ProMRI System Technical Manual Jan 2015

CAUTION Federal (U.S.A.) law restricts this device to sale by, or on the order of, a physician (or properly licensed practitioner). © 2015 BIOTRONIK, Inc., all rights reserved.

Table of Contents ProMRI System Technical Manual ®

Contents 1. Basic information...1 1.1 About this Manual...1 1.1.1 Subject of this manual...1 1.1.2 What this manual doesn’t include...1 1.2 Target Group...1 1.2.1 Cooperation between professionals from two areas of expertise...1 1.2.2 Knowledge required by the cardiology specialist...1 1.2.3 Knowledge required by the radiology specialist...1 1.3 Active device and lead ...2 1.3.1 Patient Selection, MRI indication...2 1.3.2 Intended use...2 1.3.3 Residual risk ...2 1.4 ProMRI® System...2 2. Safety Warnings...3 2.1 Magnetic Resonance Imaging - Possible Interactions...3 2.1.1 Problematic interactions ...3 2.1.2 Fields in the MRI scanner...3 2.1.3 Force of the static and gradient magnetic fields...3 2.1.4 Interactions resulting from induced AC voltages...3 2.1.5 Thermal interactions ...4 2.1.6 Image interference and artifacts...4 2.2 Warnings...4 2.2.1 Preliminary notes ...4 2.2.2 Warnings...4 3. MRI Conditions for Use...5 3.1 Patient Pre-MRI Conditions...5 3.2 MRI Scanner Limitations...5 3.3 Restrictions during the MR Scan...5 3.4 Permissible Positioning Zone and Scan Exclusion Zone...6 4. MRI Examination...7 4.1 Preliminary Examination...7 4.1.1 Cooperation between specialists...7 4.1.2 Checking the suitability of the patient and the implanted system...7 4.1.3 Performing an MR Scan and Programming the MRI Mode...7 4.2 MRI Examination...9 4.2.1 Prerequisites...9 4.2.2 Basic conditions and restrictions...9 4.2.3 Completion of the examination...9

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Table of Contents ProMRI® System Technical Manual

5. Post MR Scan Requirements ���������������������������������������������������������������������������������������������11 5.1 Follow-Up Procedure...11 6. ProMRI/ProMRI AFFIRM Clinical Studies �������������������������������������������������������������������������13 6.1 Introduction...13 6.2 Primary Objectives...13 6.3 Methods...13 6.4 Results...13 6.4.1 Primary Endpoint 1...14 6.4.2 Primary Endpoints 2 & 3...14 6.4.3 Primary Endpoints 4 & 5...17 6.5 Conclusions...21 6.5.1 Overall Results...21 7. Adverse Events...23 7.1 Observed Adverse Events...23 7.1.1 ProMRI/ProMRI AFFIRM...23

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Chapter 1 Basic information ProMRI® System Technical Manual

1. Basic information 1.1 About this Manual 1.1.1 Subject of this manual The manual provides information about the safe application of an MR scan on patients with a ProMRI® system, which consists of a ProMRI® pacemaker listed in Section 1.4 and the Setrox S and Safio S leads. This manual will focus on the MRI conditions and safety measures that are to be adhered to before and during an MR scan using the ProMRI® system.

1.1.2 What this manual doesn’t include Correct and safe use of the Entovis and Eluna pacemakers and Setrox S and Safio S leads is described in the technical manuals provided with the products and is not a subject of this manual. Correct and safe use of an MRI scanner is not described in this manual unless directly related to the ProMRI® System.

1.2 Target Group 1.2.1 Cooperation between professionals from two areas of expertise This manual is intended for physicians and medical staff who have the knowledge and experience required to prepare and perform MR scans on patients with a pacemaker. Preparation and application of an MR scan on a pacemaker patient requires close cooperation between a cardiology professional, as a specialist for the device system, and a radiology professional, as a specialist for the MR scan. The following sections describe the tasks that each of these specialists is responsible for.

1.2.2 Knowledge required by the cardiology specialist A cardiology professional is required to select and/or approve the patient for the MR scan. Additionally, they must test the device system before the exam, program the device to the MRI mode, ensure its functionality after the exam and program it back to the mode which was active before the MR scan. The cardiology professional should be knowledgeable in the following areas and subjects: • Performing pacemaker therapy • Handling the BIOTRONIK programmer and especially the following activities: -- Interrogating the active device -- Performing follow-up -- Switching parameters including programming the device to the MRI Mode • All associated risks, possible side effects, and the appropriate safety and therapy measures

1.2.3 Knowledge required by the radiology specialist The radiology professional is responsible for the successful performance of the MR scan for the purposes of the desired diagnosis. Additionally, the radiology professional is also responsible for ensuring that the restrictive conditions, for which the MRI is to be performed, are observed both before and during the MR scan.

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Chapter 1 Basic information ProMRI® System Technical Manual

The radiology professional should be knowledgeable in the following areas and subjects: • Handling MRI scanners • Preparation, performance and analysis of MR scans

1.3 Active device and lead The respective intended use of the ProMRI pacemakers and the Setrox S and Safio S lead(s) applies to use of the device system. NOTE: The technical manuals for the ProMRI pacemakers and the Setrox S and Safio S lead(s) are to be observed.

1.3.1 Patient Selection, MRI indication Before a patient with an MR conditional device system is selected for an MR scan, the following issues must be resolved: • • • •

There must be a clear indication for the MR scan. Risk/benefit analysis All of the exclusion criteria listed in this technical manual have been taken into consideration. The described restrictions and conditions for the MR scan are to be observed at all times.

1.3.2 Intended use If particular MRI conditions are fulfilled, MR scans can now be conducted on patients with a combination of a BIOTRONIK active device and lead that has been tested for this purpose.

1.3.3 Residual risk The expected risks and hazards are minimized by the measures performed in this manual. Nevertheless, a residual risk remains.

1.4 ProMRI® System The ProMRI® System consists of the following BIOTRONIK legally marketed devices listed below: Model

Order number

Model

Order number

Entovis DR

371 991

Entovis SR

371 993

Entovis DR-T

371 992

Entovis SR-T

371 994

Eluna DR

394 970

Eluna SR

394 972

Eluna DR-T

394969

Eluna SR-T

394 971

These pacemakers can be combined with any of the following leads: Lead model

Order number

Setrox S 53

350 974

Setrox S 60

350 975

Safio S 53

370 945

Safio S 60

370 946

Since the ProMRI® pulse generators and the leads are sold independently of each other, this manual informs the user about the MRI conditions for use that are to be observed. PAGE 2

Chapter 2 Safety Warnings ProMRI® System Technical Manual

2. Safety Warnings 2.1 Magnetic Resonance Imaging - Possible Interactions 2.1.1 Problematic interactions Significant mechanisms which can lead to problematic interactions with device systems are described here. Therefore, MR scans are generally contraindicated for cardiac pacemaker patients. BIOTRONIK has developed the ProMRI® System, which minimizes the effects listed below on the device system and the patients.

2.1.2 Fields in the MRI scanner The following three types of fields are generated in an MR scan: • Static magnetic field This is a consistently strong, rectified magnetic field, which is constantly emitted in the MRI scanner and its immediate surroundings, even if no scan is being performed. • Gradient magnetic fields These are low-frequency pulsed magnetic fields with a relatively low amplitude. During the MR scan, the patient is exposed to three vertical gradient magnetic fields that are facing towards each other. • HF field (high frequency field) This is a high frequency electromagnetic field which activates the protons on their resonance frequency. It is switched on several times during the imaging process but only for very short periods. The HF field is created by so-called emitting coils, which also serve as reception coils. Differentiation is made between the emitting coils (body coils) integrated in the MRI scanner with the addition of optional local emitting coils (e.g. head coil with transmitting function).

2.1.3 Force of the static and gradient magnetic fields Implanted ferromagnetic materials are subject to the force of these magnetic fields. This means that implanted devices can subject the surrounding tissue to pressure, tensile force or vibrations. The construction and choice of material in the MR conditional devices and compliance with the specified conditions serve to reduce these stresses to an acceptable minimum.

2.1.4 Interactions resulting from induced AC voltages Gradient magnetic fields and electromagnetic high frequency fields can induce electrical AC voltages in metallic devices. In some cases, these electrical energies can result in undesirable pacing or have a negative impact on the pacemaker. Constructive measures on the MR conditional devices and the restrictive prerequisites for the arrangement and conduction of the MR scan reduce the probability of occurrence and strength of this effect. However, this effect cannot be entirely excluded. Among other things, corresponding emergency precautions in this case have to be taken.

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Chapter 2 Safety Warnings ProMRI® System Technical Manual

2.1.5 Thermal interactions High-frequency electromagnetic fields induce electric voltages in the lead, which cause current conduction through the lead and the tissue electrically connected to the lead. This flow of current in turn causes warming at the electrical points of contact between the lead and the tissue, which can result in thermal damage to the surrounding tissue. This thermal tissue damage can be temporary or lasting and can cause deterioration of the lead’s pacing and sensing functions. Gradient magnetic fields can cause warming of the device housing, which can lead to thermal exposure and damage to the surrounding tissue. Due to the constructive composition of the MR conditional devices and the compliance with the tested conditions and restrictions for the MR scan, these thermal effects are kept to a tolerable measure.

2.1.6 Image interference and artifacts Not only can the MR scan have undesirable effects on the patient or the device system, but the implanted devices can also have a negative impact on the MR scan. If the devices are outside the scanning area, they can cause slight image distortion and interference. If a device is within the area shown by the MRI scanner, then artifacts, distortion and interference are probable. Consider this when selecting the image calculation parameters and the depicted area.

2.2 Warnings 2.2.1 Preliminary notes Please refer to the technical manuals for the Entovis and Eluna pacemakers and Setrox S and Safio S leads. This manual only deals with aspects that are relevant within the MR scan context. This manual does not deal with the contraindications of MRI applications, which do not result from interactions with a device system.

2.2.2 Warnings • An MR scan on a device system patient is always contraindicated for device systems which have not been identified as MR conditional by BIOTRONIK and have not been approved for MRI applications by the FDA. • An MR scan on a patient with an MR conditional device system is also contraindicated when any of the conditions listed in the MRI Conditions for Use (Section 3) are not adhered to. • The MR Conditional device system must be programmed to the MRI Mode prior to the MR scan.

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Chapter 3 MRI Conditions for Use ProMRI® System Technical Manual

3. MRI Conditions for Use 3.1 Patient Pre-MRI Conditions The following requirements must always be fulfilled in order to perform an MR scan using BIOTRONIK’s ProMRI® System: • The device system consists of a pacemaker with the respective leads that are separately labeled MR conditional and, when combined, constitutes an MR conditional device system (See Section 1.4). • There are no other active or abandoned cardiac implants (e.g., lead extensions, lead adapters or abandoned leads) in the patient’s body. • Other active or passive implants are permitted if they are identified as MR conditional by the manufacturer. Note: An MRI scan is permitted only if the product-specific conditions are met for all implants. • • • • • • •

Other implanted active medical devices are ≥ 4 cm distance from the ProMRI® system. The leads have been implanted for at least 6 weeks. The device system is implanted pectorally. The measured pacing threshold is not above 2.0 V at 0.4 ms pulse width. The pacing system should be functioning normally prior to an MRI. The battery status is neither ERI nor EOS. The device is programmed to a MRI mode immediately before the MR scan.

3.2 MRI Scanner Limitations The MRI scanner has to meet the following conditions: • Use of a clinical MRI system with a cylindrical bore or elliptical bore and a static magnetic field strength of 1.5 Tesla. • The slew rate of the MRI scanner’s gradient fields should not exceed 200 T/m/s per axis.

3.3 Restrictions during the MR Scan The following conditions must be met during the MR scan: • The MR scan should be performed with the patient in supine position. • The mean specific absorption rate (SAR) for the whole body displayed by the MR scanner must not exceed 2.0 W/kg. • The head absorption rate displayed by the MRI scanner must not exceed 3.2 W/kg. • Emergency equipment for resuscitation must be kept at hand and properly certified staff must be available. • Continuously monitor the patient’s condition during the entire MR scan using at least one of the following parameters: blood oxygen saturation, blood pressure or ECG. Note: The ECG function integrated in the MRI scanner is often not permitted for patient monitoring. Therefore, only use devices which are permitted for patient monitoring in an MRI environment.

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Chapter 3 MRI Conditions for Use ProMRI® System Technical Manual

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Chapter 4 MRI Examination ProMRI® System Technical Manual

4. MRI Examination 4.1 Preliminary Examination 4.1.1 Cooperation between specialists Preparation and conduction of an MR scan on a patient with the ProMRI® System requires close cooperation between a specialist for the device system and a specialist for the MRI technology and MR scan. One of these specialists has to perform the steps described in the following for preparation of the MR scan, the patient and his or her device system. The person responsible for each task depends on the activity or context of the scan.

4.1.2 Checking the suitability of the patient and the implanted system Cardiology and radiology professionals are required for this step, proceed as follows: Step

Action

1

Check and ensure that all requirements pertaining to the patient and the device system described in the ProMRI® System (Section 1.4) and MRI Conditions for Use (Section 3) are met.

2

Make sure the technical and clinical basic conditions for the MR scan can be met and that the necessary preparations have been made.

4.1.3 Performing an MR Scan and Programming the MRI Mode Once the conditions for an MR scan have been clarified, preliminary examination and programming to an MRI mode by the cardiologist are the final and definitive preparation measures; proceed as follows: Step 1

Action Apply the programming head of the programmer to the chest and interrogate the pacemaker. Perform full follow-up and check the following preconditions for the MR scan:

2

• Normal device functionality • Battery status is neither ERI nor EOS • Pacing threshold: max. 2.0 V / 0.4 ms Programming the MRI Mode Open the MRI program using one of the following options:

3

• Select Follow-up MRI. • Select Parameters Bradycardia Show MRI program • Select Parameters Bradycardia

Program sets MRI Mode (for Eluna only)

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Chapter 4 MRI Examination ProMRI® System Technical Manual

Step

Action Read the preliminary and basic conditions in the MRI checklist window precisely and activate the checkbox I accept the conditions for MRI examinations.

4

The software will not permit further programming of an MRI mode without this confirmation.

WARNING

Health risk to patients due to limited pacemaker function. Continuous cardiac monitoring of the patient must be ensured until the device system’s full functionality is restored in the follow-up examination. Activate one of the possible MRI modes.

5

• The OFF setting is recommended for patients not dependent on their pacemaker. • An asynchronous mode (D00, A00, V00) is recommended for pacemaker-dependent patients depending on the particular indication. Select the basic rate (for Eluna only). (For Entovis, the basic rate is set to 80 bpm.) The following parameters are set for pacemakers: • • • •

Pulse amplitude: 4.8 V Pulse width: 1.0 ms All automatic functions and Home Monitoring are deactivated. The magnet response is set to SYNC (synchronous).

NOTE: You will leave the MRI mode if you change parameters prior to programming the device.

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Chapter 4 MRI Examination ProMRI® System Technical Manual

Step 6

Action Transmit the MRI mode to the pacemaker.

NOTE: When programming the MRI mode in Entovis, the original pacemaker settings are saved in the programmer. These settings can be accessed again during the follow-up examination after completion of the MR scan, which simplifies restoration of the status from before the MR scan. The same programmer must be used as for the preliminary examination. For Eluna pacemakers, the original pacemaker settings are stored in the pacemaker when the MRI mode is programmed. Therefore, the permanent program can be restored even when the pacemaker is interrogated by a different programmer after the MR scan. 7

Print and document follow-up data (print report). Finish the preliminary examination of the patient.

8

Make sure that the patient can be immediately submitted to follow-up after completion of the MR scan.

4.2 MRI Examination 4.2.1 Prerequisites The following conditions have to be met: • The contraindications listed in the respective sections as well as the required MRI Conditions for Use are taken into consideration. • The patient is previously examined by a cardiology professional. • The pacemaker is programmed to the MRI Mode, which is suitable for an MR scan. • The technical and organizational conditions are met to be able to observe the restrictions and safety measures required during the MR scan. • Emergency equipment for resuscitation (including specialist staff certified to use it) is available.

4.2.2 Basic conditions and restrictions The MRI Conditions for Use (Section 3) have to be met during an MR scan and the device must be programmed to MRI Mode prior to the MR scan.

4.2.3 Completion of the examination After completing the MR scan, make sure the patient is monitored by a cardiology professional who performs the required follow-up cardiology examination and reprogramming of the device system.

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Chapter 4 MRI Examination ProMRI® System Technical Manual

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Chapter 5 Post MR Scan Requirements ProMRI® System Technical Manual

5. Post MR Scan Requirements After the MR scan, the patient should undergo a follow-up device interrogation. This is necessary for the patient’s safety for two reasons: • To reprogram the device back into the original pacing parameters. • To assess the device system for potential adverse effects caused by the MR scan.

5.1 Follow-Up Procedure After an MR scan, the follow-up procedure should be performed: 1. 2. 3. 4. 5. 6. 7. 8.

Apply the programming head. Interrogate the device. Reactivate the program which was effective prior to programming the MRI mode. Send the reactivated program to the device. Perform a complete follow-up. If necessary, perform further examinations. Print and document follow-up data (print report). Finish the follow-up for the patient.

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Chapter 5 Post MR Scan Requirements ProMRI® System Technical Manual

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Chapter 6 Clinical Study ProMRI System Technical Manual ®

6. Clinical Study 6.1 ProMRI Phase B Clinical Study 6.1.1 Primary Objectives This clinical investigation was designed to demonstrate the clinical safety of the ProMRI Pacemaker System when used under specific magnetic resonance imaging (MRI) conditions for full body MRI scan. The investigation included five primary endpoints, which condense into three main objectives: • Primary Endpoint 1 – Evaluation of serious adverse device effect (SADE) rate related to the implanted pacing system and MRI procedure • Primary Endpoints 2 & 3 – Evaluation of atrial and ventricular lead pacing threshold increases • Primary Endpoints 4 & 5 – Evaluation of P-wave and R-wave sensing attenuation

6.1.2 Methods The study enrolled subjects implanted with an Entovis family pacemaker (SR-T, DR-T) and one or two Setrox S 53 or 60 leads, and were willing to undergo an MRI scan. The patients selected for participation were from the investigator’s general patient population meeting the indications for use of the Entovis family pacemaker system. To qualify for enrollment, subjects were required to have measurable pacing thresholds ≤ 2.0 V @ 0.4 ms and could not be implanted with other non-MRI compatible devices. Patients received a baseline evaluation at least seven days prior to the MRI procedure, at which time the pacemaker was tested and programmed to an MRI mode before the MRI, then tested and reprogramed to the original pacing mode post-MRI. The study required a cardiac or thoracic spine MRI scan. Patients were enrolled post-implant, underwent an MRI procedure and testing, and were followed at one and three months post-MRI. During follow-up visits, a device interrogation was completed and the investigator determined if the MRI scan had any long-term effects on the function of the pacemaker system.

6.1.3 Results A total of 244 subjects were provisionally enrolled and 216 subjects were fully enrolled at 31 sites as of August 12, 2014. The cumulative implant duration of the 216 fully enrolled subjects at baseline and MRI procedure was 96.5 years (average implant duration of 0.45 ± 0.32 years) and 111.6 years (average implant duration of 0.52 ± 0.33), respectively. The patient follow-up compliance rate was 98.8% out of 341 required follow-ups. Endpoint data is provided for the Per Protocol (PP) and Intention-to-treat (ITT) Populations. The ITT population includes all subjects programmed to MRI mode with endpoint data from follow-up or Home Monitoring. At the time of data analysis, 199 had completed their 1-month follow-up. An additional four subjects had a missed 1-month follow-up, but are included in the ITT endpoint analysis using their Home Monitoring data. The average subject is a 68 year old male who weighs 191 pounds and is 68 inches in height. Primary Endpoint 1 The purpose of Primary Endpoint 1 was to evaluate the rate of Serious Adverse Device Effects related or possibly related to the implanted pacing system and the MRI procedure. Only SADEs that were pacing system and MRI related or possibly related, as adjudicated by the independent Data Monitoring Committee, were taken into account for calculation of the SADE rate.

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Chapter 6 Clinical Study ProMRI® System Technical Manual

Analysis The Data Monitoring Committee (DMC) adjudicated 25 events reported by the investigators. Of the 25 events reported by the investigators, one was adjudicated as related or possibly related to both the implanted pacing system and the MRI procedure resulting in an SADE-free rate of 99.5% (202/203), p < 0.001, 95% CI: (97.3%, 100.0%). Two additional subjects experienced events that were adjudicated as possibly related to the MRI procedure only. Accounting for the two additional events that were possibly related to the MRI, the estimated freedom from Adverse Events was 98.5% (200/203), p < 0.001, 95% CI: (95.7%, 99.7%). A rejection of the null hypothesis indicates that the SADE-free rate possibly related to the implanted pacing system and the MRI procedure is greater than 90% at 1-month post-MRI and the endpoint is met. Primary Endpoints 2 & 3 The purpose of Primary Endpoints 2 and 3 was to evaluate the percentage of atrial and ventricular pacing leads with a pacing threshold increase between the pre-MRI and 1-month post-MRI follow-up. The threshold behavior of the lead is defined as a success if the increase is not larger than 0.5 V. Table 1, Figure 1, and Figure 2 display the differences in atrial pacing thresholds and Table 2, Figure 3, and Figure 4 display the difference in ventricular pacing thresholds.

Table 1: Table 1: Atrial Pacing Threshold Results Intention-to-treat: Includes Values Imputed from Home Monitoring (N=189) Difference in Atrial Pacing Threshold (V) 0.00 ± 0.13 Mean ± SD (N) -0.70, 0.00, 0.40 Minimum, Median, Maximum

P-value*

Leads Meeting Success Criteria (%) 95% Confidence Interval Per Protocol (N=178) Difference in Atrial Pacing Threshold (V) Mean ± SD (N) Minimum, Median, Maximum Leads Meeting Success Criteria (%) 95% Confidence Interval

P < 0.001

189 (100.0%) (98.1%, 100.0%)

0.00 ± 0.12 -0.70, 0.00, 0.40 178 (100.0%) (97.9%, 100.0%)

*Exact binomial test (1-sided) for comparison to 95%

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P < 0.001

Chapter 6 Clinical Study ProMRI System Technical Manual ®

Figure 1: Histogram of PPP Atrial Pacing Threshold Differences (One-Month – Pre-MRI)

Figure 2: Histogram of ITT Atrial Pacing Threshold Differences (One-Month – Pre-MRI)

Atrial Analysis The mean threshold increase for the PP and ITT populations was 0.00 ± 0.12 V and 0.00 ± 0.13 V, respectively. Of 178 total subjects in the PP population and the 189 total subjects with data in the ITT population, all had a change in atrial pacing threshold of less than or equal to 0.5V between onemonth post-MRI and pre-MRI. A rejection of the null hypothesis (p-values: PP – <0.001, ITT – <0.001) indicates that the proportion of atrial pacing threshold success is greater than 95% and Primary Endpoint 2 is met.

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Chapter 6 Clinical Study ProMRI® System Technical Manual

Table 2: Table 2: Ventricular Pacing Threshold Results Intention-to-treat: Includes Values Imputed from Home Monitoring (N=199) Difference in Ventricular Pacing Threshold (V) 0.00 ± 0.10 Mean ± SD (N) -0.30, 0.00, 0.30 Minimum, Median, Maximum Leads Meeting Success Criteria (%) 199 (100.0%) (98.2%, 100.0%) 95% Confidence Interval Per Protocol (N=189) Difference in Ventricular Pacing Threshold (V) Mean ± SD (N) Minimum, Median, Maximum Leads Meeting Success Criteria (%) 95% Confidence Interval

P-value*

P <0.001

0.01 ± 0.10 -0.20, 0.00, 0.30 189 (100.0%) (98.1%, 100.0%)

P < 0.001

*Exact binomial test (1-sided) for comparison to 95%

Figure 3: Histogram of PPP Ventricular Pacing Threshold Differences (One-Month – Pre-MRI)

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