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Tzadok-Titration Clinical Summary_IM-7601274-EPI.pdf

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Tzadok, M., Verner, R., Kann, L., Tungala, D., Gordon, C., El Tahry,
R., & Fahoum, F. (2022). Rapid Titration of VNS Therapy Reduces
Time-To-Response in Epilepsy. Epilepsy and Behavior.
IM7601274EPI
Rapid Titration of VNS Therapy™ Reduces
Time-To-Response in Epilepsy
Key Take Away 1
The rate of titration influences the onset of response to VNS Therapy. In this
retrospective analysis, patients who were titrated
to 1.625mA at a rate per the Standard Protocol in the manufacturer's labeling
achieved response to VNS Therapy faster than
those titrated at slower speeds.
Key Take Away 2
While titration is oten slowed by complaints of side effects, the cumulative
rate of side effects reported
during faster titration was only somewhat worsened in adults and not worsened in
children.
Fast titration (< 3 months to target dose) was associated with shorter
time-to-response than “Medium” (3-6 months) and
“Slow” (> 6 mo) titration. This effect was strengthened when assessing the
population of patients that eventually responded
to VNS Therapy, as opposed to all subjects.
Excluding the pre-market
experience of VNS Therapy,
titration speed in adults and
children was not correlated
with differing rates of
adverse events.
Hazard Ratio of All Subjects
Adults Children
Patient Counts at Each Follow-Up Patient Counts at Each Follow-Up
Hazard Ratio of Responders Only
Fast vs. Slow
Fast vs. Medium
Medium vs. Slow
1.845
2.225
0.829
Dose Pace
Slow
Medium
Fast
T=90
292
39
44
T=180
260
29
19
T=0
299
40
40
Dose Pace
Slow
Medium
Fast
T=90
141
36
18
T=180
140
36
14
T=0
143
36
18
1.121; 3.035
1.246; 3.971
0.518; 1.327
Estimate Confidence Interval
Fast vs. Slow
Fast vs. Medium
Medium vs. Slow
4.536
1.955
2.320
2.769; 7.430
1.158; 3.299
1.514; 3.555
Estimate Confidence Interval
Cumulative Mean Adverse Events
Time Since Implant
1.5
1.0
0.5
0.0
0 90 180 270
Cumulative Mean Adverse Events
Time Since Implant
1.5
1.0
0.5
0.0
0 90 180 270
Dose Pace
Fast: <3 Months
Medium: 4–6 Months
Slow: >6 Months
Objective
Common titration strategies for vagus nerve stimulation (VNS)
prioritize monitoring of tolerability during small increases in
stimulation intensity over several months. Prioritization of
tolerability is partially based on how quickly side effects can be
perceived and reported by patients, and the delayed onset of
clinical benefits from VNS Therapy. Excessive caution during the
titration phase can significantly delay target dosing or prevent
a patient from reaching a therapeutic dose entirely. This study
aimed to characterize the relationship between titration speed
and the onset of clinical response to VNS Therapy.
Method
A total of 1178 subjects from LivaNova-sponsored clinical
studies were assessed for this work. While the preferred model
for this type of analysis is the Cox Proportional Hazards Model,
the study population failed the key assumption of
“Proportional Hazards”. Non-proportional hazards were
corrected with a weighting function, and the weighted Cox
regression was then employed to assess differences between
more aggressive titration strategies and more conservative
ones. The target dose was empirically defined as 1.625 mA
output current – per the outcomes of Fahoum et al 2022.
Patient-level outcomes and dosing data were segregated into
fast (<3 months), medium (3-6 months), and slow (>6 months)
cohorts based on their titration speed.
Results
The statistical model revealed a significant relationship
between titration speed and onset of clinical response, defined
as a 50% reduction from baseline in seizure frequency. Fast
titration resulted in an onset of response that was significantly
faster than medium (CI 1.16-3.30) or slow (CI 1.12-3.04) titration
speeds. This effect was stronger when analyzed only in VNS
Therapy responder subjects. Frequency of adverse events
reported between each cohort trended toward higher rates of
adverse events in adults who were titrated quickly; however,
the pediatric population appeared to be more tolerant of
titration at any speed.
Conclusion
This analysis indicates that faster titration yields faster onset
of clinical benefit and is especially practical in the pediatric
population, though attempts to accelerate adult titration may
still be warranted. The fast titration group in this analysis is
consistent with the VNS Therapy “Standard Protocol”, so
attempts should be made to follow VNS Therapy labeling if
such titration is tolerated.
Study Summary
Click here to read full paper
IM7601274EPI
Limitations
The principal limitation of this retrospective analysis is that
it utilized data collected from a variety of clinical studies of
VNS Therapy. The studies included interventional and
observational designs, different follow-up durations,
targeted patients of slightly different demographic profiles,
and the methods for data collection were not uniform
across all studies. None of these studies were prospectively
designed for the purpose of assessing the relationship
between VNS Therapy parameters and clinical response.
LivaNova USA, Inc.
100 Cyberonics Boulevard
Houston, Texas 77058
Tel: +1.800.332.1375
Fax: +1.281.218.9332
LivaNova Belgium NV
Ikaroslaan 83
1930 Zaventem
Belgium
Tel: +32.2.720.95.93
Fax: +32.2.720.60.53
©2022 LivaNova USA, Inc, a wholly-owned subsidiary of LivaNova, PLC, London,
UK. All rights reserved. LivaNova®, VNS Therapy™
, SenTiva™ and AspireSR™ are
registered trademarks of LivaNova USA, Inc.

LivaNova USA, Inc.
100 Cyberonics Boulevard
Houston, Texas 77058
USA
Tel: +1 (281) 228-7200 / 1 (800) 332-1375
Fax: +1 (281) 218-9332
www.livanova.com
© 2015-2021 LivaNova, PLC, London, UK. All rights reserved.
LivaNova is a registered United states trademark of LivaNova, PLC. NCP,
Demipulse, Demipulse Duo, Perennia,
VNS Therapy, AspireHC, PerenniaFLEX, PerenniaDURA, AspireSR, and SenTiva are
registered trademarks of
LivaNova USA, Inc. Pulse, Pulse Duo, and SenTiva Duo are trademarks of LivaNova
USA, Inc.
Brief Summary of Safety Information for the VNS Therapy™ System
[Epilepsy Indication] (February 2021)
1. INTENDED USE / INDICATIONS
Epilepsy (US)—The VNS Therapy System is indicated for use as an adjunctive
therapy in reducing the frequency of seizures
in patients 4 years of age and older with partial onset seizures that are
refractory to antiepileptic medications.
2. CONTRAINDICATIONS
Vagotomy—The VNS Therapy System cannot be used in patients ater a bilateral or
let cervical
Diathermy—Do not use short-wave diathermy, microwave diathermy, or therapeutic
ultrasound diathermy on patients
implanted with a VNS Therapy System. Diagnostic ultrasound is not included in
this contraindication.
3. WARNINGS — GENERAL
Physicians should inform patients about all potential risks and adverse events
discussed in the physician's manuals.
This document is not intended to serve as a substitute for the complete
physician's manuals.
The safety and ecacy of the VNS Therapy System have not been established for
uses outside the
“Intended Use/Indications” section of the physician's manuals.
The safety and effectiveness of the VNS Therapy System in patients with
predisposed dysfunction of cardiac conduction
systems (re-entry pathway) have not been established. Post-implant
electrocardiograms and Holter monitoring are
recommended if clinically indicated.
Postoperative bradycardia can occur among patients with certain underlying
cardiac arrhythmias.
It is important to follow recommended implantation procedures and intraoperative
product testing described in the
Implantation Procedure chapter of the physician's manuals. During the
intraoperative System Diagnostics (Lead Test),
infrequent incidents of bradycardia and/or asystole have occurred. If asystole,
severe bradycardia (heart rate < 40 bpm),
or a clinically significant change in heart rate is encountered during a System
Diagnostics (Lead Test) or during initiation
of stimulation, physicians should be prepared to follow guidelines consistent
with Advanced Cardiac Life Support (ACLS).
Diculty swallowing (dysphagia) may occur with active stimulation, and
aspiration may result from the increased
swallowing diculties. Patients with pre-existing swallowing diculties and
those with a history of drooling or
hypersalivation are at greater risk for aspiration. Use of the magnet to
temporarily stop stimulation while eating may
mitigate the risk of aspiration.
Dyspnea (shortness of breath) may occur with active VNS Therapy. Any patient
with underlying pulmonary disease or
insuciency such as chronic obstructive pulmonary disease or asthma may be at
increased risk for dyspnea.
Patients with obstructive sleep apnea (OSA) may have an increase in apneic
events during stimulation. Lowering stimulus
frequency or prolonging “OFF” time may prevent exacerbation of OSA. Vagus nerve
stimulation may also cause new onset
sleep apnea in patients who have not previously been diagnosed with this
disorder.
Device malfunction could cause painful stimulation or direct current
stimulation. Either event could cause nerve damage.
Patients should be instructed to use the magnet to stop stimulation if they
suspect a malfunction, and then to contact
their physician immediately for further evaluation.
Patients with the VNS Therapy System, or any part of the VNS Therapy System,
implanted should have MRI procedures
performed only as described in the MRI with the VNS Therapy System instructions
for use. In some cases, surgery will be
required to remove the VNS Therapy System if a scan using a transmit RF body
coil is needed.
Excessive stimulation at an excess duty cycle (that is, one that occurs when
“ON” time is greater than “OFF” time) and high
frequency stimulation (i.e., stimulation at ≥ 50 Hz) has resulted in
degenerative nerve damage in laboratory animals.
Patients who manipulate the generator and lead through the skin (Twiddler’s
Syndrome) may damage or disconnect the
lead from the generator and/or possibly cause damage to the vagus nerve.
The Wand, Programmer, and patient magnet are MR unsafe devices. These devices
are projectile hazards and must not be
brought into the MR scanner room.
Generators with AutoStim only—The AutoStim Mode feature should not be used in
patients with clinically meaningful
arrhythmias currently being managed by devices or treatments that interfere with
normal intrinsic heart rate responses
(e.g., pacemaker dependency, implantable defibrillator, beta adrenergic blocker
medications). Patients also should not
have a history of chronotropic incompetence [commonly seen in patients with
sustained bradycardia (heart rate
< 50 bpm)].
Generators with AutoStim only—For anticipated use of the AutoStim feature, it is
important to follow the recommended
pre-surgical surface assessment described in the Implantation Procedure to
determine a location for the generator to
reside in which it can accurately detect heart beats
4. WARNINGS — EPILEPSY
The VNS Therapy System should only be prescribed and monitored by physicians who
have specific training and expertise
in the management of seizures and the use of this device. It should only be
implanted by physicians who are trained in
surgery of the carotid sheath and have received specific training in the
implantation of this device.
The VNS Therapy System is not curative. Physicians should warn patients that the
VNS Therapy System is not a cure for
epilepsy and that since seizures may occur unexpectedly, patients should consult
with a physician before engaging in
unsupervised activities, such as driving, swimming, and bathing, and in
strenuous sports that could harm them or others.
Sudden unexpected death in epilepsy (SUDEP): Through August 1996, 10 sudden and
unexpected deaths (definite,
probable, and possible) were recorded among the 1,000 patients implanted and
treated with the VNS Therapy device.
During this period, these patients had accumulated 2,017 patient-years of
exposure. Some of these deaths could
represent seizure-related deaths in which the seizure was not observed, at
night, for example. This number represents an
incidence of 5.0 definite, probable, and possible SUDEP deaths per 1,000
patient-years. Although this rate exceeds that
expected in a healthy (nonepileptic) population matched for age and sex, it is
within the range of estimates for epilepsy
patients not receiving vagus nerve stimulation, ranging from 1.3 SUDEP deaths
for the general population of patients with
epilepsy, to 3.5 (for definite and probable) for a recently studied
antiepileptic drug (AED) clinical trial population similar
to the VNS Therapy System clinical cohort, to 9.3 for patients with medically
intractable epilepsy who were epilepsy
surgery candidates.
5. PRECAUTIONS — GENERAL
Physicians should inform patients about all potential risks and adverse events
discussed in the VNS Therapy physician's
manuals.
Prescribing physicians should be experienced in the diagnosis and treatment of
epilepsy and should be familiar with the
programming and use of the VNS Therapy System. Physicians who implant the VNS
Therapy System should be
experienced performing surgery in the carotid sheath and should be trained in
the surgical technique relating to
implantation of the VNS Therapy System.
The safety and effectiveness of the VNS Therapy System have not been established
for use during pregnancy. VNS should
be used during pregnancy only if clearly needed.
The VNS Therapy System is indicated for use only in stimulating the let vagus
nerve in the neck area inside the carotid
sheath. The VNS Therapy System is indicated for use only in stimulating the let
vagus nerve below where the superior
and inferior cervical cardiac branches separate from the vagus nerve.
It is important to follow infection control procedures. Infections related to
any implanted device are dicult to treat and
may require that the device be explanted. The patient should be given
antibiotics preoperatively. The surgeon should
ensure that all instruments are sterile prior to the procedure. Children 4-11
years of age may have a greater risk for
infection when compared to adolescent and adult patients (≥ 12 years). Careful
monitoring for site infection as well as the
avoidance of manipulation of the surgical site post implant in children should
be stressed.
The VNS Therapy System may affect the operation of other implanted devices, such
as cardiac pacemakers and implanted
defibrillators. Possible effects include sensing problems and inappropriate
device responses. If the patient requires
concurrent implantable pacemaker, defibrillatory therapy or other types of
stimulators, careful programming of each
system may be necessary to optimize the patient's benefit from each device.
Reversal of lead polarity has been associated with an increased chance of
bradycardia in animal studies. It is important
that the electrodes are attached to the let vagus nerve in the correct
orientation. It is also important to make sure that
leads with dual connector pins are correctly inserted (white marker band to +
connection) into the generator’s lead
receptacles.
The patient can use a neck brace for the first week to help ensure proper lead
stabilization.
Do not program the VNS Therapy System to an “ON” or periodic stimulation
treatment for at least 14 days ater the initial
or replacement implantation.
For Models 100, 101, 102 and 102R do not use frequencies of 5 Hz or below for
long-term stimulation.
Resetting the generator disables or turns the device OFF (output current = 0
mA). For Model 100, 101, 102 and 102R,
resetting the generator will result in device history loss. Patients who smoke
may have an increased risk of laryngeal
irritation.
Generators with AutoStim only—Because the device senses changes in heart rate,
false positive detection may cause
unintended stimulation. Examples of instances where the heart rate may increase
include exercise, physical activity, and
normal autonomic changes in heart rate, both awake and asleep, etc. Adjustments
to the AutoStim feature's detection
threshold should be considered; which may include turning the feature OFF.
Generators with AutoStim only—The physical location of the device critically
affects the feature's ability to properly sense
heart beats. Care must be taken to follow the implant location selection process
outlined in the Implantation Procedure.
Generators with AutoStim only—Talk to your patient about use of the AutoStim
feature since use of the feature will result
in faster battery drain and the potential for more frequent device replacements.
The physician's manual describes the
impacts to the battery life. The patient should return to their physician at
appropriate intervals to further evaluate whether
they are receiving benefit from the current AutoStim settings.
M1000 only — Since the Scheduled Programming feature allows the generator to
apply therapy increases at scheduled
intervals, it may not be appropriate for use in patients who are nonverbal or
are unable to use the patient magnet to stop
undesired stimulation. Similarly, exercise caution for use of this feature in
patients with a history of obstructive sleep
apnea, shortness of breath, coughing, swallowing diculties, or aspiration.
6. ENVIRONMENTAL AND MEDICAL THERAPY HAZARDS
Patients should exercise reasonable caution in avoiding devices that generate a
strong electric or magnetic field. If a
generator ceases operation while in the presence of electromagnetic interference
(EMI), moving away from the source may
allow it to return to its normal mode of operation.
VNS Therapy System operation should always be checked by performing device
diagnostics ater any of the procedures
mentioned in the physician's manuals.
For clear imaging, patients may need to be specially positioned for mammography
procedures, because of the location of
the generator in the chest.
Therapeutic radiation may damage the generator's circuitry, although no testing
has been done to date and no definite
information on radiation effects is available. Sources of such radiation include
therapeutic radiation, cobalt machines, and
linear accelerators. The radiation effect is cumulative, with the total dosage
determining the extent of damage. The effects
of exposure to such radiation can range from a temporary disturbance to
permanent damage, and may not be detectable
immediately.
External defibrillation may damage the generator.
Use of electrosurgery [electrocautery or radio frequency (RF) ablation devices]
may damage the generator.
Magnetic resonance imaging (MRI) should not be performed using a transmit RF
body coil for certain VNS therapy device
configurations or under certain specific conditions. In some cases, heating of
the lead caused by the transmit RF body coil
during MRI may result in serious injury. Static, gradient, and radio frequency
(RF) electromagnetic fields associated with MRI
may change the generator settings (i.e., reset parameters) or activate the VNS
device if the Magnet Mode output remains
“ON”. Note that certain magnetic resonance (MR) system head coils operate in
receive-only mode and require use of the
transmit RF body coil. Other MR systems use a transmit/receive RF head coil.
Local or surface coils may also be receive-only
RF coils that require the transmit RF body coil for MRI. The use of a receive RF
coil does not alter hazards of the transmit
RF body coil. Exposure of the VNS Therapy System to any transmit RF coil must be
avoided. Do not perform MRI scans using
any transmit RF coil in the defined exclusion zones. See MRI with the VNS
Therapy System instructions for use for details or
further instructions for special cases such as lead breaks or partially
explanted VNS Therapy systems.
Extracorporeal shockwave lithotripsy may damage the generator. If therapeutic
ultrasound therapy is required, avoid
positioning the area of the body where the generator is implanted in the water
bath or in any other position that would
expose it to ultrasound therapy. If that positioning cannot be avoided, program
the generator output to 0 mA for the
treatment, and then ater therapy, reprogram the generator to the original
parameters.
If the patient receives medical treatment for which electric current is passed
through the body (such as from a TENS unit),
either the generator should be set to 0 mA or function of the generator should
be monitored during initial stages of
treatment.
Routine therapeutic ultrasound could damage the generator and may be
inadvertently concentrated by the device, causing
harm to the patient.
For complete information related to home occupational environments, cellular
phones, other environmental hazards, other
devices, and ECG monitors, refer to the physician's manuals.
7. ADVERSE EVENTS  EPILEPSY
Adverse events reported during clinical studies as statistically significant are
listed below in alphabetical order: ataxia (loss
of the ability to coordinate muscular movement); dyspepsia (indigestion);
dyspnea (diculty breathing, shortness of
breath); hypoesthesia (impaired sense of touch); increased coughing; infection;
insomnia (inability to sleep); laryngismus
(throat, larynx spasms); nausea; pain; paresthesia (prickling of the skin);
pharyngitis (inflammation of the pharynx, throat);
voice alteration (hoarseness); vomiting.
1
The information contained in this Brief Summary for Physicians represents
partial excerpts of important prescribing
information taken from the physician’s manuals. (Copies of VNS Therapy
physician’s and patient’s manuals are posted at
www.livanova.com.) The information is not intended to serve as a substitute for
a complete and thorough understanding of
the material presented in all of the physician’s manuals for the VNS Therapy
System and its component parts nor does this
information represent full disclosure of all pertinent information concerning
the use of this product, potential safety
complications, or ecacy outcomes.
LivaNova USA, Inc.
100 Cyberonics Boulevard
Houston, Texas 77058
Tel: +1.800.332.1375
Fax: +1.281.218.9332
LivaNova Belgium NV
Ikaroslaan 83
1930 Zaventem
Belgium
Tel: +32.2.720.95.93
Fax: +32.2.720.60.53
26-0009-4600/4 (U.S.) — 1
©2022 LivaNova USA, Inc, a wholly-owned subsidiary of LivaNova, PLC, London,
UK. All rights reserved. LivaNova®, VNS Therapy™
, SenTiva™ and AspireSR™ are
registered trademarks of LivaNova USA, Inc.

Tzadok-Titration Clinical Summary_IM-7601274-EPI.pdf




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