OPTIMIZER® Smart Mini Implantable Pulse Generator INSTRUCTIONS FOR USE Part No.: 13-290-011-US Rev.
Impulse Dynamics (USA) Inc. Suite 100 50 Lake Center Executive Parkway 401 Route 73 N Bldg. 50 Marlton, NJ 08053-3425 CCM™ is a trademark of Impulse Dynamics. OPTIMIZER® is a US registered trademark property of Impulse Dynamics The information provided in this document may change without prior notice. No part of this manual may be reproduced or transmitted in any form or by any method, including electronic and mechanical means, without prior written express consent from Impulse Dynamics.
TABLE OF CONTENTS EXPLANATION OF SYMBOLS ON LABELS .......................................................................................... I 1.0 THE OPTIMIZER SMART MINI SYSTEM ................................................................................... 1 1.1 Description of the OPTIMIZER Smart Mini System ......................................................... 1 1.2 OPTIMIZER Smart Mini IPG Implantable Leads Requirements ....................................... 1 1.
6.6 Transmitting Devices .................................................................................................... 11 6.7 Cellular and Mobile Phones .......................................................................................... 11 7.0 POTENTIAL ADVERSE EFFECTS ........................................................................................... 12 8.0 DEVICE IMPLANTATION ......................................................................................................
APPENDIX I.......................................................................................................................................... 27 Physical Characteristics ............................................................................................................ 27 Battery Specifications ............................................................................................................... 27 Current Consumption .................................................................
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EXPLANATION OF SYMBOLS ON LABELS Symbol Description CE Conformity marking, 0344 - Notified Body Number 0344 Caution: Federal (USA) law restricts this device to sale by or on the order of a physician.
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1.0 THE OPTIMIZER SMART MINI SYSTEM The OPTIMIZER Smart Mini system is comprised of the following components: • OPTIMIZER Smart Mini Implantable Pulse Generator (IPG) • Intelio Programmer • Vesta Charger The OPTIMIZER Smart Mini IPG is designed to be used with two commercially available ventricular pacing leads but may also be used with an additional, optional atrial lead. 1.
Pacing Leads Suitable for use with the OPTIMIZER IPG for CCM Signal Delivery Current Offerings as of January 2, 2019 Medtronic CapSureFix Novus MRI™ SureScan™ 4076, 5076, 5086 Leads Medtronic SelectSecure ™ MRI SureScan™ 3830 Lead Bipolar lead approved for transvenous intracardiac ventricular pacing YES YES YES YES YES YES Standard IS-1 bipolar connector YES YES YES YES YES YES YES, 4.2 mm2 YES, 3.6 mm2 YES, 6.9 mm2 YES, 6.0 mm2 YES, 4.5 mm2 YES, 4.
1.4 OPTIMIZER Smart Mini IPG Physical Characteristics Model CCM X11 Height (mm) 61.3 ± 1.5 Width (mm) 44.0 0.5 Thickness (mm) 11.0 ± 0.5 Volume (cm3) 23.0 ± 0.5 Mass (g) 31 3.0 Exposed Metallic Surfacea (cm2) 32.5 X-ray ID The ID comprises the following 3 elements: • Manufacturer Code: “ID” for Impulse Dynamics ID.OSM.y • Model Number Code: “OSM” for OPTIMIZER Smart Mini • Year code: “A” for 2019, “B” for 2020, “C” for 2021, etc.
1.5.2 Battery Behavior The battery voltage of the OPTIMIZER Smart Mini IPG, when its battery is fully charged, is approximately 4.1 V. When battery voltage of the OPTIMIZER Smart Mini IPG drops to 3.5 V, the IPG places itself in OOO mode (Standby mode) and stops performing any functions except telemetric communication with the Intelio Programmer and Vesta Charger. The IPG will return to normal behavior whenever, during the battery recharging process, its battery voltage rises above 3.6 V.
Relative humidity has no impact on the OPTIMIZER Smart Mini IPG. 2.0 USER PROFILE AND TRAINING The operators of the OPTIMIZER Smart Mini System include patients, physicians (and the trained medical personnel who assist them), and Impulse Dynamics representatives.
• Lead fracture • Lead displacement • Atrial or ventricular perforation • Rare cases of pericardial tamponade Perforation of the ventricular wall can induce direct stimulation of the phrenic nerve or the diaphragm. An impedance change demonstrated on a check-up can be indicative of lead fracture, lead displacement, lead insulation damage, or perforation (also see: Potential Adverse Effects, Section 7).
5.1.3 Atrial Arrhythmias Potentially Caused by CCM Therapy Pulses Atrial and supraventricular arrhythmias could theoretically be initiated when CCM-induced ventricular activity is conducted retrograde to the atria, resulting in premature atrial depolarization. The OPTIMIZER Smart Mini IPG may sense the ventricular activation resulting from the retrograde-induced atrial event and deliver CCM therapy as programmed.
5.3 RF Ablation Warning: RF ablation can cause the OPTIMIZER Smart Mini IPG to inhibit CCM therapy delivery or to revert to its “DOWN” mode (equivalent to OOO mode, with no delivery of CCM) with the possible loss of statistical data. Depending on the amount of energy coupled into the system, the device could also be damaged.
5.6 Therapeutic Ultrasound Warning: Direct exposure of the OPTIMIZER Smart Mini IPG to therapeutic ultrasound can damage the device. In addition, the OPTIMIZER Smart Mini IPG can inadvertently concentrate the ultrasound field and cause harm to the patient. Therapeutic ultrasound can be used provided the implant is located far away from the ultrasound field. Precautionary programming of the OPTIMIZER Smart Mini IPG to OOO mode reduces the risk of adverse effects.
5.10 Handling Warning: Do not implant the OPTIMIZER Smart Mini IPG if the package is damaged or if the device has been dropped onto a hard surface from a height of 12 in or more while still in the shipping box. Do not implant the device if it has been dropped onto a hard surface after unpacking. Damaged packages or dropped devices should be returned to Impulse Dynamics for evaluation. 5.
If a TENS unit is used nonetheless, the TENS electrodes should be attached as far as possible from the OPTIMIZER Smart Mini IPG and its leads. In addition, aiming for a limited current path, consider placing the TENS electrodes as close to each other as possible. The patient’s peripheral pulse should be closely monitored while TENS is applied. Precautionary programming the OPTIMIZER Smart Mini IPG to OOO mode reduces the risk of adverse effects. 6.
As a general guideline, patients implanted with an OPTIMIZER Smart Mini IPG who would like to use a mobile phone are advised to hold the phone to the ear that is contralateral to the implant site. Patients should not carry the phone in a breast pocket or on a belt closer than 10 in from the implanted IPG because some phones emit signals even when they are turned on but not in use.
8.0 DEVICE IMPLANTATION 8.1 General Considerations Generally, the OPTIMIZER Smart Mini IPG is implanted in the right pectoral region of the chest. Two right ventricular leads are placed for CCM therapy delivery, one of these preferably in an anterior septal and the other in a posterior septal location, approximately half way between base and apex. Placing both leads in an anterior or posterior septal location is an acceptable alternative, provided the leads are separated by at least 3/4 in.
Open the shelf box outside the sterile field and remove the TYVEK/PETG molded insert. Establish a link between the IPG and the Programmer by performing the following steps: 1. Place the Intelio Programming Wand over the OPTIMIZER Smart Mini IPG 2. Open the Optimizer SM application on the Intelio Programmer 3. Click on the Start OPTIlink button shown on the OPTIlink Session Pane 4.
Note: Provided the connectors are correctly installed, the connector retention force in the terminals is at least 2.24 lbf. Clean each lead connector with sterile distilled water (if using saline, wipe each connector dry with a surgical sponge afterwards) and fully insert each lead connector into its respective connector terminal in the header of the OPTIMIZER Smart Mini IPG.
o ▪ When OPTIset has completed its proposal of CCM algorithm timing, click the Accept & Continue button ▪ When the OPTIset window appears again, click the OPTIset: Propose CCM Amplitude button ▪ When the OPTIset: CCM AMPLITUDE is shown, enable the CCM Channels (one at a time) ▪ When OPTIset has completed its proposal of CCM algorithm amplitude, set the CCM Amplitude to 5.
When placing the IPG into the subcutaneous pocket, take special care to allow a smooth curvature of redundant lead segments within the pocket and place them around the IPG or in the pocket inferior to the device. Secure the IPG to the fascia with a non-absorbable suture and close the pocket. Radiographs should be obtained after device implantation to verify device and lead placement as well as rule out pneumothorax, even if there are no symptoms.
Clean each lead connector with sterile distilled water (if using saline, wipe each connector dry with a surgical sponge afterwards) and fully insert each lead connector into its respective connector terminal in the header of the OPTIMIZER Smart Mini IPG. Note: Before tightening the set screws, verify that the tip of each lead connector is fully inserted into its respective lead tip terminal. Tighten the tip set screw for each lead using the sterile #2 Allen torque wrench included in the IPG package.
10.3 Extend on Low CCM% If the percentage of CCM therapy a patient receives during scheduled CCM therapy delivery periods is lower than 90%, the OPTIMIZER Smart Mini IPG offers the option of extending this CCM therapy delivery time period. When the Extend on Low CCM% feature is enabled, the OPTIMIZER Smart Mini IPG extends the On Time period for CCM therapy delivery based on the percentage of CCM therapy delivered during the original 1 hour On Time period.
10.5 Sensing Through leads implanted in the heart, the OPTIMIZER Smart Mini IPG can sense, detect, and analyze electrical signals generated by the heart. The signal input and controller circuitry of the OPTIMIZER Smart Mini IPG are designed to receive these electrical signals, analyze the characteristics of each signal (for example, magnitude and timing), and to determine whether or not to deliver CCM therapy, if CCM therapy is to be delivered, and when to deliver it.
10.6 CCM Inhibit Parameters By analyzing the train of sensed cardiac events based on their succession and their temporal order, the OPTIMIZER Smart Mini IPG “decides” for each heartbeat whether to deliver CCM therapy or not. 10.6.1 CCM Inhibit Cycles One can program the number of cycles for which CCM therapy delivery will continue to be inhibited after the initial inhibiting event. With the OPTIMIZER Smart Mini Programmer application, the number of CCM inhibit cycles can be set to values between 1 and 16.
• LS Out of Alert: A local sense event detected after the end of the Local Sense Alert Window triggers an LS Out of Alert condition. The Local Sense Alert Window is the time interval during which the leading edge of valid LS events triggers CCM therapy delivery. How this is programmed is detailed in Section 10.7.3. • Ventricular Tachycardia (VT): Whenever the ventricular tachycardia rate limit is exceeded, CCM therapy delivery is automatically inhibited.
Valid Local Sense events detected outside the Alert Window are considered to be PVCs and inhibit CCM therapy delivery for a programmable number of cycles. Inhibiting Local Sense events can be detected even between a triggering Local Sense event and the start of the corresponding CCM therapy, which in this case will not be delivered. The Local Sense Alert Window is the time interval during which the leading-edge of valid LS events is used to trigger CCM therapy delivery.
• 10.8 Post LS Refractory Period: The time interval after the LS event where all signals are masked from detection. With the OPTIMIZER Smart Mini Programmer application, the duration can be set to values between 15 ms and 250 ms in 5 ms increments. CCM Therapy Delivery CCM therapy is a pulse train comprising a programmable number of consecutive pulses, each with two phases of opposite polarity and programmable duration. 10.8.
10.9 Parameter Restrictions and Warnings Whenever a parameter value is modified, the OPTIMIZER Smart Mini Programmer application performs a check of the modified value against all the other parameter values currently programmed into the OPTIMIZER Smart Mini IPG. If the modified parameter value violates the one of the following restrictions, then an error message is generated and displayed in the error message window. 1.
9. Post LS Refractory period should not be greater than the CCM Train Delay Rationale: If the CCM Train Delay is shorter than the Post LS Refractory period, then the CCM therapy will be delivered within the Post LS Refractory period while the LS event is not sensed. 11.0 SERVICE AND WARRANTY 11.
APPENDIX I As a convenience to the user, the following overview provides a brief and succinct summary of the characteristics of the OPTIMIZER Smart Mini IPG. Some of the information is also presented in the IFU in text form. Physical Characteristics Model CCM X11 Height (mm) 61.3 ± 1.5 Width (mm) 44.0 0.5 Thickness (mm) 11.0 ± 0.5 Volume (cm3) 23.0 ± 0.5 Mass (g) 31 3.0 Area of Exposed Metal Can (cm2) 32.5 Radiopaque ID ID.OSM.
Safe Mode Mode Description DOWN Mode Occurs when the device encounters conditions considered to be the result of faulty device hardware or firmware. In this mode, the device is completely quiescent; CCM therapy is not delivered and cardiac events are not sensed.
A/V REFRACTORY PARAMETERS Parameter Name Values Post-V Atrial Refractory Period1 148.0 ms to 452.2 ms in 7.8 ms increments Post-V RV Refractory Period 148.0 ms to 452.2 ms in 7.8 ms increments 1 Active only when the OPTIMIZER Smart Mini IPG is in ODO-LS-CCM mode.
CCM TRAIN PARAMETERS Balancing 40 ms to 100 ms in 10 ms increments First Phase Polarity “Positive” or “Negative”. Phase Duration 4 possible between 5.13 ms and 6.60 ms. Interval 0 ms to 7 ms in 1 ms increments CCM Channels RV and/or LS Default Settings CCM THERAPY Mode OFF Timed1 7 hs/day CCM Magnet Mode Off 1 day Extend on low CCM% OFF 1 The default setting in the U.S. is 5 hs/day CCM SCHEDULE Start Time 00:00 End Time 23:59 SENSING Atrium Sensitivity 1.
TIMING ALGORITHM LS Assignment V2 LS Alert Start -10 ms LS Alert Width 30 ms LS BLANKING REFRACTORIES Pre A LS Refractory Period 0 ms Post A LS Refractory Period 0 ms Pre RV LS Refractory Period 0 ms Post RV LS Refractory Period 0 ms Post LS Refractory Period 20 ms CCM TRAIN CCM Train Delay 30 ms CCM Amplitude 7.5 V Number of Biphasic Pulses 2 Balancing 40 ms First Phase Polarity Positive Phase Duration 5.
APPENDIX II Battery Charge Longevity The battery charge longevity for the OPTIMIZER Smart Mini IPG can be estimated from the following tables. Note: The battery charge longevity data below are conservative estimates. Table 1 shows the charge longevity as a function of parallel lead impedance when CCM therapy delivery is set to 7 hours per day under the following conditions: • Number of pulses per CCM train: 2 • Phase duration: 5.
Table 2 Parallel Lead (V1+V2) Impedance (Ω) CCM Amplitude (V) Charge Longevity (days) 220 4.5 38 220 6 25 220 7.5 16 250 4.5 52 250 6 29 250 7.5 19 300 4.5 57 300 6 36 300 7.5 22 600 4.5 88 600 6 57 600 7.5 32 900 4.5 113 900 6 77 900 7.5 36 1200 4.5 130 1200 6 83 1200 7 39 Battery Current Drain The battery current drain of the OPTIMIZER Smart Mini IPG is highly dependent on the amount of energy used when CCM therapy delivered to the patient.
VBAT (V) Parallel Lead (V1+V2) Impedance (Ω) CCM Amplitude (V) Average Measured Current Drain (mA) 3.5 300 6 1.22 3.5 300 7.5 2.2 3.5 600 4.5 0.41 3.5 600 6 0.78 3.5 600 7.5 1.5 3.5 900 4.5 0.34 3.5 900 6 0.6 3.5 900 7.5 1.3 3.5 1200 4.5 0.31 3.5 1200 6 0.5 3.5 1200 7.5 1.2 4.1 220 4.5 1.21 4.1 220 6 1.46 4.1 220 7.5 2.13 4.1 250 4.5 0.7 4.1 250 6 1.42 4.1 250 7.5 1.8 4.1 300 4.5 0.68 4.1 300 6 1.08 4.1 300 7.5 1.47 4.
APPENDIX III Statement of FCC Compliance The OPTIMIZER Smart Mini IPG is approved for wireless transmission under FCC ID 2AY43CCMX11. The OPTIMIZER Smart Mini IPG has been tested and found to comply with the limits pursuant to the following parts of the FCC rules: • 47 CFR Part 95 Subpart I - Medical Device Radio Communications Service These limits are designed to provide reasonable protection against harmful interference in a residential installation.
Electromagnetic Immunity GUIDELINES AND MANUFACTURER’S DECLARATION – ELECTROMAGNETIC IMMUNITY OF THE OPTIMIZER SMART MINI IMPLANTABLE PULSE GENERATOR The OPTIMIZER Smart Mini IPG, part of the OPTIMIZER Smart Mini System is intended for use in an electromagnetic environment as specified below. The patient implanted with the OPTIMIZER Smart Mini IPG must ensure that it is used within the specified environment.
ISO 14117:2019 Clause 4.8 - Protection from AC magnetic field exposure in the range of 1 kHz to 140 kHz ISO 14117:2019 Clause 4.
ISO 14117:2019 Clause 5 - Testing above frequency of 3000 MHz Standard does not require testing of devices above 3 GHz. Electromagnetic fields > 3 GHz are not expected to interfere with device operation because of the increased device protection afforded by the attenuation of the enclosure and body tissue at microwave frequencies, the expected performance of EMI control features implemented to meet lowerfrequency requirements, and the reduced sensitivity of circuits at microwave frequencies.
GTRI E3 Representative Security and Logistical Systems (Electronic article surveillance, metal detectors, RFID) Per E3 protocol Per E3 protocol See section on Cautions → Store Anti-Theft Systems/Airport Security Screening Systems in this manual Electronic Article Surveillance (EAS) systems, such as those found at department stores: • Do not linger near an EAS system longer than is necessary. • Be aware that EAS systems are often hidden or camouflaged near the exits for businesses such as retailers.
Electromagnetic Emissions The OPTIMIZER Smart Mini IPG must emit electromagnetic energy in order to perform its intended function when communicating with the Intelio Programmer or the Vesta Charger. Nearby electronic equipment may be affected.
ETSI EN 301 489-1 and ETSI EN 301 489-27 GUIDELINES AND MANUFACTURER’S DECLARATION – ELECTROMAGNETIC EMMISSIONS OF THE OPTIMIZER SMART MINI IPG PURSUANT TO: ETSI EN 301 489-1 V2.2.
APPENDIX IV Wireless Technology RF wireless technology is used in the communication between an OPTIMIZER SMART MINI Implantable Pulse Generator (IPG) and an INTELIO Programmer. It occurs through an encrypted channel over an RF link that complies with the requirements of the Medical Implant Communication System (MICS) (range specified to 2 m, 402–405 MHz) of the MedRadio Band.
• Good quality link – 3 green signal waves • Medium quality link – 2 yellow signal waves • Low quality link – 1 red signal wave QoS for Communications between the Vesta Charger and the OPTIMIZER Smart Mini IPG MedRadio in the MICS sub-band (402 to 405 MHz) wireless technology enables communication between the OPTIMIZER Smart Mini IPG and the Vesta Charger.
If the Vesta Charger and the OPTIMIZER Smart Mini IPG do not communicate within a programmable time period, the patient may see the “Long Time Without Downloading Data From IPG” alert screen displayed by the Vesta Charger: In this case, instruct the patient to attempt to charge their OPTIMIZER Smart Mini IPG with their Vesta Charger. If the patient is able to charge their implanted device successfully, then the alert screen should no longer be displayed by the Vesta Charger.
Troubleshooting Wireless Connection between OPTIMIZER Smart Mini IPG and Vesta Charger If you experience issues with establishing a wireless connection between the OPTIMIZER Smart Mini IPG and the Vesta Charger, try the following: • Whenever the Vesta Charger is not being used to charge the OPTIMIZER Smart Mini IPG, place it in an area that is frequented by the patient (e.g., bedside table in the bedroom), connected to its AC Adapter, and the AC Adapter plugged into the wall outlet.
APPENDIX VI Scientific Background About Heart Failure and Cardiac Contractility Modulation Heart failure is a condition wherein the heart muscle does not pump blood as well as it should, generally resulting in reduced cardiac output, possibly due to reduced contraction force or impaired relaxation or other deficiencies.
Over the years of evaluation of cardiac contractility modulation therapy and use of the therapy outside the USA in countries that accept the CE Mark, CCM was delivered using various models of the OPTIMIZER System, which includes an implantable pulse generator (IPG) that is programmable and has a rechargeable battery. In principle, the OPTIMIZER System is implanted in a procedure which is similar to a pacemaker implantation.
APPENDIX VII Current Clinical Summary: FIX-HF-5C Study Design FIX-HF-5C was a prospective, randomized, third-party blinded, multicenter study involving 160 patients. Key inclusion criteria included EF ≥ 25% and ≤ 45%, normal sinus rhythm, QRS duration <130 ms and NYHA Class III or ambulatory IV heart failure despite GDMT (including ICD when indicated).
Other safety endpoints included all-cause death, cardiovascular death, composite rate of all-cause death or all-cause hospitalizations, composite rate of cardiovascular death or worsening heart failure-related hospitalizations, and overall rate of AEs and SAEs. Demographics and Baseline Characteristics Of the 160 eligible patients, 74 were randomized to the CCM group and 86 were randomized to the control group.
Figure 2 shows that the Bayesian model’s point estimate is very similar to the estimate from just the FIX-HF-5C study. However, the model further incorporates the high quality data from the previous randomized, blinded trial which increases the precision of the estimate. If FIX-HF-5C were a standalone trial, the middle CI would be appropriate.
Table 5: Peak VO2 Treatment Effect Across Studies Bayesian VO2 Estimate Bayesian Posterior Probability Imputation (Death = 0) 0.836 0.989 Imputation (Death = lowest peak VO2) 0.693 0.988 Completed Cases (No Imputation) 0.603 0.978 Completed Cases (No Imputation) 0.749 0.999 Imputation (Death = 0) 0.799 0.960 Imputation (Death = lowest peak VO2) 0.611 0.957 Completed Cases (No Imputation) 0.480 0.916 Imputation (Death = 0) 1.074 1.00 Completed Case (No Imputation) 1.080 1.
Table 8: Change in Peak VO2 in Tests with RER ≥ 1.05 at 24 Weeks by Study Difference (95% CI) in Peak VO2 (mL/kg/min) Between Groups p-value (1-sided) Pooled data 0.62 (0.11. 1.14) 0.009 FIX-HF-5C 0.43 (-0.25, 1.11) 0.1100 FIX-HF-5 Subgroup 0.83 (0.06, 1.61) 0.017 Safety Results The incidence of AEs in this study was relatively low. Comparisons between the groups did not show any statistical differences between CCM and control groups with respect to any AE tabulated for the analysis.
Current Clinical Summary: FIX-HF-5C2 Introduction Prior versions of the OPTIMIZER device used under the current US IDE have required sensing of atrial depolarization via an atrial lead to properly time the delivery of CCM pulses. Accordingly, the presence of atrial fibrillation or flutter imposed a technical limitation to the delivery of CCM signals.
examination, medication evaluation, blood testing, CPX test, NYHA assessment, and an assessment of adverse events. Data collection for assessment of the study endpoints was concluded with the 24-week visit. Results Number of Investigators and Number of Sites There were 8 sites participating in the FIX-HF-5C2 study and 8 principal investigators are shown in Table 11 below.
Baseline Characteristics Baseline characteristics of subjects in the FIX-HF-5C2 study are presented in Table 13 along with baseline characteristics of the FIX-HF-5C study groups. Of primary note are the comparisons between the OPTIMIZER group in the FIX-HF-5C2 study and the Control group from the FIX-HF-5C study, as these groups form the primary comparison groups for the efficacy analyses. At a nominal 0.05 level of significance, FIX-HF-5C2 subjects were older (66.3 ± 8.9 vs. 62.8 ± 11.
Table 13: Baseline Characteristics: ITT Population FIX-HF-5C2 FIX-HF-5C OPTIMIZER OPTIMIZER P-value1 Control P-value1 66.3 ± 8.9 (60) 63.1 ± 10.9 (74) 0.071 62.8 ± 11.4 (86) 0.049 Male 53 (88.3%) 54 (73.0%) 0.032 68 (79.1%) 0.182 Ethnicity (White) 40 (66.7%) 55 (74.3%) 0.346 61 (70.9%) 0.590 CHF Etiology (Ischemic) 41 (68.3%) 46 (62.2%) 0.473 51 (59.3%) 0.299 Prior MI 36 (60.0%) 36 (48.6%) 0.224 51 (59.3%) 1.000 Prior CABG 13 (21.7%) 18 (24.3%) 0.837 23 (26.7%) 0.
Table 14: Baseline Medications: ITT Population FIX-HF-5C2 FIX-HF-5C OPTIMIZER OPTIMIZER P-value1 Control P-value1 ACEi/ARB/ARNi 45 (75.0%) 61 (82.4%) 0.393 72 (83.7%) 0.212 ACE inhibitor 29 (48.3%) 40 (54.1%) 0.603 49 (57.0%) 0.317 ARB 8 (13.3%) 18 (24.3%) 0.128 22 (25.6%) 0.096 ARNi 9 (15.0%) 3 (4.1%) 0.035 3 (3.5%) 0.028 Beta Blocker 57 (95.0%) 72 (97.3%) 0.656 82 (95.3%) 1.000 Diuretic 44 (73.3%) 57 (77.0%) 0.689 67 (77.9%) 0.558 Secondary Diuretic 5 (8.
Baseline heart failure medications are summarized in Table 14. The only significant differences were a greater use of ARNi’s, anti-arrhythmics, and anticoagulants in FIXHF-5C2 subjects. The greater ARNi use reflects the fact that they were introduced toward the end of the FIX-HF-5C study. The greater use of anti-arrhythmics and anticoagulants likely represents the inclusion of patients with atrial fibrillation; those patients were excluded in the FIX-HF-5C study.
Figure 4: Bayesian Modeled Treatment Mean Difference (Δ) Peak VO2 by Time Figure 5: 24-Week Modeled Mean PVO2 Treatment Difference by Study 59
The Bayesian Posterior Probability that ∆3 is greater than 0 (indicating superiority of FIX-HF-5C2 device to FIX-HF-5C control) is 1. Because this exceeds 0.975, the null hypothesis is rejected and superiority is claimed with respect to the primary endpoint. Frequentist Analysis The Bayesian analysis indicates that the FIX-HF-5C2 OPTIMIZER group had a superior increase in Peak VO2 over the FIX-HF-5C Control group with a posterior probability which exceeds the 0.975 required for statistical significance.
Table 18: Efficacy Summary: ITT Population FIX-HF-5C2 FIX-HF-5C OPTIMIZER OPTIMIZER Difference1 Control Difference1 Mean ± SD (n) 15.0 ± 2.9 (60) 15.5 ± 2.6 (73) -0.48 ± 2.76 15.4 ± 2.8 (86) -0.36 ± 2.87 (min, max) (9.8, 19.9) (9.8, 19.7) [95% CI] [14.2,15.8] [14.9,16.1] Variable Peak VO2 (ml/kg/min) Baseline 2 P-value 12 Weeks Mean ± SD (n) 16.0 ± 3.3 (52) 15.6 ± 3.2 (67) (min, max) (10.2, 22.2) (9.0, 23.3) [95% CI] [15.1,16.9] [14.8,16.4] P-value 0.43 ± 3.25 [-1.31, 0.
Secondary Effectiveness Analyses Since the primary endpoint was met, the secondary endpoint of total CCM delivery could be formally tested. Total CCM delivery is presented in Table 19 for the IP populations. Results are presented for all available data and for the multiple imputation approach as described previously.
Primary Safety Endpoint The primary safety endpoint was the composite endpoint of the percentage of subjects in the OPTIMIZER group who experienced either an OPTIMIZER device or OPTIMIZER procedure related complication through the 24-week follow-up period, as determined by an independent events adjudication committee (EAC).
Adverse Events All site reported non-serious adverse events and adjudicated serious adverse events from study start date to 24 weeks; are tabulated in Table 21 and Table 22 in the ITT population. The total number of events and the number and percent of subjects having at least one event of the type listed is given. Event rates were similar to those seen in both the FIX-HF-5C OPTIMIZER and control groups. At a nominal 0.
Table 21: Adjudicated Serious Adverse Events, Day 0-168: ITT Population Variable All General Medical Arrhythmia FIX-HF-5C2 OPTIMIZER # Events Subjects2 26 19 (31.7%) (20.3%, 45.0%) 8 7 (11.7%) (4.8%, 22.6%) 3 2 (3.3%) Worsening Heart Failure 7 General Cardiopulmonary 2 Bleeding 1 Neurologic 1 Thromboembolism 1 Local Infection 1 Sepsis 1 ICD or Pacemaker System Malfunction 1 OPTIMIZER System Malfunction 0 (0.4%, 11.5%) 5 (8.3%) (2.8%, 18.4%) 2 (3.3%) (0.4%, 11.5%) 1 (1.7%) (0.0%, 8.
Table 22: Non-Serious Adverse Events, Day 0-168: ITT Population Variable All General Medical Arrhythmia FIX-HF-5C2 OPTIMIZER # Events Subjects2 39 26 (43.3%) (30.6%, 56.8%) 23 19 (31.7%) (20.3%, 45.0%) 1 1 (1.7%) Worsening Heart Failure 3 General Cardiopulmonary 4 Bleeding 2 Neurologic 0 Thromboembolism 1 Local Infection 5 Sepsis 0 ICD or Pacemaker System Malfunction 0 OPTIMIZER System Malfunction 0 (0.0%, 8.9%) 3 (5.0%) (1.0%, 13.9%) 4 (6.7%) (1.8%, 16.2%) 2 (3.3%) (0.4%, 11.5%) 0 (0.
The incidence of overall non-serious adverse events was significantly higher in the OPTIMIZER subject cohort of the FIX-HF-5C2 study than for the control group of the FIX-HF-5C study. It was not significantly greater than the incidence on non-serious adverse events in the OPTIMIZER group for the FIX-HF-5C study. The higher rate between the FIX-HF-5C2 OPTIMIZER subjects and subjects in the control group for FIX-HF-5C can be attributed to differences in general medical events and localized infection.
