSION R OBERT J. R USSO, MD

65 The number of patients living with permanent pacemakers or ICDs in the United States is increasing dramatically as a result of expanded indications (Figure 1). Between 1990 and 2005, an estimated 2.8 million pacemakers and 690,000 ICDs were implanted in the United States. 5-7 The number of implanted devices continues to increase without an apparent plateau. As the number of implanted cardiac devices is increasing, the clinical indications for MRI are expanding as well (Figure 2). Marketing research estimates that approximately 27.5 million MRI procedures were completed in 2007 (The Medical Information Division of IMV, LTD). It is predicted that there is a 50-75% probability that a patient with a pacemaker or ICD will have the need for an MRI over their lifetime after implantation of a cardiac device. 8 Most physicians consider the presence of a pacemaker or ICD to be an absolute contraindication to an MRI study. Patients are denied the examination, even when MR is clearly the superior diagnostic modality or when there is no acceptable alternative imaging test available. To provide optimal care to the increasing number of patients with an implanted cardiac device, health care professionals must have the capability to perform MR imaging with minimal risk and full knowledge of the possible complications of the examination. Number of Scan (millions) Figure 2 Estimate of total domestic MRI scan procedure volume in millions (data from Kalin and Stanton 2005, Roguin et al ). The present study will create a registry of patients with pacemakers and ICDs who will undergo clinically indicated MRI and will document any adverse event or change in device parameters that may be associated with the imaging procedure. The results of this registry will provide the medical community with an accurate documentation of risk to patients and will establish a protocol of patient screening and device reprogramming for the purpose of maximizing the safe performance of MRI as a diagnostic tool in patients with implantable cardiac devices when indicated. This protocol will also benefit the community by providing more patients with implantable devices access to the best and most appropriate diagnostic imaging available. 1.3 MRI in Patients with Cardiac Devices Recent studies have suggested that MRI can be performed with minimal risk in patients who have pacemakers or ICDs as long as the patients are monitored by a cardiologist or other qualified physician and the device output is modified appropriately pre- and post-scan. However, there is VERSION R OBERT J. R USSO, MD

66 controversy related to the risk of performing MR studies in patients with cardiac devices, 1, 2 and current protocols have not been sufficiently evaluated to allow routine imaging. 1, 9 Published studies examining the safety of MRI in patients with cardiac devices have been relatively small (1-82 patients), and primarily involved patients with pacemakers. 2 These studies have reported varying effects of MRI on pacemakers and leads including impedance changes, battery depletion and an increase in pacing thresholds (Table 1). Shellock et al. 10 tested both pacemakers and ICDs in a phantom system and reported that magnetic field interactions do not create a hazard. There was no significant temperature change in the device. No memory corruption, hardware changes, or changes in device parameters were seen. Martin et al. 11 studied 54 patients with pacemakers undergoing MRIs. A total of 107 leads and 61 pulse generators were evaluated with no severe adverse events reported. Two leads required reprogramming due to increased pacing thresholds. Sommer et al. 12 studied 82 patients undergoing 115 extra-thoracic MRIs. No serious adverse events were observed and none of the leads required a change in programmed output. Nazarian et al. 13 studied 31 pacemaker and 24 ICD patients who underwent a total of 68 MRI studies. No serious adverse events and no significant changes in device parameters were observed. VERSION R OBERT J. R USSO, MD

67 Table 1. Previous Studies of MRI in Patients with Pacemakers (PM) or ICDs. a) Case Reports and Retrospective Studies Author Year Device #Patients/ #Studies Condition Findings Iberer et al PM 1/1 No adverse effect Alagona et al PM 1/1 Inbar et al PM 1/1 Gimbel et al PM 5/5 Retrospective Garcia-Boloa et al PM 1/2 Fontaine et al PM 1/1 Anfinsen et al ICD Fiek et al ICD 1/1 Inadvertent 1/1 Inadvertent Rozner et al PM 2/2 Roguin et al ICD 1/1 Wollmann et al ICD 1/3 Naehle et al ICD 1/1 Mikolich & Martin PM 1/1 Sommer et al PM 18/18 Sommer et al PM 45/51 Valhaus et al PM 32/34 Heatlie et al PM 5/6 Non-PM dependent 1.5 T Brain 1.5 T Brain T Cardiac Brain C-Spine 1.0 T Brain 1.5 T Brain C-Spine 0.5 T Brain 0.5 T Brain 1.5 T Thorax Lumbar 1.5 T Cardiac 1.5 T Brain 1.5 T Brain 1.5 T Cardiac 0.5 T Brain Cardiac 0.5 T Multiple 0.5 T Multiple 0.5 T Cardiac No adverse effect No adverse effect Two second pause No adverse effect Rapid pacing Inappropriate sensing, battery voltage transient change to EOL. Unable to communicate with device. Transient change to ERI in 1 patient. No adverse effect. No adverse effect. No adverse effect. No adverse effect Asynchronous mode due to activation of the reed switch in all patients No adverse effect Decrease in battery voltage recovered at 3 months Pacing at maximum voltage at a fixed rate of 100 beats/ minute in 1 patient. VERSION R OBERT J. R USSO, MD

68 c) Prospective Studies at 1.5 or Greater Tesla Field Strength Author Year Device #Patients/ #Studies Condition Findings Martin et al P 54/62 Coman et al. 31 (abstract) 2004 ICD 11/11 Del Ojo et al P 13/13 Gimbel et al P 10/11 All pacemaker dependent Gimbel et al ICD 7/8 Nazarian et al P 31 ICD 24 Sommer et al P 1.5 T Multiple 1.5 T Cardiac Vascular General 2.0 T Multiple 1.5 T Brain C-Spine 1.5 T Brain L-Spine Significant change in pacing threshold in 9.4% of leads, and 1.9% of leads requiring an increase in programmed output. Brief asymptomatic pause in 1patient. Unable to communicate with device in 1 patient. No adverse effect. Small variances in pacing threshold were seen in four patients. Power on reset electrical reset requiring reprogramming in 1 patient. 55/ T No adverse effect. 82/115 All nonpacemaker dependent 1.5 T Extra-thoracic Significant increase in pacing threshold, decreased lead impedance, and decrease in battery voltage. No inhibition of pacing or arrhythmias and no leads which required an increase in pacing output. Table modified from Shinbane et al. 2 VERSION R OBERT J. R USSO, MD

69 Although no pacemaker or ICD is presently labeled as safe for MRI scanning, 4 the FDA recognizes that on a case-by-case basis, the diagnostic benefit from MRI may outweigh the presumed risks for some pacemaker and ICD patients. 3 The FDA has stated that it is committed to working with manufactures to pursue studies that would allow the modification or removal of device warning and contraindications on the device label. 3,4 The American College of Radiology considers a the presence of a permanent pacemaker or ICD to be a relative contraindication for MRI, and that imaging should be assessed on a case-by-case as well as a site-by-site basis. 35 A Scientific Statement from the American Heart Association providing recommendations for the performance of MR examinations in patients with pacemakers or ICDs includes guidelines for pre- and post-scanning procedures for device setting, monitoring and emergency equipment, and appropriate personnel that should be present at the site (Appendix F) Preliminary Data At Green Hospital patients with a history of permanent pacemaker or ICD placement have successfully undergone MR imaging after pre-procedure evaluation by a cardiologist. The most common types of scans ordered are for the evaluation of the brain or spine, where the benefits of superior imaging by MRI clearly outweigh the risks. Since January 2004, more than 125 scans in 100 patients with implanted devices have been performed at the Green MRI facility with no serious adverse events observed. In 2 cases, minor changes in pacing threshold were observed that did not require reprogramming of any device parameters. Appropriate requests for MRI scans involving patients with cardiac devices have increased, and are now averaging 3-4 cases per week. Results of retrospective clinical observations were presented at the American Heart Association 2008 Scientific Sessions 37 (See sections 2.2 and 2.3). 1.5 Capability of the Principal Investigator The Principal Investigator for this study is well-suited to conduct the research. His research laboratory includes an Advanced Cardiovascular Imaging fellow, a research coordinator, and a biostatistician. The research facilities of the Cardiac MRI Program have 3 computers workstations connected to a server, with redundant file architecture and off site backup. In addition, the laboratory is equipped the appropriate support hardware including printers, copier, and fax machine. The facilities are secure with limited keyed access. The Principal Investigator has a successful track record of conducting two investigator-initiated, multicenter studies: (1) a 23-center, 800-patient, randomized clinical trial with one-year follow-up (Angiography Vs Intravascular ultrasound-direct stent placement The AVID Trial) and (2) a 20-center, 252-patient, prospective cohort with one-year follow-up The Left Main IVUS Registry ). VERSION R OBERT J. R USSO, MD

70 2. INVESTIGATIONAL PLAN 2.1 Study Design This is a prospective, multicenter registry of cases where Magnetic Resonance Imaging (MRI) studies are performed on patients with pacemakers or implantable cardioverter defibrillators. Clinical care Patient with cardiac device and MRI clinically indicated Research Subjects enrolls in study Device parameters recorded Magnetic resonance imaging Clinical Care Device parameters recorded Restore or Adjust settings Parameter Change? Yes No Follow-up interrogation within 7 days Research Follow-up Interrogation at 3 months Follow-up interrogation at 3-6 months or when clinically indicated Follow-up Interrogation at 6 months Figure 3. The sequence of steps that precede and follow subject enrollment into the MagnaSafe Registry. VERSION R OBERT J. R USSO, MD

71 2.2 Baseline Data on Device Parameter Changes Clinical experience: device parameter changes in subjects undergoing MRI To date, more than 120 patients with cardiac devices have undergone a clinically indicated MRI at Green Hospital. Results from pre- and post-scan interrogations were used to standardize the interrogation protocol, including the pacing rate and pulse width duration for threshold measurements. The magnitude of changes in device parameter measurements anticipated for patients undergoing MRI are based on published research data 11-13, 36 and clinical data collected previously. 37 The average battery voltage, pacing lead impedance, shock lead impedance, pacing threshold, and P and R wave amplitude changes in patients undergoing MRI at Green Hospital were 0 ± 0.02 V, -4.8 ± 28 ohms, 0.9 ± 0.8 ohms, 0.03 ± 0.15 V, ± 0.45 mv, and ± 0.82 mv respectively. These findings also highlighted the need to use a relative change for the P and R wave amplitudes. Based on our observed measurements, a significant P and R wave amplitude change will be defined as a decrease by 50% and 25%/50%, respectively Sub-study: device parameter changes in subjects without MRI Published studies do not provide adequate data on short-term variability of measured values in patients not undergoing MRI with which to compare our research results. To provide further reference values, a sub-study conducted will examine 100 patients not undergoing an MRI that will have 2 sequential interrogations one hour apart to simulate the duration of an MRI scan. The same protocol that is used for interrogation of devices immediately prior to and following the MRI will be used and is described below. Battery voltage, lead impedances, and P and R wave amplitudes were recorded. Pacing thresholds were measured at a fixed pulse width of 0.4 ms and the same pacing rate. The range and variance of the device measurements (including pacing thresholds and battery voltage) will be used as a basis for comparison with our research values. To date, 30 patients have been enrolled in this sub-study. In subjects that did not undergo MRI, 6.7% of generators had a battery voltage decrease of 0.02 V, 3.6% of pacing leads had an impedance change of 50 ohms and 17.6% of defibrillator leads had lead impedance changes of 2 ohms. There were no P wave decreases of 1.0 mv and no R wave decreases 2.0 mv. None of the pacing leads had a threshold increase 0.5 V. In this control group, the mean battery voltage change was ± V and the mean lead impedance change was 5.1 ± 24.2 ohms. The mean change in pacing lead threshold measurements was 0.00 ± 0.14 V. Most importantly, there were essentially equal numbers of lead threshold increases as there were decreases. When these parameters were compared with patients who VERSION R OBERT J. R USSO, MD

72 underwent MRI in our retrospective chart review, the changes in measurements were similar in both groups Defining a Significant Parameter Change Based on a comparison of the retrospective clinically-performed MRI group with the control group described above in section 2.2, published literature and standard-of care medical judgment, the following are defined as a significant parameter change after an MR scanning: 1) A battery voltage change 0.04 V. 2) Pacing lead impedance change 50 ohms. 3) A shock lead impedance change 3 ohms 4) A P wave decrease of 50%. 5) An R wave decrease of 25% and 50% 6) A pacing lead threshold increase 0.5 V, at fixed pacing rate and pulse width duration of 0.4 msec. 2.3 Anticipated Observations The general hypothesis of this study is that the risk of magnetic resonance imaging (MRI) in patients with implanted cardiac devices can be minimized by adherence to a protocol of pre-procedure and post-procedure device interrogation and reprogramming. A minimal risk MRI examination is defined for the purpose of this protocol as: (a) an imaging study performed with up to a 0.5% risk of generator or lead failure requiring immediate replacement in pacemaker patients and up to a 2% risk in ICD patients; (b) up to a 5% risk of requiring permanent reprogramming of the implanted device; and (c) up to a 10% risk of requiring temporary reprogramming of the implanted device Device failure To determine the background rate of device failure requiring lead or generator replacement (pacemakers and ICD s), post-market approval annual reports submitted to the US Food and Drug Administration (FDA) by manufacturers of pacemakers and ICDs were reviewed. 5 During the period , 2.25 million pacemakers and 415,780 ICDs were implanted in the United States. Overall, 17,323 devices or 0.65% (8834 pacemakers and 8489 ICDs) were explanted due to confirmed malfunction. In other words, the annual combined device malfunction replacement rate was 6.5 per 1000 implants. The device specific replacement rate per 1000 implants was 3.9 for pacemakers and 20.4 for ICDs. Battery/capacitor abnormalities (4085 malfunctions [23.6%]) and electrical issues (4708 malfunctions [27.1%]) accounted for half of the total device failures. The annual pacemaker malfunction replacement rate per 1000 implants decreased significantly during VERSION R OBERT J. R USSO, MD

73 the study, from a peak of 9.0 in 1993 to a low of 1.4 in 2002 (P=0.006 for trend). In contrast, the ICD malfunction replacement rate per 1000 implants, after decreasing from 38.6 in 1993 to 7.9 in 1996, increased markedly during the latter half of the study, peaking in 2001 at 36.4 (P=.04 for trend). More than half of the reported ICD malfunctions occurred in the last 3 years of the study. Overall, the annual ICD malfunction replacement rate was significantly higher than the pacemaker malfunction replacement rate (20.7 versus 4.6 replacements per 1000 implants) Temporary and permanent device reprogramming The need for temporary and permanent reprogramming is based on maintaining adequate safety margins for pacing threshold outputs and P and R wave sensing. Anticipated rates of temporary and permanent reprogramming of the implanted devices are based on the frequency of these events that were observed in published research data 11-13, 36 and clinical data collected at Green Hospital 37. A change of 0.5 V was considered to represent the need for temporary or permanent reprogramming of the threshold output. In our study, the rate of these events was 1.2% in pacemakers and 0% in ICDs. A significant P and R wave change was defined as a decrease in amplitude of 1.0 mv and 2.0 mv, respectively. This could require reprogramming of the lead sensitivity. In our study, the rate of these events was 5.8% in pacemakers and 3.3% in ICDs. Since arrhythmia detection and treatment in ICDs requires anesthesia and a delivered shock, the decision was made that it is unwarranted to require patients to undergo follow up defibrillator threshold testing Anticipated rates of clinically significant events Based on these findings, the following rates of clinically relevant events are anticipated: Anticipated Observation #1: The observed percentage of patients undergoing MRI for clinical care who then require immediate generator or lead replacement will be 0.5% for pacemakers and 2% for ICDs. Anticipated Observation #2: The observed percentage of patients undergoing MRI for clinical care who then require permanent reprogramming of the pacemaker or ICD device will be 5%. Anticipated Observation #3: The observed percentage of patients undergoing MRI for clinical care who then require temporary reprogramming of the pacemaker or ICD device will be 10%. VERSION R OBERT J. R USSO, MD

74 2.4 Inclusion Criteria 1. Male or female 18 years or older 2. Able to provide informed consent 3. Permanent implanted pacemaker or ICD 4. Strong clinical indication for MRI; in the clinical setting where MRI is the diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology as determined by the ordering physician. 5. Patient is scheduled for non-thoracic MRI (joint, extremity, brain, pelvis, cervical, and lumbar or sacral spine) 6. Cardiac leads of any age 2.5 Exclusion Criteria 1) Metallic objects that represent a contraindication to MR imaging, including: intra-orbital or intra-ocular retained metal fragments, and intracranial vascular clips and coils 2) Claustrophobia unresponsive to oral pre-procedure sedatives provided by the ordering physician 3) Morbid obesity (abdominal diameter >60 cm) which results in contact with the magnet facade 4) ICD or pacemaker generator placement prior to ) Has an ICD and is pacing dependent 6) Pregnancy 7) Device generator battery voltage at elective replacement indicated (ERI) 8) Presence of active implantable medical device (other than pacemaker or ICD) 9) Presence of abandoned leads (with the exception of post CABG temporary epicardial pacing wires) 10) Presence of implanted cardiac device in the abdominal position 11) Pacemaker or ICD that is labeled as MRI-Conditional (approved by the FDA for exposure to MRI). 2.6 Conditions which do not require exclusion from the present protocol 1. Prior MRI with pacemaker or ICD in place (patients may undergo repeat scanning) 2. Coronary stent placement (without minimum time from stent implant exclusion) 3. Non-coronary stent placement (including aortic stent grafts) 4. Vascular shunts 5. Mechanical heart valves 6. Prior coronary artery bypass surgery (including the associated sternal wires) 7. Prior joint replacement surgery VERSION R OBERT J. R USSO, MD

75 2.7 Transdermal drug patches with metallic backing The FDA recommends that healthcare professionals referring patients to have an MRI scan identify those who are wearing a transdermal drug-delivery patch before the patients undergo MRI. The healthcare professional should advise these patients about the procedures for removing and disposing of the patch before the MRI scan, and replacing the patch after the MRI scan. The MRI facilities should follow published safe practice recommendations concerning patients who are wearing patches. VERSION R OBERT J. R USSO, MD

76 3. STUDY PROTOCOL 3.1 Overview The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. MR examination of patients with permanent implanted cardiac devices will only be performed if there are highly compelling circumstances and when the benefits clearly outweigh the risks in the opinion of the ordering physician. Completion of the study Inclusion/Exclusion form by the participating physician will document that the ordering physician has requested the present non-thoracic MRI study as the clinically indicated diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and has been selected independent of this research protocol. Enrolling in the research study will not add any additional physical risk to the patient. Patients with a pacemaker or ICD who are scheduled for a clinically-indicated MRI will be invited to enroll in the study. Enrollment will be open to patients with either pacemakers or ICDs until the target enrollment of either 1000 pacemakers or 500 ICDs is reached, then enrollment will be limited to the type of device that has not yet reached the target enrollment. At this time, Green Hospital is the only heath care facility in San Diego performing MR on patients with implanted cardiac devices. The MRI suite is equipped to provide the necessary monitoring and emergency care, and a cardiologist or other qualified physician with expertise in device interrogation and programming will be available for each scan. All patients with a pacemaker or ICD scheduled for an MRI will be invited to enroll in the study. In this study, up to 34 additional sites will be recruited to participate in the registry (see Section 10). MRI compatible equipment will be required to monitor vital signs (non-invasive blood pressure monitoring, pulse oximeter, and single lead cardiac rhythm monitor) while performing scans on patients with implanted devices. Recommendations from the American Heart Association for performance of MR examination in patients with pacemakers or ICDs will be followed (Appendix F). 1 VERSION R OBERT J. R USSO, MD

77 3.2 MRI Protocol Specific MRI Precautionary Procedures During the Performance of Clinically- Indicated Scanning 1. Initiate each study in a standard fashion using Normal Operating Mode 2. The patient will be weighed and the technologist will enter an accurate weight for the purpose of determining SAR levels during the examination. 3. If the patient cannot be weighed, then a weight obtained during inpatient status may be used or the patient s best estimate of a recent weight. 4. If a SAR limit is reached during an examination, parameters should be changed as needed to maintain Normal Operating Mode (TR, number of slices, or flip angle). These changes should be documented and it should also be noted whether this resulted in a successful diagnostic scan. 5. If it is clinically necessary to change to First Level Controlled Operating Mode, a study deviation form should be filled out explaining the reason for the change Protocol for the Performance of MRI a) A cardiologist, other qualified physician, or other qualified medical professional/midlevel provider (such as Nurse Practitioner or Physician s Assistant) will review the medical record to determine suitability for the imaging study. b) A signed written informed consent will be obtained. c) The radiology technical staff will use the standard screening form to evaluate the patient for MRI contraindications: aneurysm clips or coils, infusion pumps, nerve stimulators, metal shavings in the eye, ferrous metal implants, transdermal drug patches with metallic backing, cochlear implants, an allergy to gadolinium, morbid obesity, pregnancy and severe claustrophobia. d) ACLS trained personnel and a crash cart, including a non-mri compatible defibrillator and transcutaneous pacemaker, will be available throughout the procedure to respond to an adverse clinical event. e) All patients will be monitored throughout the procedure with continuous cardiac rhythm recording and pulse oximetry. In addition, a blood pressure will be obtained at 5 minute intervals. f) All patients will undergo device interrogation in the MRI suite, but outside of the magnet room immediately prior to and following the scan. The results of the device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. VERSION R OBERT J. R USSO, MD

78 3.3 Pacemaker Device Interrogation Protocol Patient with a Cardiac Device Patient with an ICD Patient with a Pacemaker Yes Pacemaker dependent? Pacemaker dependent? Yes No No Disable antitachycardia therapy and Disable pacing and sensing functions (OVO/ODO) Disable pacing and sensing functions (OVO/ODO) Reprogram to asynchronous pacing mode (VOO/DOO) and Disable magnet response No MRI MRI MRI MRI Figure 4. The MagnaSafe Registry Flowchart. VERSION R OBERT J. R USSO, MD

79 3.3.1 Pacemaker pre-scan interrogation Pre-scan interrogation will include the following: Baseline device parameter settings, determination of the patient s underlying rhythm and full interrogation of the device. a) Interrogation of the device will include: battery voltage measurement; measurement of the P and R wave amplitudes (if present at a pacing rate of 40 bpm); measurement of the lead impedance for all leads (atrial when present, right ventricular, and left ventricular when present); and pacing threshold measurements of all leads. b) Pacing threshold measurements will be performed at 10 bpm above the programmed pacing rate or the patient s intrinsic rate. The pacing rate for testing can be increased by increments of 10 bpm if there is insufficient suppression of the patient s underlying rhythm. c) Pacing threshold measurements will measure the pacing amplitude and will be performed with a fixed pulse width of 0.4 ms, regardless of the permanent pacing output. If the pulse width cannot be safely decreased to 0.4 ms to test a lead, the amplitude threshold test should be performed at the programmed pulse width Pacemaker programming during the scan a) The pacing rate will gradually be decreased to 40 bpm. If the patient has an intrinsic rhythm, the device will be programmed to no pacing (ODO or OVO). The patient will be observed for 5 minutes prior to the scan. If symptoms of presyncope are noted, the pacing function will be reprogrammed to an asynchronous pacing mode (DOO or VOO). b) If the patient has a pacemaker which does not allow permanent reprogramming to an ODO or OVO mode, the patient will be reprogrammed to an asynchronous pacing mode (DOO or VOO) and the pacing output for all active leads, and pulse width should be set to a minimum value. c) If there is no intrinsic rhythm when the device is reprogrammed to 40 bpm, the patient will be considered dependent and the device programmed to an asynchronous pacing mode (DOO or VOO). The patient will be observed for 5 minutes prior to the scan to ensure that the asynchronous pacing is well-tolerated. If not, the original pacing parameters will be restored and the scan will not be performed. These patients will remain enrolled in the study and the results recorded. d) Immediately following the scan, initial pacemaker parameters will be restored Pacemaker post-scan interrogation a) Post-scan interrogation will include: Battery voltage measurement; measurement of the P and R wave amplitudes (if present at a pacing rate of 40 bpm); measurement of the lead impedance for all leads; and pacing threshold measurements of all leads. VERSION R OBERT J. R USSO, MD

80 b) All threshold measurements will be performed at the same pacing rate and pulse width amplitude as the pre-scan interrogation. c) If there is a significant increase in pacing threshold ( ms or any increase at a wider pulse width) after the scan compared with before the scan, the pacing output will be increased to maintain a amplitude safety margin at the physician s discretion. d) If there is a significant decrease in the P and R wave amplitudes, the sensitivities will be adjusted to maintain adequate atrial and ventricular electrogram detection. 3.4 ICD Device Interrogation Protocol ICD pre-scan interrogation a) ICD pre-scan interrogation will include: Baseline device parameter settings, determination of the patient s underlying rhythm and full interrogation of the device. b) If there is no intrinsic rhythm when the device is reprogrammed to pace at 40 bpm, the patient will be considered dependent and will be excluded from the study. c) Interrogation of the pacing functions (thresholds, impedances, and P and R waves) will be performed as described for the pacemaker patients above. Additionally, the shock impedance of the SVC and RV coils will be determined (RV only when an SVC coil is not present) as long as this can be done painlessly. d) All tachycardia therapy functions and all pacing or bradycardia therapy functions will be disabled. e) Immediately following the scan, initial parameters will be restored ICD post-scan interrogation a) Post-scan interrogation will include: all pacing functions and shock impedances as described above. b) All threshold measurements will be performed at the same pacing rate and pulse width amplitude as the pre-scan interrogation. c) If there is a significant increase in pacing threshold ( ms or any increase at a wider pulse width) after the scan compared with before the scan, the pacing output will be increased to maintain a amplitude safety margin as per physician discretion. d) If there is a significant decrease in the P and R wave amplitudes, the sensitivities will be adjusted to maintain adequate atrial and ventricular electrogram detection. VERSION R OBERT J. R USSO, MD

81 3.5 Monitoring During the Scan a) A cardiologist, qualified physician, or other qualified medical professional/midlevel provider (such as Nurse Practitioner or Physician s Assistant) who is trained in ACLS and has pacemaker/icd expertise will be in attendance for the study and will be able to visualize and hear the subject throughout the procedure. If a medical professional other than a qualified physician is monitoring the procedure, a qualified physician must directly supervise the key portions of the procedure (initial interrogation and post-scan reprogramming), and must be immediately available to furnish assistance and direction throughout the performance of the procedure. In addition, the supervising qualified physician must be immediately available to provide medical intervention (such as placement of a temporary pacemaker) if required. b) The patient will be instructed to alert the MR system operator to any unusual sensations or problems. c) Blood pressure, pulse oximetry and electrocardiogram will be monitored throughout the procedure. d) If a magnet response occurs when the patient enters the scanner, they will be removed and the device will be reprogrammed with the magnet response disabled. If the magnet response function is not programmable, the physician monitoring the scan will determine if the patient can tolerate the procedure at the magnet heart rate. If they can, the scan will be completed. If they cannot, the scan will not be performed, the patient will remain enrolled in the study, and the results recorded. e) If the patient experiences new onset atrial fibrillation during the MRI scan, symptomatic bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation, the scan will be stopped immediately, the patient will be removed from the scanner into the holding area, initial device parameters will be restored immediately, and all further treatment will be performed as per ACLS protocol or the discretion of the monitoring physician. 3.6 Follow-up Interrogations Parameter changes requiring multiple follow-up visits Parameter changes that will require multiple follow-up visits to ensure patient safety and/or determine if the change is temporary or permanent: 1) A battery voltage change 0.04 V. 2) Pacing lead impedance change 50 ohms. 3) A shock lead impedance change 3 ohms 4) A P wave decrease of 50% 5) An R wave decrease of 25% 6) A pacing lead threshold increase 0.5 V, at fixed pacing rate and pulse width duration of 0.4 msec. VERSION R OBERT J. R USSO, MD

82 3.6.2 Subjects requiring multiple follow-up visits a) If patients had a parameter change as listed in section above, the patient will be asked to return for three follow-up interrogations. Follow-up interrogations will be scheduled: 1. Between 2-7 days after the procedure. 2. Three months (± 30 days) after the MRI procedure. 3. Six months (± 30 days) after the MRI procedure. b) Device reprogramming will be based on clinical judgment of the interrogating clinician. c) The results of each follow-up device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. d) Subjects with a significant parameter change who have medical conditions that preclude them from completing multiple follow-up visits will not be required to complete research follow-up interrogations Subjects requiring single follow-up visits a) If no parameter changes requiring multiple follow-up visits occur (see 3.6.1), the patient will be required to return for a single device interrogation between 2-7 months after the MRI procedure. b) Device reprogramming will be based on clinical judgment of the interrogating clinician. c) The results of the 2-7 month device interrogation will be collected by the staff at the performing center and transmitted to the coordinating center via a web-based data input system. In addition, a copy of the device interrogation print-outs will be mailed to the coordinating center. d) If the patient returns for a 2-7 month device interrogation at another institution, then the coordinating center will obtain the data from the medical record as previously outlined in the informed consent/release of medical records. 3.7 Variables to be Collected Patient Medical Record 1. Demographics (age, sex, height, weight) 2. Make and model of device and leads 3. Date of device and lead implant 4. Presence of a mechanical heart valve 5. Clinical indication for the MRI scan 6. History of coronary artery disease 7. History of cardiomyopathy of any etiology 8. History of diabetes VERSION R OBERT J. R USSO, MD

83 9. Use of beta blockers/anti-arrhythmics 10. Ejection fraction 11. History of a previous MRI scan in the presence of a pacemaker or ICD MRI Study Procedure Record 1. Date of MRI 2. Body region scanned (Brain, Spine, etc.), coil used 3. Duration of scan (SAR limit reached) 4. Device setting during scan 5. Loss of capture during scan Device Interrogation 1. Lead Impedance a. Measurement must be performed using the programmed lead polarity (bipolar versus unipolar). b. For all pacing leads c. Shock impedance for ICD leads including SVC and RV coils when present and when it can be performed painlessly. 2. Lead Threshold a. Capture management algorithms must be disabled. b. Threshold measurements must be performed using the programmed lead polarity (bipolar versus unipolar). c. Measured amplitude at the fixed pulse width of 0.4 ms for each lead d. If the pulse width cannot be safely decreased to 0.4 ms for testing, the amplitude threshold test will be performed at the programmed pulse width both pre and post-scan. 3. Battery Voltage 4. P/R Wave Amplitude measured at a pacing rate of 40 bpm if there is an intrinsic rhythm 5. Induced arrhythmia (new onset atrial fibrillation or flutter during the MRI scan, symptomatic bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation) 3.8 Primary Outcomes Significant Parameter Changes during or immediately after MRI Scan, or at clinical follow-up: 1. Change in Lead Impedance a. Increase or decrease in pacing lead impedance 50 Ω b. Increase or decrease in shock lead impedance 3 Ω. 2. Change in Lead Threshold a. Increase in pacing threshold ms VERSION R OBERT J. R USSO, MD

84 b. Any increase at a wider pulse width. 3. Change in P/R Wave Amplitude a. Decrease in P wave measurement 50%. b. Decrease in R wave measurement 25% and 50%. 4. Loss of capture during scan 5. Induced Arrhythmia (new onset atrial fibrillation or flutter during the MRI scan, symptomatic bradycardia with a heart rate <40 bpm, ventricular tachycardia or ventricular fibrillation) 6. Device failure requiring generator replacement 7. Lead failure requiring replacement 3.9 Secondary Outcomes Significant Parameter Changes during or immediately after MRI Scan, or at clinical follow-up: 1. Any increase or decrease in Lead Threshold 2. Any increase or decrease in Battery Voltage 0.04V 3. Any inability to perform the scan because the patient did not tolerate reprogramming the pacing functions of the device to VOO/DOO 3.10 Reporting Events Reporting Adverse Events The following outcomes will be considered adverse events: 1. Death 2. Electrical reset-to-on 3. Loss of pacemaker capture for patients programmed to an asynchronous mode (VOO, DOO). 4. New onset atrial fibrillation or atrial flutter during the MRI scan 5. Ventricular fibrillation or ventricular tachycardia 6. Syncope 7. Device failure requiring immediate generator or lead replacement. A description of each adverse event will be reported to the Coordinating Center within 48 hours of the event. The Coordinating Center will report adverse events to the FDA as soon as possible, but no later than 7 calendar days after first learning of the event. Any Unexpected Adverse Device Effects (UADE) observed that appear to be related to the MRI will be reported by the site investigator to the reviewing IRB and the Coordinating Center as soon as possible, but no later than 10 business days after the investigator first learns of the effect. The coordinating center will conduct an evaluation of the UADE, and report the results of the evaluation VERSION R OBERT J. R USSO, MD

85 to the FDA, all reviewing IRBs, participating investigators, and cardiac device vendors within 10 business days after the coordinating center first receives notice of the effect Reporting Protocol Deviations Protocol limitations or follow-up visits that establish continued safety of a research procedure that are not performed as scheduled or as described will be reported to the reviewing IRB and to the Coordinating Center within five (5) working days of their occurrence or within five (5) working days of the investigator becoming aware of their occurrence. The following procedures not performed appropriately will be considered reportable safety protocol deviations and will be reported to the reviewing IRB and to the coordinating center: 1. Subject eligibility for enrollment. 2. Monitoring vital signs during the MRI scan. 3. Interrogating the device before and after the MRI scan. 4. Setting device functions appropriately for the scan: a. Disable tachycardia therapy functions in ICDs. b. Program pacemaker dependent subjects to DOO/VOO. c. Program pacemaker non-dependent subjects to ODO/OVO. 5. Maintenance of normal operating mode during performance of the MRI scan. 6. One week follow-up interrogation of a device with a significant post-mri parameter change. 4. DATA MANAGEMENT 4.1 Data Collection Electronic case report forms will be developed on a secure, 21 CFR PART 11 compliant, web-based site. Electronic Data Capture will be managed by KIKA Medical Inc. (Boston, MA) using their Veracity web-based software platform. KIKA Medical is ISO 9001:2000 and ISO 13485:2003 certified since October Investigators at participating registry sites will complete an electronic Inclusion/Exclusion, Initial Case Report Forms and any applicable follow-up forms for each subject visit. The software can identify values that are out of range by flagging the field of entry, and can generate a list of errors. The remote-entry database for this registry will incorporate passwordprotection and encryption design features such that each site will only be able to view data that they will enter. Investigators will not be able to access data entered by any of the other sites. The Coordinating Center will have access to all submitted data and patient related information required to complete the analysis. VERSION R OBERT J. R USSO, MD

86 4.2 Data Monitoring Central statistical trial monitoring by the Coordinating Center will be used to check for missing or invalid data. 38 Range checks will be built into the registry database to identify unlikely or implausible values. The Veracity software system provides the coordinating center with the ability to download and monitor data at any time, and can generate reports for data overview to identify issues with data entry. The software will also generate reports of number enrolled at each site, data values, and monitoring reports. 5. STATISTICAL CONSIDERATIONS 5.1 Data Analysis Data will be summarized in table form separately for the 1000 pacemaker patients and for the 500 ICD patients. For each patient with a significant parameter change, summary information regarding clinical, device, and MRI descriptors will be provided. Estimated proportions of each type of significant parameter change event will be accompanied by 39, 40 95% confidence interval upper bounds based on the Score method with continuity correction. Table 2 shows the upper bounds of the 95 percent confidence intervals for possible observed event rates. For example, if there are no observed events in 500 patients, we can be 95% certain that the population event rate is not more than 1%. If there are no observed events in 1000 patients, then we can be 95% certain that the population event rate is not more than 0.5%. The association between the frequency of parameter changes and the following variables will be examined: type of scan, length of time in scanner, single versus multiple scans, type of lead (A, RV, LV, shock), type of device (ICD, Pace), pacer dependency, time from implant. A control group (see section 2.2.2) will be used to compare the relative frequency of parameter changes in patients with cardiac devices undergoing MRI to patients with cardiac devices not undergoing MRI. VERSION R OBERT J. R USSO, MD

87 Table 2. Upper bound of the 95% confidence interval for possible observed event rates. Upper bound of the 95% confidence interval Observed event rate Based on 500 patients Based on 1000 patients 0% 1.0% 0.5% 1% 2.5% 1.9% 2% 3.8% 3.1% 3% 5.0% 4.3% 4% 6.2% 5.5% 5% 7.4% 6.6% 6% 8.6% 7.7% 7% 9.7% 8.8% 8% 10.8% 9.9% 9% 11.9% 11.0% 10% 13.1% 12.1% 5.2 Sample Size Using the mean yearly replacement rate due to spontaneous malfunction of 0.46% (±-0.22) for pacemakers, and 2.07% (±-1.16) for ICDs as a benchmark 5, sample sizes of 1000 pacemaker and 500 ICD cases were selected. A case was defined as a patient who provided informed consent, entered the scanner, and underwent MR imaging of one or more anatomic regions during a single examination session. If the patient returned on a subsequent day for repeat MRI, then a separate informed consent was obtained and the data were entered as a unique case. 6. R I S K A N A L Y S I S 6.1 Justification for Investigation The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. MR examination of patients with permanent implanted cardiac devices will only be performed if there are highly compelling circumstances and when the benefits clearly outweigh the risks in the opinion of the ordering physician. Completion of the study Inclusion/Exclusion form by the participating physician will document that the ordering physician has requested the present non-thoracic MRI study as the clinically indicated diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and has been selected independent of this research protocol. Enrolling in the study will not add any additional physical risk to the patient. VERSION R OBERT J. R USSO, MD

88 The results of this registry will provide the medical community with an accurate assessment of risk to patients and provide a protocol allowing the safe utilization of MRI as a diagnostic tool in patients with implantable cardiac devices when indicated. It will benefit the community by providing more patients with implantable devices access to the best diagnostic tools available. 6.2 Risks a) Risks associated with MRI with cardiac devices: 1. Pacemaker or ICD dysfunction 2. Pacemaker or ICD damage 3. Arrhythmia 4. Death b) Serious adverse events associated with MRI in patients with cardiac devices are rare, and the majority of cases that have been reported resulted from failure to follow established safety guidelines. 1, 9 No deaths have been reported in studies in which patients were appropriately scanned and properly monitored 1, and occurrence of arrhythmia is very infrequent. c) Changes in device parameters such as pacing thresholds, battery voltage, and lead impedance are not considered serious risk to the subject. Limited data is available on the incidence of such parameter changes, and it is the purpose of this study to generate this data. Previous studies have reported the incidence of significant changes in pacing threshold after MRI scans to be between 3-10% (See section 2.2 and 2.3). d) Device interrogations do not pose any risk to the subject. e) The risk of confidentiality breach is extremely low as the investigators are the only ones with access to the data, and the data will be secured in a password-protected computer. 6.3 Risk Management Procedures The American Heart Association Recommendations for the Performance of Magnetic Resonance Examinations in Patients with Pacemaker of Implantable Cardioverter-Defibrillators will be followed (Appendix F). 1 a) ACLS trained personnel and a crash cart, including a non-mri compatible defibrillator and transcutaneous pacemaker, will be available throughout the procedure to respond to an adverse clinical event. b) All patients will be monitored throughout the procedure with continuous cardiac rhythm recording and pulse oximetry. In addition, blood pressure will be monitored and recorded at the beginning, middle and end of scan. c) To limit the risk of MR imaging: Examinations will be limited to non-thoracic studies, using normal, normal operating mode and gradient switching speeds. VERSION R OBERT J. R USSO, MD

89 d) A physicist with knowledge of clinical magnetic resonance imaging will not be in attendance during the examination. While the presence of a physicist is recommended in the ACC/AHA guidelines, the number of persons with this skill set is severely limited and would not be feasible for a large scale multicenter protocol. In addition, the present protocol is meant to represent real world medical practice where technical staff would not be available at all but a few institutions. e) To minimize the risk of dysfunction and arrhythmia associated with the MRI scan: 1. Pacemaker output will be turned off or set to pace continually and not to respond to external input. 2. For subjects with ICDs, defibrillation (shock) function will be disabled. 3. MRI scans will be limited to non-thoracic studies to minimize RF exposure to device. 4. The subject s vital signs will be monitored during the scan, and an external defibrillator is available in the MRI suite. A physician trained in ACLS and pacemaker/icd expertise will be in attendance for the study and will be able to visualize and hear the subject the entire time. A blood pressure cuff, pulse oximeter, and ECG electrodes will be placed. 5. Device parameters will be measured at the post-scan device interrogation, and the device will be reprogrammed to adjust to any changes. f) To prevent breach of confidentiality, data will be kept in a password-protected computer in a locked research office. No personal identifiers will be released. The results of the research may be published or presented, but subjects will remain anonymous. The effectiveness of these measures is high. g) Any Unexpected Adverse Device Effects (UADE) observed as a result of the MRI will be reported by the site investigator to the reviewing IRB and the coordinating center as soon as possible but no later than 10 working days after the investigator first learns of the effect. The coordinating center will evaluate the event (See Appendix A2) to determine if any modifications are needed to the protocol or if the investigation should be terminated. The results of the evaluation will be reported to the FDA, all reviewing IRBs, participating investigators, and cardiac device vendors, within 10 working days after the coordinating first receives notice of the effect. 7. DESCRIPTION OF THE DEVICE Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. VERSION R OBERT J. R USSO, MD

90 8. STUDY MONITORING 8.1 Name and Address of Monitor: Robert J. Russo, MD, Principal Investigator 8.2 Overview of Study Monitoring Plan This monitoring schedule may be revised based on accrual rate, history of protocol deviations or noncompliance with good clinical practice guidelines (GCP), magnitude of data corrections required and/or IRB request. See APPENDIX A1: Study Monitoring Plan for details Site visits Site visits may be conducted and will be limited to one visit during the course of the study that may be scheduled within one month of enrollment of the 10 th patient at that site, or prior to one year of initiation of the study whichever occurs first. At each site visit: a) The protocol will be reviewed with MRI technical staff, and the performing cardiologist or other qualified physician to: 1. Verify the clinical site has followed the approved protocol 2. Ensure the trial staff is adequately informed about the trial and has not delegated responsibilities to unauthorized individuals. b) Medical records will be reviewed to: 1. Verify that only eligible subjects are enrolled. 2. Determine whether all unanticipated adverse device effects are reported appropriately. c) Study records will be reviewed to: 1. Determine all essential documents are maintained. 2. Verify trial records are accurate, complete, and current Remote monitoring Remote study monitoring will conducted from the Coordinating Center. Data entry will be monitored monthly. We feel that remote monitoring is sufficient for this study for the following reasons: a) This is an observational study and the data generated from this trial will be used for scientific purposes and not for product labeling changes. b) The pacemakers and ICD devices in this study were previously implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant VERSION R OBERT J. R USSO, MD

91 c) The MRI procedure is being conducted for clinical purposes at the discretion of the ordering physician. The decision to have an MRI will be based on clinical indication, and is not part of this research protocol. Enrolling in the study will not add any additional physical risk to the patient. Completion of the Inclusion/Exclusion form by the participating study physician will document that the ordering physician has requested a non-thoracic MRI study as the diagnostic modality of choice for a specific disease state without acceptable alternative imaging technology, and that the imaging study has been selected independent of this research protocol. d) Source documents will be forwarded by the participating sites to the coordinating center: 1. Signed investigator agreement 2. A copy of a CV of each investigator 3. Copy of each site IRB approved protocol and informed consent 4. Hard copies of device interrogation print-outs for each subject 5. Copy of signed consent forms for each subject e) Detailed written instructions of the protocol to be used to acquire complete interrogation data during the MRI procedure will be provided to investigators. All primary outcomes of the study are recorded on the printed interrogation outputs that will be forwarded to the coordinating center. Thus, the source documents needed to verify the primary outcome variables will be available for review at the Coordinating Center. f) Remote monitoring of electronic data entry will be conducted via a password protected data base that allows remote monitoring of subject enrollment, data entry, and subject follow-up tracking. Electronic Data Capture will be managed by KIKA Medical Inc. (Boston, MA) using their Veracity web-based software platform. KIKA Medical is ISO 9001:2000 and ISO 13485:2003 certified since October Using the Veracity software, electronic entries can be compared to these source documents, and any entries that differ from the source documents will be marked for inquiry. The program will be used to generate monitoring reports. 8.3 Registry Reports a) Monthly Registry Report. The study Statistician will prepare monthly trial reports for review by the Lead Investigator, and the Data Safety Monitoring Board. b) Annual Registry Report. The study Statistician will prepare yearly summary reports that will be sent to the site investigators summarizing numbers of patients enrolled, reasons for MRI scans, and any adverse events noted. c) Final Registry Report and Publications. A final report will be sent to the site investigators with the results of the registry. The Lead Investigator will submit a manuscript on behalf of the investigators at the participating centers with the registry final results. VERSION R OBERT J. R USSO, MD

92 9. MANUFACTURING INFORMATION Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 10. INVESTIGATOR INFORMATION 10.1 Site Selection and Training Sites will be selected for participation in the registry based on: 1) Experienced clinical/academic centers with expertise in MR imaging and electrophysiology 2) Sufficient MRI volume to enroll cases in a one-year period 3) Availability of competent clinical support staff 4) Cardiologist or other qualified physician with a working knowledge of pacemaker and ICD function and programming and a willingness to participate in the study. Other qualified physician includes, but is not limited to, a physician board certified in cardiac surgery, critical care medicine, or anesthesiology, with training in pacemaker and ICD function and programming. A detailed Investigator s Manual will be supplied to all enrolling institutions. The manual will include a set of step-by-step instruction for the pre- and post-procedure interrogation of the pacemaker or ICD Qualifications for the participating clinical site Principal Investigator 1) Board certified general cardiologist, a cardiologist with subspecialty training in cardiac electrophysiology, or other qualified physician with appropriate training and experience to supervise the performance of the protocol. 2) Able to interrogate an implanted cardiac device with the assistance of an industry device representative 3) Able to program/reprogram implanted cardiac device parameters with the assistance of an industry device representative 4) Able to place and utilize a temporary external cardiac pacemaker 5) Hospital privileges to place a temporary transvenous cardiac pacemaker VERSION R OBERT J. R USSO, MD

93 10.3 Clinical Study Agreement No investigator will be added to the study until the agreement is signed. 11. INSTITUTIONAL REVIEW BOARD INFORMATION Institutional Review Board approval will be required of all sites prior to enrolling any patients in the registry. Patient information collected for the registry will be protected in accordance with the standards sets forth by the Health Insurance Portability and Accountability Act (HIPAA). 12. SALES INFORMATION Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 13. INVESTIGATIONAL LABELING Descriptions of the device properties, manufacturing information, sales information, and investigational labeling are not applicable to this request and are not included in the application. The pacemakers and ICD devices involved in this study were implanted into subjects for clinical purposes at an earlier time; devices were FDA approved and commercially available at the time of implant. Multiple vendors and models will be included in the registry. Thus, this item does not apply to our present protocol. 14. INFORMED CONSENT MATERIALS The informed consent includes all risks specified by the American Heart Association in the Recommendations for the Performance of MR Examinations in Patients with Pacemakers and ICDs. 1 See Appendix B: Sample Consent VERSION R OBERT J. R USSO, MD

94 15. DATA SAFETY MONITORING BOARD A Data Safety Monitoring Board (DSMB) composed of three Green Hospital cardiologists with expertise in electrophysiology will review the accumulated data monthly to determine if any trends are noted regarding adverse events. The DSMB will be established following the FDA Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees (2006). The DSMB will meet quarterly and will review the data stripped of any personal identifiers. If, in the opinion of the DSMB, information becomes known that could benefit subgroups of patients undergoing MRI, that information will be shared with the site investigators. 16. T I M E L I N E It is anticipated that clinical site selection will begin in February Patient enrollment is expected to begin in March The initial abstract submission of preliminary results will be in October 2010, for presentation at the American College of Cardiology Annual Scientific Sessions March Additional presentations will be made at the American Heart Association Scientific Sessions November 2010 and the American College of Cardiology Scientific Sessions March Presentation of final results is anticipated at American Heart Association, Annual Scientific Session in November VERSION R OBERT J. R USSO, MD

95 17. REFERENCES 1. Levine GN, Gomes AS, Arai AE, Bluemke DA, Flamm SD, Kanal E, Manning WJ, Martin ET, Smith JM, Wilke N, Shellock FS. Safety of magnetic resonance imaging in patients with cardiovascular devices: an American Heart Association scientific statement from the Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Council on Cardiovascular Radiology and Intervention: endorsed by the American College of Cardiology Foundation, the North American Society for Cardiac Imaging, and the Society for Cardiovascular Magnetic Resonance. Circulation. 2007;116(24): Shinbane JS, Colletti PM, Shellock FG. MR in patients with pacemakers and ICDs: Defining the issues. J Cardiovasc Magn Reson. 2007;9(1): Faris OP, Shein M. Food and Drug Administration perspective: Magnetic resonance imaging of pacemaker and implantable cardioverter-defibrillator patients.[comment]. Circulation. 2006;114(12): Faris OP, Shein MJ. Government viewpoint: U.S. Food & Drug Administration: Pacemakers, ICDs and MRI.[comment]. Pacing & Clinical Electrophysiology. 2005;28(4): Maisel WH, Moynahan M, Zuckerman BD, Gross TP, Tovar OH, Tillman D-B, Schultz DB. Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports.[see comment]. JAMA. 2006;295(16): Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y, American Heart Association Statistics Committee and Stroke Statistics S. Heart disease and stroke statistics update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e Zhan C, Baine WB, Sedrakyan A, Steiner C. Cardiac device implantation in the United States from 1997 through 2004: a population-based analysis. Journal of General Internal Medicine. 2008;23 Suppl 1: Kalin R, Stanton MS. Current clinical issues for MRI scanning of pacemaker and defibrillator patients. Pacing & Clinical Electrophysiology. 2005;28(4): Roguin A, Schwitter J, Vahlhaus C, Lombardi M, Brugada J, Vardas P, Auricchio A, Priori S, Sommer T. Magnetic resonance imaging in individuals with cardiovascular implantable electronic devices. Europace. 2008;10(3): Shellock FG, Fischer L, Fieno DS. Cardiac pacemakers and implantable cardioverter defibrillators: in vitro magnetic resonance imaging evaluation at 1.5-tesla. Journal of Cardiovascular Magnetic Resonance. 2007;9(1): Martin ET, Coman JA, Shellock FG, Pulling CC, Fair R, Jenkins K. Magnetic resonance imaging and cardiac pacemaker safety at 1.5-Tesla. J Am Coll Cardiol. 2004;43(7 (Print)): Sommer T, Naehle CP, Yang A, Zeijlemaker V, Hackenbroch M, Schmiedel A, Meyer C, Strach K, Skowasch D, Vahlhaus C, Litt H, Schild H. Strategy for safe performance of VERSION R OBERT J. R USSO, MD

96 extrathoracic magnetic resonance imaging at 1.5 tesla in the presence of cardiac pacemakers in non-pacemaker-dependent patients: a prospective study with 115 examinations.[see comment]. Circulation. 2006;114(12): Nazarian S, Roguin A, Zviman MM, Lardo AC, Dickfeld TL, Calkins H, Weiss RG, Berger RD, Bluemke DA, Halperin HR. Clinical utility and safety of a protocol for noncardiac and cardiac magnetic resonance imaging of patients with permanent pacemakers and implantablecardioverter defibrillators at 1.5 tesla. Circulation. 2006;114(12): Iberer F, Justich E, Stenzl W, Tscheliessnig KH, Kapeller J. Nuclear magnetic resonance imaging of a patient with implanted transvenous pacemaker. Herz. 1987;7: Alagona P, Jr., Toole JC, Maniscalco BS, Glover MU, Abernathy GT, Prida XE. Nuclear magnetic resonance imaging in a patient with a DDD Pacemaker. Pacing & Clinical Electrophysiology. 1989;12(4 Pt 1): Inbar S, Larson J, Burt T, Mafee M, Ezri MD. Case report: nuclear magnetic resonance imaging in a patient with a pacemaker. American Journal of the Medical Sciences. 1993;305(3): Gimbel JR, Johnson D, Levine PA, Wilkoff BL. Safe performance of magnetic resonance imaging on five patients with permanent cardiac pacemakers. Pacing Clin Electrophysiol. 1996;19(6 (Print)): Garcia-Bolao I, Albaladejo V, Benito A, Alegria E, Zubieta JL. Magnetic resonance imaging in a patient with a dual-chamber pacemaker. Acta Cardiologica. 1998;53(1): Fontaine JM, Mohamed FB, Gottlieb C, Callans DJ, Marchlinski FE. Rapid ventricular pacing in a pacemaker patient undergoing magnetic resonance imaging. Pacing & Clinical Electrophysiology. 1998;21(6): Anfinsen O-G, Berntsen RF, Aass H, Kongsgaard E, Amlie JP. Implantable cardioverter defibrillator dysfunction during and after magnetic resonance imaging. Pacing & Clinical Electrophysiology. 2002;25(9): Fiek M, Remp T, Reithmann C, Steinbeck G. Complete loss of ICD programmability after magnetic resonance imaging.[see comment]. Pacing & Clinical Electrophysiology. 2004;27(7): Rozner MA, Burton AW, Kumar A. Pacemaker complication during magnetic resonance imaging.[comment]. J Am Coll Cardiol. 2005;45(1): ; reply Roguin A, Donahue JK, Bomma CS, Bluemke DA, Halperin HR. Cardiac magnetic resonance imaging in a patient with implantable cardioverter-defibrillator. Pacing Clin Electrophysiol. 2005;28(4 (Print)): Wollmann C, Grude M, Tombach B, Kugel H, Heindel W, Breithardt G, Bocker D, Vahlhaus C. Safe performance of magnetic resonance imaging on a patient with an ICD. Pacing & Clinical Electrophysiology. 2005;28(4): Naehle CP, Sommer T, Meyer C, Strach K, Kreuz J, Litt H, Lewalter T, Schild H, Schwab JO. Strategy for safe performance of magnetic resonance imaging on a patient with implantable cardioverter defibrillator. Pacing & Clinical Electrophysiology. 2006;29(1): VERSION R OBERT J. R USSO, MD

97 26. Mikolich JR, Martin ET. Images in cardiovascular medicine. Constrictive pericarditis diagnosed by cardiac magnetic resonance imaging in a pacemaker patient. Circulation. 2007;115(7):e Sommer T, Lauck G, Schimpf R, von Smekal A, Wolke S, Block W, Gieseke J, Schneider C, Funke HD, Schild H. [MRI in patients with cardiac pacemakers: in vitro and in vivo evaluation at 0.5 tesla].[see comment]. Rofo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 1998;168(1): Sommer T, Vahlhaus C, Lauck G, von Smekal A, Reinke M, Hofer U, Block W, Traber F, Schneider C, Gieseke J, Jung W, Schild H. MR imaging and cardiac pacemakers: in-vitro evaluation and in-vivo studies in 51 patients at 0.5 T.[see comment]. Radiology. 2000;215(3): Vahlhaus C, Sommer T, Lewalter T, Schimpf R, Schumacher B, Jung W, Luderitz B. Interference with cardiac pacemakers by magnetic resonance imaging: are there irreversible changes at 0.5 Tesla?[see comment]. Pacing & Clinical Electrophysiology. 2001;24(4 Pt 1): Heatlie G, Pennell DJ. Cardiovascular magnetic resonance at 0.5T in five patients with permanent pacemakers. Journal of Cardiovascular Magnetic Resonance. 2007;9(1): Coman JA, Martin ET, Sandler DA, Thomas JR. Implantable Cardiac Defibrillator Interactions with Magnetic Resonance Imaging at 1.5 Tesla. J Am Coll Cardiol. 2004;43:138A. 32. Del Ojo JL, Moya F, Villalba J, Sanz O, Pavon R, Garcia D, Pastor L. Is magnetic resonance imaging safe in cardiac pacemaker recipients? Pacing & Clinical Electrophysiology. 2005;28(4): Gimbel JR, Bailey SM, Tchou PJ, Ruggieri PM, Wilkoff BL. Strategies for the safe magnetic resonance imaging of pacemaker-dependent patients. Pacing Clin Electrophysiol. 2005;28(10 (Print)): Gimbel JR, Kanal E, Schwartz KM, Wilkoff BL. Outcome of magnetic resonance imaging (MRI) in selected patients with implantable cardioverter defibrillators (ICDs). Pacing Clin Electrophysiol. 2005;28(4 (Print)): Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Jr., Froelich JW, Gilk T, Gimbel JR, Gosbee J, Kuhni-Kaminski E, Lester JW, Jr., Nyenhuis J, Parag Y, Schaefer DJ, Sebek-Scoumis EA, Weinreb J, Zaremba LA, Wilcox P, Lucey L, Sass N, Safety ACRBRPoM. ACR guidance document for safe MR practices: 2007.[see comment]. AJR. 2007;American Journal of Roentgenology. 188(6): Nazarian S, Hansford R, Roguin A, Zviman MM, Lardo AC, Calkins H, Berger RD, Bluemke DA, Halperin HR. Abstract 2803: Clinical Utility of Magnetic Resonance Imaging of Patients with Permanent Pacemakers and Implantable-Cardioverter Defibrillators at 1.5 Tesla. Circulation. 2008;118(18_MeetingAbstracts):S_ Cohen JD, Costa HS, Russo RJ. Abstract 2804: Pacemaker and Implantable Cardioverter Defibrillator Safety for Patients Undergoing Magnetic Resonance Imaging (The MagnaSafe Registry). Circulation. 2008;118(18_MeetingAbstracts):S_778-. VERSION R OBERT J. R USSO, MD

98 38. Baigent C, Harrell FE, Buyse M, Emberson JR, Altman DG. Ensuring trial validity by data quality assurance and diversification of monitoring methods. Clin Trials. 2008;5(1): Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods.[see comment]. Statistics in Medicine. 1998;17(8): Tobi H, van den Berg PB, de Jong-van den Berg LT. Small proportions: what to report for confidence intervals? Pharmacoepidemiol Drug Saf. 2005;14(4): VERSION R OBERT J. R USSO, MD

99 MagnaSafe Multicenter Registry Protocol for Pre- and Post-MRI Interrogations 1) Press Interrogate. for initial interrogation ( Quick Start / Interrogate ) a) PRINT programmed settings and patient data from the programmer. 2) Generate NEW interrogation values created at the time of interrogation (not from stored values) for the following parameters: a) Battery Voltage. For BSC/Guidant a value of Good or ERT is given. b) PRINT screen of battery voltage measurement from programmer. c) PACING LEAD IMPEDANCE. d) SHOCK LEAD IMPEDANCE. Perform NEW shock lead impedance measurements if this can be done without a low voltage shock being delivered. e) PRINT screen of impedance measurements from programmer. 3) Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm emerges. a) The patient is dependent if they do not have a stable heart rate when the device is reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic b) PRINT strip of the underlying rhythm from the programmer. 4) For the non-dependent patients only, measure an intrinsic P-WAVE AND R-WAVE. You may use either automatic or manual sensing programmer protocol. a) PRINT strip of the P and R wave electrograms with the measurements. 5) THRESHOLD MEASUREMENTS. IMPORTANT: Use the same pacing rate, pulse width, lead polarity and mode Pre- and Post. a) Perform threshold measurements at 10 beats above the patient s intrinsic rate (if not paced) or 10 beats above the pacing lower rate limit (if paced). Record at what rate the threshold is tested. Testing can be performed in DDD, AAI or VVI mode. If the patient has a competing rhythm, test rate can be increased by 10 bpm until the underlying rhythm is suppressed. b) Test threshold using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased (but this must be recorded on CRF). c) If auto-capture is programmed on, turn the auto-capture off and perform the threshold testing using the routine amplitude decrement mode. When disabling auto-capture, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. d) Record whether the threshold is being tested in a unipolar or bipolar mode. e) PRINT electrograms demonstrating the loss of capture for each lead. 6) PRINT the summary of all of the recorded measurements. 7) Note any reprogramming of device. VERSION R OBERT J. R USSO, MD

100 M AGNAS AFE R EGISTRY D ETAILED P ROCEDURE M ANUAL Before the Scan: Patient is scheduled for a clinically-indicated MRI without acceptable alternative imaging available for a compelling reason by a referring physician. Investigator is notified of potential patient for enrollment. Patient has a permanent pacemaker/icd. If patient has an ICD, they are NOT pacer dependent. Patient is scheduled for a non-thoracic MRI Patient does not have abandoned leads or an abdominal implant. (Optional) Obtain a signed note for the patient chart from the ordering physician indicating: the reason for the MRI is compelling; there is no alternative test available; and the risks and benefits have been preliminarily discussed with the patient. (See Ordering Physician Authorization Letter ) Patient presents 30 minutes prior to MRI to the MRI suite. Patient is screened by MRI staff, routine clinical screening. Clinical informed consent obtained (use site clinical consent for MRI form). Research project described. Inclusion/Exclusion criteria form completed. Patient agrees to be enrolled and is consented for the research project. Research consent signed. Make 3 copies of the signed original. (One copy given to patient, one copy placed in patient chart, one copy to be mailed to coordinating center, and the original placed in research file.) Patient is hooked up to the noninvasive monitor, ECG (3 lead ok), pulse oximetry, BP. Obtain demographic information (top of case report form). Need accurate height and weight to enter into the scanner prior to MRI for accurate SAR calculations. The patient is considered enrolled in the MagnaSafe Registry once they enter the scanner room (when the device is exposed to the magnet). If the patient enters the MRI scanner room, and the scan is not completed for some reason, the protocol and CRFs should still be completed as usual. The patient should be treated as if they completed a scan (the device was exposed to the magnet and the patient is enrolled ). If the patient was consented, but did NOT enter the MRI scanner room for some reason (the device was not exposed to the magnet), they will be considered consented, not enrolled. VERSION R OBERT J. R USSO, MD

101 Pre-Scan Device Interrogation: 1. Interrogate. Press for initial interrogation ( Quick Start / Interrogate ) PRINT programmed settings and patient data from the programmer. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Please note that if the battery voltage reading is ERI, the scan should not be performed. The patient will be considered consented, not enrolled. Note: For Boston Scientific/Guidant pacemakers a value of Good is given. PRINT screen of battery voltage measurement from programmer if possible. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. PRINT screen of impedance measurements from programmer. 5. Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm recovers. 6. The patient is deemed dependent if they do not have a stable intrinsic heart rate when the device is temporarily reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic with a pacing rate less than their programmed lower rate limit. 7. The patient is deemed not dependent if they have a stable intrinsic heart rate and are asymptomatic when the device is temporarily reprogrammed to a lower rate limit of 40 ppm. PRINT strip of the underlying rhythm from the programmer. 8. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). If patient has atrial fibrillation, you do not need to record a P wave even if available. No calculation of a decrease in P wave amplitude should be performed if the patient is in atrial fibrillation even if the programmer is able to measure a P wave. VERSION R OBERT J. R USSO, MD

102 9. For recording purposes, use the lower value of the range reported for the P and R waves (ie. R wave measures mv, please record 10 ) PRINT strip of the P and R wave electrograms with the measurements if available. If the electrograms are not available, then print the screen of the measurement values. 10. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. It is important that the threshold testing after the MRI is performed at the same rate. Testing can be performed in the DDD, AAI or VVI mode. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Please note that if there is ANY change in the threshold when tested at a pulse width other than 0.4 ms, this will be an event and the patient will be required to return for multiple follow ups. Also record whether the threshold is being tested in a unipolar or bipolar mode. If at all possible, test the threshold using the same polarity programmed for the lead. If Autocapture/Capture Management is programmed on, turn the Autocapture/Capture Management off and perform the threshold testing using the routine amplitude decrement mode. When disabling Autocapture/Capture Management, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. Record on the Case Report Form whether the lead was tested in unipolar or bipolar mode. It is important that the postscan threshold measurement is performed with the same lead polarity. PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 11. PRINT the summary of all of the recorded measurements. VERSION R OBERT J. R USSO, MD

103 Programming during the MRI: For non-dependent pacemaker patients: 1. Program the device to ODO or OVO. Monitor patient for 5 minutes to ensure that they are not symptomatic. If the patient is symptomatic, they will be considered dependent and you must follow the instructions for dependent pacemaker patients. 2. Turn the magnet response OFF. In some devices, when the pacing is programmed off (ODO/OVO), the magnet response cannot be disabled. The patient should not have a magnet response since pacing is turned off. However, when at all possible, the magnet response should be disabled regardless. If the magnet response cannot be programmed OFF, note this on the case report form. PRINT from the programmer the screen displaying the new programming settings. Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. For dependent pacemaker patients: 1. Program the device to DOO or VOO at the previously programmed lower rate limit. Monitor the patient for 5 minutes to ensure that these settings are tolerated. The pacing rate may be increased in 10 ppm intervals if necessary for suppression of any ectopy. 2. Turn the magnet response off. If the magnet response cannot be disabled, the observing physician must determine if the patient can tolerate the magnet pacing rate for the duration of the MRI examination. If the patient cannot tolerate the magnet pacing rate, they will not enter the scanner and will be considered consented, not enrolled. PRINT from the programmer the screen displaying the new programming settings. Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. For ICD patients: If an ICD patient is determined at this point to be pacing dependent in the setting of having an ICD, they cannot be enrolled in the study and will be considered consented, not enrolled. The patient cannot enter the magnet. For non-dependent ICD patients: 1. Program the pacing to OFF (ODO or OVO). 2. Turn all tachycardia therapies to off. VERSION R OBERT J. R USSO, MD

104 PRINT from the programmer the screen displaying the new programming settings. Be sure that you have also previously printed the initial programming values so that they can be restored at the conclusion of the study. It is also helpful to print a summary page of the changes made if available (usually found under the Reports menu). This will ensure that you have noted all of the programming changes made during the scan and all of the original parameters are restored following the scan.be sure the Demographics information and MRI scanner information is filled out on the Case Report Form. Device information from the interrogation can be filled out on the Case Report form. The MRI Scanner: 1. Patient enters the MRI scanner and is positioned for the scan. Ensure that the monitor is displaying the ECG, pulse oximetry and blood pressure when the table moves into the tube. 2. Please note the time when the patient enters the scanner room. 3. Blood pressure, oxygen level saturation, and pulse should be monitored throughout the exam and values recorded at the beginning, middle and end of the exam on the Case Report Form. 4. Take initial heart rate, pulse ox, and blood pressure readings and enter on the case report form. 5. Complete other information on the Case Report Form: MRI Procedure Body region scanned, contrast used, reason for the scan. 6. Initiate scan. 7. Many sequences will cause interference on the ECG. Therefore, it is important that the pulse oximeter is in place at all times and a sufficient wave form is present to monitor the patient s pulse. 8. Monitor the patient for: death, electrical reset to on, loss of pacemaker capture for patients programmed VOO or DOO, a new episode of atrial fibrillation that occurs after the patient enters the MRI scanner room, ventricular tachycardia or ventricular fibrillation after the patient enters the MRI scanner room, and syncope. Immediate intervention or ACLS protocols should be followed as necessary. If any of these events occur, the Adverse Event Form must be filled out and filed with the coordinating center and your institutional IRB. 9. There is a risk that the magnet will cause the device to undergo a hard reset and enter backup mode. In patients who are dependent and reprogrammed to VOO, this will result in a reversion to VVI mode. The magnet can then inhibit pacing and the patient will be asystolic. This must be recognized immediately and the patient removed from the scanner. VERSION R OBERT J. R USSO, MD

105 The device should no longer be inhibited when the patient is removed from the scanner room. The procedure should be aborted at this point and the device reprogrammed to initial values. A full follow up interrogation should be performed as described below and the patient will be followed according to the multiple follow up schedule. If this occurs, the Adverse Event Form must be filled out and filed with the coordinating center and your institutional IRB. Please note that St. Jude Medical devices will require engineering assistance to reprogram the device. Please place a call immediately to bradycardia technical services and they will guide you through the reset process. 10. Monitor the patient for pre-syncope, a heart rate <40 bpm with symptoms of bradycardia, and other patient symptoms and complaints. These should be noted on the Case Report Form if they occur. 11. Note on the Case Report Form the scan sequences used. 12. Instruct your technicians that normal operating mode should be maintained if at all possible. Note if the SAR limit is reached on any scan. Note which scan sequence was being performed when SAR limit was reached. If normal operating mode is maintained, note the parameter that is changed. If it is necessary to change to First Level Controlled Operating Mode, this should be recorded. If SAR is reached on multiple sequences, please record each one and the steps taken regarding Normal Operating Mode or First Level Controlled Operating Mode. Note: If it is necessary to change to First Level Controlled Operating Mode, a Study Deviation form must be filled out. 13. Take mid-scan readings of heart rate, pulse ox, and blood pressure and enter on the case report form. 14. Take end-of-scan readings of heart rate, pulse ox, and blood pressure and enter on the case report form. 15. Once the scan is completed, the patient is removed from the MRI scanner room and the follow up interrogation is performed immediately. 16. All of the following events are considered adverse events if they occur during the MRI scan: a. Death b. Electrical reset-to-on c. Loss of pacemaker capture for patients programmed to an asynchronous mode (VOO, DOO) d. New onset atrial fibrillation occurring during the MRI scan e. Ventricular tachycardia f. Ventricular fibrillation g. Device failure requiring immediate generator or lead replacement. VERSION R OBERT J. R USSO, MD

106 Note: If any of these Adverse Event events occur, an Adverse Event Form must be completed, and the event reported to the Coordinating Center within 48 hours of the event. Report to the reviewing IRB according to site policy. These patients will require multiple follow-up visits. Note: If any UADE (unanticipated adverse device effects) occur (any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity or degree of incidence in the investigational plan or application) then an Adverse Event Form must be filled out and filed as soon as possible, but no later than 10 business days after the investigator first learns of the effect. Report to the reviewing IRB according to site policy. These patients will require multiple follow-up visits. VERSION R OBERT J. R USSO, MD

107 Post-Scan Device Interrogation: 1. Restore initial parameters. Ensure that tachycardia therapies are all turned on and restored to initial detection criteria. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: If the battery voltage decreased by 0.04 V, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. Note: For Boston Scientific/Guidant pacemakers a value of Good is given. A repeat measurement will either be listed as Good or ERT. If ERT is noted after the scan, please mark this as a battery voltage change of 0.04 V and schedule the patient for multiple follow up visits. PRINT screen of battery voltage measurement from programmer. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: If the pacing lead impedance in any lead changed by 50 Ω, this is a significant event. This must be marked on the Case Report Form under the Follow- Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. Note: If the shock lead impedance changed by 3 Ω, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT screen of impedance measurements from programmer. 5. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). VERSION R OBERT J. R USSO, MD

108 6. For recording purposes, use the lower range of the reported P and R waves (ie. R wave measures mv, please record 10 ). If patient has atrial fibrillation, you do not need to record a P wave even if available. No calculation of a decrease in P wave amplitude should be performed if the patient is in atrial fibrillation even if the programmer is able to measure a P wave. Note: If the P wave measurement decreased by 50%, this is a significant event. If the R wave measurement decreased by 25%, this is a significant event. These must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT strip of the P and R wave electrograms with the measurements. 7. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. Testing can be performed in the DDD, AAI or VVI mode. It is important that the threshold testing after the MRI is performed at the same rate, with the same pulse width, and in the same mode as before the MRI, if at all possible. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Also record whether the threshold is being tested in a unipolar or bipolar mode. The threshold should be tested using the same polarity as used in the pre-mri interrogation. If Autocapture/Capture Management is programmed on, turn the Autocapture/Capture Management off and perform the threshold testing using the routine amplitude decrement mode. When disabling Autocapture/Capture Management, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. It is important to duplicate the pre-scan threshold testing (pacing rate, pulse width, and lead polarity). Note: If both the pre-mri and post-mri threshold tests are performed at a pulse width of 0.4 ms and there is a decrease in the threshold in any lead by 0.5 V, this VERSION R OBERT J. R USSO, MD

109 is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. If the pre-mri and post-mri threshold tests are performed at a pulse width other than 0.4 ms and there is any decrease in the threshold in any lead, this is a significant event. This must be marked on the Case Report Form under the Follow-Up Schedule and the patient must be scheduled for multiple follow ups: 7 days, 3 months and 6 months. PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 8. PRINT the summary of all of the recorded measurements. 9. PRINT a summary of the current programmed parameters. If there were any changes made to the programming of the device, this must be listed on the Case Report Form under Other Outcomes. 10. Determine if there were any changes to the device parameters that require multiple follow-up visits: A pacing lead threshold increase 0.5 V when measured at 0.4 ms. (If the threshold had to be tested at a pulse width other than 0.4 ms, then ANY increase in the threshold will require multiple follow-up visits.) Decrease in battery voltage 0.04 V A pacing lead impedance change of 50 ohms A shock lead impedance change of 3 ohms A P wave decrease of 50% An R wave decrease of 25% 11. Schedule single or multiple follow-up visits as needed. 12. Record CRF data in online data base entry system within 2 days. 13. Report any Adverse Events or UADE to the Coordinating Center and reviewing IRB. 14. Report Protocol Deviations that might affect the safety of subjects to the Coordinating Center and reviewing IRB 15. Mail hard copies of consents and interrogation reports to the coordinating center by FedEx. VERSION R OBERT J. R USSO, MD

110 Follow-up Visit Interrogation: 1. Interrogate. Press for initial interrogation ( Quick Start / Interrogate ) PRINT programmed settings and patient data from the programmer. 2. Perform a NEW battery voltage measurement (need a new value, not the one on the initial printout). This is the value that will be recorded on the case report form, not the one that came out on the initial interrogation. Note: For Boston Scientific/Guidant pacemakers a value of Good or ERT is given. PRINT screen of battery voltage measurement from programmer if possible. 3. Perform NEW pacing lead impedance measurements. These are the values that will be recorded on the case report form, not the one that came out on the initial interrogation. 4. Perform NEW shock lead impedance measurements if can be done without a low voltage shock being delivered. Need to record both the RV and SVC coil impedances if reported by the programmer. PRINT screen of impedance measurements from programmer. 5. Determine the underlying rhythm. If the patient appears to be dependent, confirm by gradually lowering the pacing rate to see if an escape rhythm recovers. 6. The patient is deemed dependent if they do not have a stable intrinsic heart rate when the device is temporarily reprogrammed to a lower rate limit of 40 ppm OR if they are symptomatic with a pacing rate less than their programmed lower rate limit. 7. The patient is deemed not dependent if they have a stable intrinsic heart rate and are asymptomatic when the device is temporarily reprogrammed to a lower rate limit of 40 ppm. PRINT strip of the underlying rhythm from the programmer. 8. For the non-dependent patients, measure an intrinsic P and R wave (can use either automatic or manual sensing programmer protocol). If patient has atrial fibrillation, you do not need to record a P wave even if available. 9. For recording purposes, use the lower value of the range reported for the P and R waves (ie. R wave measures mv, please record 10 ) PRINT strip of the P and R wave electrograms with the measurements if available. If the electrograms are not available, then print the screen of the measurement values. VERSION R OBERT J. R USSO, MD

111 10. Threshold measurements: Will be performed at 10 beats above the patient s intrinsic rate (if not currently paced) or 10 beats above the pacing lower rate limit (if the patient is paced). If the patient has a competing intrinsic rhythm that makes measurement of the threshold difficult, the test pacing rate can be increased by 10 ppm intervals until the underlying rhythm is suppressed for the threshold measurement. Please record at what rate the threshold is tested. Testing can be performed in the DDD, AAI or VVI mode. Threshold will be tested using an amplitude decrement mode. The threshold needs to be measured at a fixed pulse width of 0.4 ms, regardless of the programmed pulse width. If the threshold is greater than the highest amplitude at a pulse width of 0.4, then the pulse width can be increased but this must be recorded on the case report form. The same pulse width must be used for the pre and post scan interrogations. If the threshold is less than 0.25 V at a pulse width of 0.4 ms, then the threshold recorded on the case report form should be 0.25 V. Also record whether the threshold is being tested in a unipolar or bipolar mode. If autocapture is programmed on, turn the autocapture off and perform the threshold testing using the routine amplitude decrement mode. When disabling autocapture, the lead may default to test in unipolar mode. Adjust and test in bipolar mode if possible. Whenever possible, try to duplicate the threshold testing performed at the time of the MRI (pacing rate, pulse width, and lead polarity). PRINT screen shot of the electrograms demonstrating the loss of capture for each lead. 11. PRINT the summary of all of the recorded measurements. 12. Confirm any follow-up visits that were required. 13. Record CRF data in remote data base entry system within 2 days. 14. Report any Adverse Events or UADE to the Coordinating Center and reviewing IRB. 15. Report Protocol Deviations that might affect the safety of subjects to the Coordinating Center and reviewing IRB 16. Mail hard copies of consents and interrogation reports to the coordinating center by FedEx. VERSION R OBERT J. R USSO, MD

112 IDE Document Mail Center (HFZ-401) Center for Devices and Radiological Health Food and Drug Administration 9200 Corporate Boulevard Rockville, MD September 8, 2009 RE: Supplement to IDE G MagnaSafe Registry 5-day Notice of IDE Change This supplement submission contains modifications to the protocol allowable under 21 CFR812.35, and we are providing notice of these changes within 5 working days. These changes do NOT affect validity of data/information; patient risk to benefit relationship; scientific soundness of plan; or rights, safety or welfare of subjects. The protocol currently states that the PI and physician supervising the MRI scan must be a cardiologist. The intent of this was to indicate that a physician with the appropriate expertise will be present during the scan to program devices, interpret parameter changes, and to handle emergent situations. We would like to amend the protocol to clarify this intent, and allow inclusion of physicians with appropriate training and expertise to supervise the procedure who may not have the specific title of cardiologist. For example, a physician who is board certified in cardiothoracic surgery, and is accredited by the HRS/NASPE (Heart Rhythm Society/North American Society of Pacing and Electrophysiology) is also qualified to oversee the procedure. The new version containing these and other minor changes is dated version A detailed description of the changes, cross-referenced to the appropriate sections of the previous version ( ) of the protocol, is provided in the attached table. A red-lined version of the protocol with tracked changes is also provided. We have enclosed 2 hard copies of the revised documents and, per the instructions accessed at an electronic copy is being provided for this submission and it is an exact duplicate of the original paper submission dated IDE # G Page 1 of 3

113 If you require any additional information, please do not hesitate to contact me by phone , pager or In addition, my research associate Heather Costa may be contacted at by phone or Sincerely, Robert J. Russo. MD, PhD Applicant/Sponsor: Dr. Robert J. Russo Scripps Clinic, SW Torrey Pines Road La Jolla, CA / FAX: Contact Person: Heather S. Costa Scripps Clinic, SW Torrey Pines Road La Jolla, CA Phone: FAX: IDE # G Page 2 of 3

114 Minor changes to the protocol were made as follows. The new version is dated version Location Change Reason 1 Footer Version date changed New version Section 1.3 Page 8 Section 3.1 Page17 Section Page18 Section 3.5 Page 21 Section Page30 Section 10.1 Page 32 Section 10.1 Page 32 Section 10.2 Page 32 Section Page 13 Section Page14 Section 2.5 Page 16 Changed cardiologist to cardiologist or other qualified physician Changed #4 to read: 4) Cardiologist or other qualified physician with a working knowledge of pacemaker and ICD function and programming and a willingness to participate in the study. Inserted the following: Other qualified physician includes, but is not limited to, a physician board certified in cardiac surgery, critical care medicine, or anesthesiology, with training in pacemaker and ICD function and programming. Changed #1 to read: 1) Board certified general cardiologist, a cardiologist with subspecialty training in cardiac electrophysiology, or other qualified physician with appropriate training and experience to supervise the performance of the protocol. Unit abbreviation changed to: There were no P wave decreases of 1.0 mv and no R wave decreases 2.0 mv. None of the pacing leads had a threshold increase 0.5 V. Removed: (instead of an absolute decrease of 1.0 V) from #4 (instead of an absolute decrease of 2.0 V) from #5 Now reads: 4) A P wave decrease of 50%. 5) An R wave decrease of 25% Changed index to indicated in number 7. Device generator battery voltage at elective replacement indicated (ERI) Clarification to include qualified physicians who do not technically hold the title of cardiologist. Correction of unit abbreviation. Correction to clarify parameter change measurement used. Correction IDE # G Page 3 of 3

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117 MagnaSafe Multicenter Registry TO: RE: MagnaSafe Participating Sites MagnaSafe Registry Exclusion of MRI-Conditional Devices DATE: November 4, 2011 Dear Colleague, During the course of the MagnaSafe Registry, the first MRI-conditional cardiac device was approved by the FDA for marketing in the United States. These devices are beginning to appear for clinically indicated MRI procedures at various locations throughout the country. After careful consideration, we have decided to exclude FDA approved MRI-conditional devices from the MagnaSafe registry, and maintain the registry as a source of information on the risk of MRI for patients with cardiac devices that were not specifically designed for MRI exposure. MRI procedures on patients with MRI-conditional devices should be performed according to the device label, following the specified MRI conditions for use and device programming. However, these patients should not be consented for, or enrolled in, the MagnaSafe Registry. Clinically-indicated MRI studies performed on patients with MRI-conditional devices (approved by FDA for use in MRI) are covered under Medicare NCD, so inclusion in a research study is not required for Medicare coverage of the MRI. Sites that are participating in the MagnaSafe Registry can also participate in post-market studies associated with the MRI-conditional devices. If you require any additional information, please do not hesitate to contact me by phone , pager or Russo.Robert@scrippshealth.org. In addition, my research associate Heather Costa, may be contacted by phone at or Costa.Heather@scrippshealth.org. Sincerely, Robert J. Russo. MD, PhD IDE # G Page 1 of 1

118 Center for Devices and Radiological Health Food and Drug Administration Document Mail Center WO66-G New Hampshire Ave Silver Spring, MD June 27, 2013 RE: Supplement to IDE G MagnaSafe Registry Supplement - 28 Request for Additional Enrollment To Whom It May Concern: This supplement to IDE G associated with the MagnaSafe Registry is being submitted to request an amendment to the IDE as follows: We are requesting approval for an increase in total enrollment from 1500 total cases to 2500 total cases with an extended investigation to allow continued enrollment of pacemakers so that the target enrollment of ICDs may be reached. Our original request for the study was to enroll 1000 Pacemakers and 500 ICDs. This request was based on our sample size estimate and the expected enrollment ratio of pacemaker to ICDs to be approximately 2:1. However, enrollment has reached 1200 cases, and the rate of enrollment of pacemakers to ICDs has been steady at 3:1, rather than 2:1. The slower than expected enrollment rate of ICDs may be due to the additional registry exclusions associated with ICDs. ICD cases are excluded if the patient is pacing dependent, while dependent patients with pacemakers are not excluded (about 26% of all pacemaker cases have been pacemakerdependent). In addition, abandoned leads are more likely to be present in cases where patients have been upgraded from a pacemaker to an ICD (the original pacing lead being capped off and left in place), and these cases must also be excluded. IDE # G Page 1 of 2

119 Currently, more than 1200 cases have been enrolled in the MagnaSafe registry, and throughout enrollment, the proportion of ICDs has remained steady at 25%. To reach the full sample size target of at least 500 ICD cases, we are requesting to continue enrollment to a total of 2500 total cases using the current protocol. As part of this process, we are requesting an extended investigation to allow sites to continue to enroll subjects that have pacemakers as well as those with ICDs until a total of 2500 devices have been enrolled. Logistically, it is difficult for sites to continue to participate in MagnaSafe while performing procedures for ICDs only, while excluding pacemakers. In addition, Medicare only allows coverage of MRIs in patients with pacemakers or ICDs if they are performed in a research study, such the MagnaSafe Registry, which meets CED (coverage with evidence development) criteria. A submission to Medicare to request expanded NCD coverage of MRI with devices will require data that has been accepted as a peer reviewed publication with adequate sample size. Specifically, as it relates to risk:benefit for patients enrolled in MagnaSafe: 1) There is a public health need for patients with pacemakers and ICD to have continued access to MRI procedures (and Medicare coverage), and 2) The most recent annual report for this IDE (the MagnaSafe Registry) on the first 1000 subjects enrolled in the study has been submitted and accepted by the FDA. These data provide preliminary evidence that the procedure is effective and no significant safety concerns have been identified. We have enclosed 2 hard copies of this document, and per the instructions accessed at ments/ucm pdf, an electronic copy is being provided for this submission and it is an exact duplicate of the original paper submission dated June 27, 2013 If you require any additional information, please do not hesitate to contact me by phone , pager or Russo.Robert@scrippshealth.org. In addition, my research associate Heather Costa may be contacted by phone at or Costa.Heather@scrippshealth.org. Sincerely, Robert J. Russo. MD, PhD Applicant/Sponsor Torrey Pines Road La Jolla, CA Phone: FAX: costa.heather@scrippshealth.org Contact Person: Heather S. Costa Scripps Clinic, SW-206 IDE # G Page 2 of 2

120 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service July 30, 2013 Food and Drug Administration New Hampshire Avenue Document Control Center WO66-G609 Silver Spring, MD Scripps Clinic Attention: Mr. Robert Russo Torrey Pines Road La Jolla, CA Re: G090031/S028 MagnaSafe Registry Dated: June 27, 2013 Received: June 28, 2013 CMS Category: Category B4 Annual Report Due: March 10, 2014 Dear Mr. Robert Russo, The Food and Drug Administration (FDA) has reviewed the supplement to your investigational device exemptions (IDE) application for the MagnaSafe Registry which is proposing an expansion of your investigation to 2500 total cases. Your supplement is approved and you may implement that change in accordance with the investigational site waiver granted in our March 10, 2009 letter. Your investigation is limited to 35 institutions and 2500 subjects. If you have any minor clarification questions concerning the contents of the letter, please contact Dharmesh Patel at or for Sincerely yours, Owen P. Faris -S Bram D. Zuckerman, M.D. Director Division of Cardiovascular Devices Office of Device Evaluation Center for Devices and Radiological Health