Restore, Itrel, Synergy, Intellis, and Vanta Spinal Cord Stimulation Systems, Pisces, Specify and Vectris Spinal Cord St

{0} # **SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)** ## **I. GENERAL INFORMATION** Device Generic Name: Stimulator, Spinal-Cord, Totally Implanted For Pain Relief Device Trade Name: Restore, Itrel, Synergy, Intellis, and Vanta Spinal Cord Stimulation Systems; Pisces, Specify and Vectris Spinal Cord Stimulation Leads Device Product Codes: LGW, QRB Applicant's Name and Address: Medtronic Neuromodulation 7000 Central Avenue, N.E. MS RCW235 Minneapolis, MN 55432 USA Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P840001/S469 Date of FDA Notice of Approval: January 24, 2022 Medtronic’s implantable neurostimulation system was first approved for spinal cord stimulation as an aid in the management of chronic, intractable pain for the trunk or limbs on Nov. 30, 1984 (PMA P840001). Since then, Medtronic has twice used published clinical literature to clarify or expand the Indications for Use (IFU) of the spinal cord stimulation systems. Supplements S045 and S047 requested approval to list specific pain etiologies along with the existing general indication. The IFU approved through those submissions are provided in Table 1 below; the etiologies added by each supplement are in italics. The current supplement was submitted to expand the IFU for Medtronic Spinal Cord Stimulator (SCS) Systems to include painful diabetic peripheral neuropathy (PDPN) of the lower extremities. PMA P840001: FDA Summary of Safety and Effectiveness Data Page 1 {1} **Table 1: SCS indication history** | Submission | Approved Indications for Use | | --- | --- | | P840001 Approved 11/30/1984 | The Medtronic ITREL Spinal Cord Stimulation System is indicated as an aid in the management of chronic, intractable pain of the trunk or limbs. | | P840001/S045 Approved 6/22/2000 | The Medtronic Implantable Neuromodulation System is indicated as an aid in the management of chronic intractable pain of the trunk and limbs, including chronic and intractable unilateral or bilateral pain associated with the following: • *Failed Back Syndrome or Low Back Syndrome or Failed Back* • *Radicular Pain Syndrome or Radiculopathies resulting in pain secondary to Failed Back Syndrome* • *Post-Laminectomy Pain* • *Multiple Back Operations* • *Unsuccessful Disk Surgery* • *Degenerative Disk Disease (DDD)/ Herniated Disk pain refractory to conservative and surgical interventions.* | | P840001/S047 Approved 6/22/2000 | The Medtronic Implantable Neuromodulation System is indicated as an aid in the management of chronic intractable pain of the trunk or limbs, including unilateral or bilateral pain associated with the following: • Failed Back Syndrome or Low Back Syndrome or Failed Back • Radicular Pain Syndrome or Radiculopathies resulting in pain secondary to Failed Back Syndrome or Herniated Disc • Post-Laminectomy Pain • Multiple Back Operations • Unsuccessful Disk Surgery • Degenerative Disk Disease (DDD)/ Herniated Disk pain refractory to conservative and surgical interventions. • *Peripheral Causalgia* • *Epidural Fibrosis* • *Arachnoiditis or Lumbar Adhesive Arachnoiditis* • *Complex Regional Pain Syndrome (CRPS) or Reflex Sympathetic Dystrophy (RSD) or Causalgia* | \*New indications in *italicized text* above were approved in the corresponding submissions. PMA P840001: FDA Summary of Safety and Effectiveness Data Page 2 {2} ## II. INDICATIONS FOR USE This device is indicated for spinal cord stimulation (SCS) systems as an aid in the management of chronic, intractable pain of the trunk and/or limbs-including unilateral or bilateral pain associated with the following conditions: - • Failed Back Syndrome (FBS) or low back syndrome or failed back - • Radicular pain syndrome or radiculopathies resulting in pain secondary to FBS or herniated disk - • Postlaminectomy pain - • Multiple back operations - • Unsuccessful disk surgery - • Degenerative Disk Disease (DDD)/herniated disk pain refractory to conservative and surgical interventions - • Peripheral causalgia - • Epidural fibrosis - • Arachnoiditis or lumbar adhesive arachnoiditis - • Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD), or causalgia - • Diabetic peripheral neuropathy of the lower extremities ## III. CONTRAINDICATIONS Diathermy - Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (all now referred to as diathermy) on patients implanted with a neurostimulation system. Energy from diathermy can be transferred through the implanted system and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death. ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Medtronic implantable neurostimulation system labeling. Safety information was updated in accordance with the most recent American Diabetes Association's Standard of Medical Care in Diabetes to address the increased risk and potential complications for diabetic peripheral neuropathy patients. Additional warnings were added to provide guidance for managing patients presenting with risk factors or sub-optimal glycemic control. ## V. DEVICE DESCRIPTION ### System Description The Medtronic SCS system uses an implantable multi-programmable PMA P840001: FDA Summary of Safety and Effectiveness Data Page 3 {3} neurostimulation system to deliver electrical stimulation to neural targets in the spinal cord. A Medtronic SCS system is comprised of the following components: The major components of an SCS system include: - Leads and Extensions – Leads are used for both the stimulation trial, or evaluation, and implanted SCS therapy. The lead delivers the stimulation to the targeted nerve through electrodes on the end of the lead. The extension connect the lead to the neurostimulator. - External Neurostimulator (ENS) – The ENS provides stimulation for patients during an evaluation or during intraoperative testing. - Implantable Neurostimulator (INS) – The INS provides stimulation for the patient after a successful evaluation. - Clinician Programmer – Used by the clinician to configure and maintain the patient’s therapy through adjustment of the available therapy parameters (amplitude, rate, pulse width, cycling, soft start and stop and electrode configuration) and the creation of programs which consist of a specific set of values for each of the therapy parameters. - Patient Programmer – Used by the patient to maintain their therapy through stimulation intensity adjustment and program selection. The programs are pre-set by the clinician. - Patient recharger – Used by the patient to charge the battery of a rechargeable INS. A plug-in charger recharges the patient recharger. The SCS product portfolio includes several implantable neurostimulators and leads to best serve individual patient and clinician needs, such as primary cell and rechargeable neurostimulators and variable electrode size and spacing in the leads. Stimulation pulses are controlled in terms of output amplitude (milliamps; mA), pulse width (μsec) and rate (Hz). Multiple electrodes on a lead may be activated. Some programming restrictions apply, based on options selected. Electrical current generated by the neurostimulator travels along the leads to the distal electrodes. Figure 1 shows a representation of a SCS system powered by a neurostimulator. ## Principles of Operation Spinal cord stimulation is the application of mild electrical stimulation to the spinal cord to relieve chronic, intractable pain of the trunk and/or limbs. Neurostimulation therapy is based on the gate control theory of pain. The stimulation of specific nerve targets is thought to interfere with the perception of pain transmitted or generated by abnormally functioning neural structures. The function of the stimulation system is accomplished with a power source and one or more leads, with the optional use of lead extensions. For Medtronic SCS systems, PMA P840001: FDA Summary of Safety and Effectiveness Data Page 4 {4} an implantable neurostimulator (INS) is the power source that generates and controls the electrical stimulation, which is delivered to electrodes at the distal end of the lead(s) in the spine, as shown in Figure 1.  Figure 1. Representation of implanted SCS system. ### System Components All of the Medtronic SCS System components within the scope of this submission are commercially available in the United States and have been approved by the FDA through supplements to PMA P840001. Table 2 lists all implantable system components and the associated document control numbers. There are no changes proposed for these devices; the only changes proposed are to the labeling concerning the Indications for Use. Table 2: Implantable SCS system components and control devices | Device model number and product family name | Doc control number | | --- | --- | | Neurostimulators | | | 97715 Intellis™ Implantable Neurostimulator System with AdaptiveStim™ Technology | P840001/S344 | | 97716 Intellis™ Implantable Neurostimulator System | P840001/S344 | | 97725 Wireless External Neurostimulator | P840001/S344 | | 977005 Sequentia™ LT Implantable Neurostimulator | P840001/S471 | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 5 {5} | 977006 Vanta™ with AdaptiveStim™ Implantable Neurostimulator | P840001/S471 | | --- | --- | | **Leads** | | | 977A160 Vectris® SureScan® MRI 1x8 SC (Subcompact) Lead Kit | P840001/S219 | | 977A175 Vectris® SureScan® MRI 1x8 SC (Subcompact) Lead Kit | P840001/S219 | | 977A190 Vectris® SureScan® MRI 1x8 SC (Subcompact) Lead Kit | P840001/S219 | | 977A260 Vectris® SureScan® MRI 1x8 Compact Lead Kit | P840001/S219 | | 977A275 Vectris® SureScan® MRI 1x8 Compact Lead Kit | P840001/S219 | | 977A290 Vectris® SureScan® MRI 1x8 Compact Lead Kit | P840001/S219 | | 977C165 Specify® SureScan® MRI 5-6-5 Lead | P840001/S308 | | 977C190 Specify® SureScan® MRI 5-6-5 Lead | P840001/S308 | | 977C265 Specify® SureScan® MRI 2x8 Lead | P840001/S308 | | 977C290 Specify® SureScan® MRI 2x8 Lead | P840001/S308 | | 977D160 Vectris® 1x8 SC (Subcompact) Trial Screening Lead Kit | P840001/S219 | | 977D260 Vectris® 1x8 Compact Trial Screening Lead Kit | P840001/S219 | | **Extension** | | | 37081 1x8 Extension | P840001/S074 | | **Patient Control Devices** | | | 97745 Controller | P840001/S344 | | 97755 Recharger | P840001/S344 | | **Clinician Control Devices** | | | A710 Intellis Clinical Programmer Application | P840001/S344 | | 8880T2 Communicator | P840001/S344 | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 6 {6} | A71200 Vanta™ / Sequentia™ LT Clinician Programmer Application (CPA) | P840001/S471 | | --- | --- | | A71300 Stimulation Trialing Clinician Programmer Application (CTA) | P840001/S471 | | A72200 MyStim PC Patient Programming Application (PPA) | P840001/S471 | In addition, accessory kits are used in conjunction with Medtronic SCS implantable systems and are commercially available in the US. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of chronic, intractable pain associated with PDPN of the lower extremities. Treatment of PDPN is based on two different approaches: glycemic control and symptomatic pain treatment. Treatment of the underlying diabetes, if possible, is generally the primary approach to pain management. Improvements in control of blood-sugar levels for diabetic neuropathy patients is initially addressed. Pharmacologic treatments are delivered to address the symptoms of pain. These include tricyclic anti-depressants, anti-convulsants (α-2-δ modulators: gabapentin, pregabalin or valproate), and selective serotonin/norepinephrine re-uptake inhibitors (SSRI/SNRI). It is recommended that comorbidities should be evaluated before selecting a first-line therapy. Subsequently, if a patient is refractory to one of the first-line therapies, a second or combination of other first-line drugs should be prescribed. Second-line therapies include opioid analgesics for acute rescue therapy. The emergent recognition of dependence syndromes associated with the use of opioids complicates the treatment of symptoms refractory to first-line treatments. Non-pharmacologic treatments include physical therapy, cognitive therapy, and transcutaneous nerve stimulation (TENS). These therapies would be provided in conjunction or following first-line medical treatment, but before more invasive therapies are considered, and only under the direction of a pain management specialist. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The Medtronic implantable neurostimulation system for the treatment of chronic intractable pain of the trunk and/or limbs is approved for commercial distribution in Argentina, Australia, Belarus, Bosnia and Herzegovina, Brazil, Canada, China, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, European Union, Guatemala, Indonesia, Israel, Japan, Kazakhstan, Korea, South, Kuwait, Malaysia, Mexico, Morocco, Peru, Saudi Arabia, Singapore, South Africa, Taiwan, Thailand, Turkey, Ukraine, USA, Uruguay, and Vietnam. The device has not been PMA P840001: FDA Summary of Safety and Effectiveness Data Page 7 {7} withdrawn from marketing for any reason related to its safety or effectiveness. ### VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of a Medtronic implantable neurostimulation system. The implantation of a spinal cord stimulation system involves risks that are similar to other spinal procedures. In addition to those risks associated with surgery, the following adverse events may occur with implantation or use of a neurostimulation system: - Allergic or immune system response to the implanted materials - Infection - Lead, extension, or neurostimulator erosion through the skin or migration - Leakage of cerebrospinal fluid - Loss of pain relief may return patients to their underlying pain condition - Patients on anticoagulation therapies may be at greater risk for postoperative complications such as hematomas that can result in paralysis - Persistent pain at the neurostimulator site - Placement of the epidural lead-extension is a surgical procedure that may expose patients to risks of epidural hemorrhage, hematoma, or paralysis - Radicular chest wall stimulation - Seroma or hematoma at the neurostimulator site - Change in stimulation, possibly related to cellular changes around the electrode(s), shifts in electrode position, loose electrical connections, lead or extension fractures, which has been described by some patients as uncomfortable stimulation (jolting or shocking sensation). - Formation of reactive tissue around the lead in the epidural space can result in delayed spinal cord compression and paralysis, requiring surgical intervention. Time to onset can range from weeks to many years after implant. - Stimulation-dependent gastrointestinal symptoms such as nausea, diarrhea, incontinence, or constipation - Stimulation-dependent bladder symptoms such as urinary retention, incontinence, or frequency ### IX. SUMMARY OF NONCLINICAL STUDIES Pre-clinical studies previously submitted to FDA in the Original PMA application (P840001) and supplements continue to support the safety of the commercially available Medtronic implantable neurostimulation system for treatment of chronic PMA P840001: FDA Summary of Safety and Effectiveness Data Page 8 {8} intractable pain of the trunk and/or limbs. No additional preclinical studies were required to evaluate the safety of Medtronic SCS therapy for the treatment of PDPN of the lower extremities. The previously approved supplements which support the Medtronic SCS therapy system and its components are listed above in Table 2. # X. SUMMARY OF PRIMARY CLINICAL STUDY(IES) A Medtronic implantable neurostimulation system is indicated for spinal cord stimulation systems as an aid in the management of chronic, intractable pain of the trunk and/or limbs-including unilateral or bilateral pain. The safety and effectiveness of a Medtronic implantable neurostimulation system has been previously established for indicated patients suffering from a variety of conditions (see Section I, Table 1). The clinical evidence to support safety and effective use of the Medtronic implantable neurostimulation system in the diabetic neuropathy population is based on a systematic review of published clinical scientific literature of commercially available SCS systems. Primary evidence comes from two randomized controlled trials in patients with painful diabetic peripheral neuropathy (PDPN). Additional supplemental clinical evidence for safety was identified through a literature review, and the Medtronic product surveillance registry data, investigating adverse event data related to SCS use in patients with painful diabetic neuropathy (PDN), and included reports reflecting the experience of patients treated with SCS for any condition where a diagnosis of diabetes was considered. PDN encompasses many different types of neuropathy, including PDPN, autonomic neuropathy, proximal neuropathy, and mononeuropathy. # A. Study Design The safety and effectiveness of the Medtronic implantable neurostimulation system to treat PDN was based on clinical safety outcome data from the Medtronic Product Surveillance Registry (PSR) and a systematic review of published scientific literature reporting on the use of any commercially available spinal cord stimulation (SCS) systems for the treatment of chronic intractable pain in a diabetic population. A systematic review of published literature was conducted by searching Embase and MEDLINE for terms relating to SCS and diabetes. Additionally, a systematic search of the published literature was conducted to identify recent guidelines on perioperative care of diabetic patients. # Safety Safety objective: Identify risks relevant to SCS to which diabetic patients are PMA P840001: FDA Summary of Safety and Effectiveness Data Page 9 {9} predisposed and to characterize the safety profile of SCS to treat PDN. The safety profile of Medtronic implantable neurostimulation systems to treat PDN was characterized through analysis of data from Medtronic’s Product Surveillance Registry (PSR) and published scientific literature. The analysis characterized the overall safety profile by common adverse events, as well as specifically examining the risks to which the diabetic population are pre-disposed such as inherent surgical complications that may occur more frequently or have greater impact in these patients. Publications reflecting the experience of patients treated with SCS for PDN and patients treated with SCS for any condition where a diagnosis of diabetes was considered were included. Publications reporting on studies where adverse events were reported in a comprehensive manner were pooled with data from the PSR to create an overall safety profile. ### **Effectiveness** Effectiveness objective: Characterize the clinical benefits related to pain relief for SCS used to treat PDN, when compared to the standard-of-care. The effectiveness of Medtronic implantable neurostimulation systems to treat PDN was demonstrated through analysis of clinical study results identified from the systematic review of published scientific literature. The probability of treatment success (aka Responder Rate or Proportion of successfully treated subjects) defined by a specific threshold for pain reduction or Patient Global Impression of Change (PGIC) rating and the magnitude of pain relief as measured through reduction in pain scores from a Numeric Rating Scale (NRS) or Visual Analog Scale (VAS) were considered in determining effectiveness. Additionally, all publications reporting on the non-comparative studies (i.e. prospective single-arm studies) were included and summarized. ### **B. Medtronic Product Surveillance Registry (PSR)** The PSR is sponsored by Medtronic and is comprised of a global network of hospitals, clinics, and clinicians from which reliable “real-world” product safety and patient clinical outcome information is generated. The purpose of the registry is to provide continuing evaluation and periodic reporting of safety and effectiveness of market-released products for their intended use. The registry was revised in 2010 to collect more details on the pain sub-indication, including diabetic neuropathy as a primary or ‘other’ indication. Any indication that was not collected as the primary indication is referred to as a secondary indication. PMA P840001: FDA Summary of Safety and Effectiveness Data Page 10 {10} # **Data selection** Patients were identified as receiving SCS for the treatment of diabetic neuropathy if they met one of the following criteria: 1. Primary indication was specified as diabetic neuropathy (“Primary”), or 2. Primary indication was “Other chronic pain” and the free text specified diabetic neuropathy (“Primary (Other)”), or 3. Secondary indication was specified as diabetic neuropathy or the free text for an “other” secondary indication specified diabetic neuropathy (“Secondary”). Diabetic neuropathy patients with active follow-up time in the PSR after the 2010 revision were included. # **C. Literature Search Strategy** The databases searched include Embase and MEDLINE. Elsevier provides access on a single search platform via Embase.com. The databases were searched to ensure comprehensive coverage of globally published clinical evidence for medical device products and therapies. Embase, published by Elsevier, provides access to biomedical literature, with over 32 million records from over 8,300 currently published journals from 95 countries. MEDLINE is the largest component of PubMed (http://pubmed.gov/), the online database of biomedical journal citations and abstracts created by the U.S. National Library of Medicine (NLM®). MEDLINE contains bibliographic citations and author abstracts from more than 5,600 medical and life science journals published in the United States and 70 other countries. The database contains over 21 million citations. Two separate systematic searches and reviews were conducted. For both searches, the publications identified from databases were assessed for inclusion in the review though 2 steps. First, two reviewers independently screened initial search results for the selection criteria. Next, full-text copies of the selected publications were assessed independently by the same two reviewers for inclusion as final selections. Differences in selection between the 2 reviewers were discussed to confirm selection or rejection. A third party was not necessary to resolve disputed selections. 1. Clinical practice guidelines on perioperative care of diabetic patients a. Search terms (including expanded terms): Diabetes AND Clinical practice guideline or consensus statement AND peri-, post-, pre-operative or surgical b. Search dates: 2016-2021 c. Selection criteria: The guideline must provide specific recommendations for steps to be taken to avoid complications PMA P840001: FDA Summary of Safety and Effectiveness Data Page 11 {11} of surgery in a diabetic population. The publication must include a comprehensive list of specific steps, which are generalizable to SCS procedures. 2. Safety and effectiveness of SCS to treat PDN a. Search terms (including expanded terms): Diabetes AND spinal cord stimulation or dorsal column stimulation b. Search dates: 1984-2021 c. Selection criteria: i. Safety: Publication must include data on a distinctly identifiable diabetic population and report comprehensive detail on adverse events or an analysis of the impact of a diabetic state on a safety-related outcome ii. effectiveness: Publication must include data from prospective studies on SCS to treat PDN with quantifiable information regarding pain reduction, probability of treatment success, or quality of life improvements. Any available meta-analyses were included if the report synthesized new data based on prospective studies. # **Results of search and screening** # *Clinical practice guidelines for perioperative care of diabetic patients* Initial screening was performed on 178 titles and abstracts resulting in the selection of 39 publications for full-text review. After full-text review, 11 publications were selected for inclusion. Guidelines are summarized in Table 3. PMA P840001: FDA Summary of Safety and Effectiveness Data Page 12 {12} Table 3. Selected Guidelines | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Berhe et al. Intl. J. Surg. 2017^{1} Guideline on peri-operative glycemic control for adult patient with diabetic mellitus: Resource limited areas | Review and guideline of diabetic patients undergoing surgery, differentiated by minor or major surgery, aimed at resource limited health systems | - Urinalysis and electrolyte test results should be available at pre-operative screening - Prioritize operation for first of the day - Fast before surgery, unless procedure later in day, then light meal with half dose of fast acting insulin - When fasting, check glucose every 2 hours, and 1 hour prior to surgery - Target range for blood glucose: - 108-180 mg/dL and 72-216 mg/dL is acceptable - Postpone elective surgery if over 300 mg/dL or HbA1c >69 mmol/L, and consult specialist for management | - Post-operative infection - Surgery stress causing diabetic ketoacidosis - Hyperglycemia - Hyperosmolar state - Increased morbidity and mortality - Hypoglycemia leading to somnolence, confusion, seizures, irreversible neurological injuries - Impaired wound healing - Increased occurrence in cardiac arrhythmias | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 13 {13} | Chan et al. Anaesth. Intensive Care Med. 2020^{2} Preoperative cardiac optimization | Guideline for peri-operative cardiac optimization, considering diabetes among other comorbidities | - Peri-operative target for blood glucose of 6-10 mmol/L - Glycemic control should be checked at time of surgery. - Diabetic patient should be identified early in pre-operative pathway - Tests for comorbidities should be conducted including electroconvulsive therapy (ECT), urea and electrolytes for all patients - Surgery should be scheduled early in the day to avoid disruption of glycemic control | Autonomic neuropathy can cause perioperative hemodynamic instability | | --- | --- | --- | --- | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 14 {14} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Cheisson et al. Anaesthesia, critical care & pain medicine. 2018^{3} Perioperative management of adult diabetic patients. Intraoperative period. | Practice guideline focusing on the intra-operative management of diabetic patients from the French Society of Anaesthesia and Intensive Care and the French Society for the Study of Diabetes | - Avoid prolonged fasting by scheduling procedures early in the day - Have a blood glucose goal of 5-10 mmol/L, avoiding hypoglycemia - If insulin is required, use fast acting analog subcutaneously with electronic syringe with IV glucose - Replace insulin pump with immediate IV management during procedure - Monitor glucose every 1-2 hours and potassium every 4 hours if under insulin control, and consider 3.8 mmol/L hypoglycemia requiring intervention - All solutes may be used, including Ringer's lactate, in the peri-operative period - Peri-operative control is dictated by 3 factors: diabetes type, pre-operative control, and type of surgery - Manage risk of nausea and vomiting as to facilitate resumption of food intake after surgery - Manage post-operative pain | - Infections - Delayed wound healing - Increased morbidity and mortality | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 15 {15} | | | closely to avoid hyperglycemia | | | --- | --- | --- | --- | | Cheisson et al. Anaesthesia, critical care & pain medicine. 2018^{4} Perioperative management of adult diabetic patients. Postoperative period. | Practice guideline focusing on the post-operative management of diabetic patients from the French Society of Anaesthesia and Intensive Care and the French Society for the Study of Diabetes | • Maintain subcutaneous insulin via electronic syringe until glucose stabilizes (<10 mmol/L) and discontinue when normal feeding resumes • Manage discontinuation with appropriate slow and fast acting insulins Resume treatments based on diabetes type, management regimen, and post-operative glucose levels | Hyperglycemia (ketoacidosis) and hypoglycemia | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 16 {16} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Dortch et al. Aesthetic surgery journal. 2016^{5} Perioperative Glycemic Control in Plastic Surgery: Review and Discussion of an Institutional Protocol | Practice guideline for care of diabetic patients undergoing plastic surgery with specific procedure examples as well as a generalized protocol from the Mayo Clinic | - Outpatient guidelines: Pre-operative screening to include HbA1c - If HbA1c > 8%, refer to primary care physician for optimization - Monitor blood glucose in postanaesthesia unit - Goal of < 180 mg/dL following surgery - Patients should be instructed to resume customary monitoring and resume fast acting insulin if discontinued prior to surgery | - Wound infection - Wound healing - Impaired immunologic defense mechanisms - Increased mortality | | Livshetz & Nett. Tech. Orthop. 2019^{6} Perioperative Management of Diabetes for Total Joint Arthroplasty: A Consensus Article | Review covering questions of screening, HbA1c level cut-offs, and guidelines for practice in total joint arthroplasty | - Given lack of consensus for HbA1c limits of 7%, <8% seems prudent to mitigate risks - All patients should be screened for HbA1c levels and orthopedic surgery should be postponed if spot glucose checks results in >200 mg/dL on the day of surgery - ADA guidelines should be followed for peri-operative glucose control (pre-prandial 80-130 mg/dL and < 180 mg/dL post-prandial) | - Wound complications - Thrombosis - Surgical site infection | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 17 {17} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Mumdzic & Munir, Surgery. 2020^{7} Perioperative management of diabetes and corticosteroid supplementation | Peri-operative guidance on peri-operative diabetes management and supplemental corticosteroid treatment | - Pre-operative evaluation should include history, kidney function, blood count and coagulation profile, updated HbA1c - Refer for expert optimization of glucose control if HbA1c > 8.5% for elective surgeries - Intra-operative levels of 6-10 mmol/L should be the goal (6-12 mmol/L is acceptable) - Diet-managed Type 2 diabetics may not require therapy and are not at risk for hypoglycemia, though if they become hyperglycemic they can be managed with fast acting insulin - Management of glucose should be made with consideration of surgery complexity as to how many missed meals will be experienced | - Increased postoperative morbidity and mortality | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 18 {18} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Robinson et al. Anaesth. Intensive Care Med. 2020^{8} Perioperative management of diabetes | Review of perioperative diabetes management with background information, management steps and recommendations on special populations/situations | - Referrals for surgery should include HbA1c in last 3 months, BMI, eGFR, and accurate medication list - Thorough pre-operative assessment for cardiovascular disease, diabetic nephropathy, autonomic neuropathy, peripheral neuropathy, diabetic retinopathy, obesity, autoimmune disease, and HIV - Postpone elective surgery if HbA1c > 69 mmol/L to confirm optimization and consult with multidisciplinary team to proceed - Minimize fasting time by early scheduling (first of day or within first 1/3rd of schedule) - Perioperative glucose management plan should be made based on pre-operative levels to adjust medications including insulin - Intra-operative levels of 6-10 mmol/L should be the goal (6-12 mmol/L is acceptable) - Patients should be provided with information on managing their diabetes upon discharge | - Post-operative infection (surgical site or systemic) - Cardiovascular events - Acute kidney injury - Stroke | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 19 {19} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | Simha & Shah. JAMA. 2019^{9} Perioperative Glucose Control in Patients With Diabetes Undergoing Elective Surgery. | Description of management of blood glucose in perioperative period with guidance on insulin management | - HbA1c should be check in all patients - Postpone elective surgery if HbA1c > 8% and would require intensifying of diabetes management strategies - Postpone elective surgery in severe hyperglycemia (>250 mg/dL) - Reduce insulin prior to surgery (50-75%), with half-dose on day of surgery if glucose is elevated - Schedule procedure in the AM to reduce duration of fasting - Intra-operative management to <180 mg/dL without causing hypoglycemia - Re-check blood glucose post-operatively, with a goal of pre-prandial 100-140 mg/dL and random 100-180 mg/dL | - Wound infection - Pneumonia - Sepsis - Cardiovascular events | | Stryker. The Journal of arthroplasty. 2016^{10} Modifying Risk Factors: Strategies That Work Diabetes Mellitus. | Peri-operative guidance on checking and managing blood glucose in patients, with and without diabetes diagnosis undergoing total joint arthroplasty | - Peri-operative screening in all patients, with >200 mg/dL further screened for HbA1c - Goal of <7% HbA1c, though may be higher with individual cases | - Delayed wound healing - Deep infection - Thrombosis - Mortality | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 20 {20} | Author and Title | Summary | Recommendations | Noted complications | | --- | --- | --- | --- | | | | - Unmanageable levels should be referred to dietician or patient's primary physician - Short acting insulin or oral regimens withheld on morning of surgery, with long acting agents or infusion pumps continued - Post-operative insulin regimens can resume after resumption of regular diet | | | Wang et al. Clinical neurology and neurosurgery. 2021^{11} Preoperative optimization for patients undergoing elective spine surgery. | General perioperative guideline on management of patients in regard to medications, diabetes, hypertension, smoking, renal function, BMI, psychosocial aspects, and frailty. | - HbA1c goal of < 7% - Pre-prandial glucose 90-130 mg/dL - Post-prandial glucose < 180 mg/dL - First-start surgical case (early in the surgery day) - Insulin Glucose Tolerance Test (GTT), IV management perioperative) for >200 mg/dL - Continue home insulin, discontinue atypical hyperglycemic agents - Cancellation of procedure if in diabetic ketoacidosis or >400 mg/dL | - Delayed wound healing - Infection - Thrombosis - Mortality | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 21 {21} # *Safety and effectiveness* Initial screening was performed on 319 titles and abstracts resulting in the selection of 69 publications for full-text review. After full text review, articles were selected for inclusion based on safety, effectiveness, or as meta-analyses. The following number of publications were selected for each category: - Safety: 19 publications. Several studies resulted in multiple publications. Safety information was extracted from the publication with the longest follow-up from each study that included comprehensive adverse event information and is included in Table 4. - Effectiveness: 12 publications. Several studies resulted in multiple publications. Effectiveness data was extracted from all publications and included in total for each cohort. - Meta-analyses: 2 publications reported meta-analyses of randomized controlled studies of SCS to treat PDN. The reports are summarized in Table 6. PMA P840001: FDA Summary of Safety and Effectiveness Data Page 22 {22} Table 4: Selected reports of SCS to treat a diabetic patient population | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | Tesfaye (1996)^{12} and Daousi (2005)^{13} | Prospective observational study of SCS to treat PDN with a double-blind test stimulation period and pain ratings of background and peak pain with the stimulator on or off 10 subjects, 8 receiving implant followed for clinical performance outcomes Follow-up: 3 and 6 months and end of study with a median of 14 moths and a range=9-20 months. (Tesfaye, 1996) Patients were then followed-up at 3 and 7 years after the study end. (Daousi, 2005) | Of 8 subjects receiving SCS implant: 3 deaths at 2 mo, 2 yr, and 4 yr. All from myocardial infarction 1 explant due to lack of pain relief 2 superficial infections treated with antibiotics 2 lead migration with revision 2 skin peeling at antenna site 1 hematoma at implant site w/out clinical impact 1 lead failure due to trauma, replaced | Relevance: The earliest report of a prospective study specifically examining the use of SCS to treat PDN. Relatively long follow-up allowed for characterization of the comorbid health burden which leads to early mortality in this population. Limitations: Small, Non-comparative study. SCS technology is from a previous generation of single-lead systems and externally powered neurostimulators, limiting the potential flexibility for reprogramming and patient compliance. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 23 {23} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | Petrakis (1999)^{14} | Study of SCS delivered to diabetic patients with peripheral arterial occlusive disease examining changes in microcirculation and predictors of success 64 subjects Mean follow-up duration of 58 months (range 20-128 months) | 8 battery replacement procedures following normal end of device life 2 lead migrations requiring lead revision 2 Infections requiring explant | Relevance: Use of Medtronic SCS systems. Includes a description of the use of SCS in a specific diabetic population. Peripheral Vascular Diseases are common in diabetic patients and represent and overlap in affected populations. Limitation: Non-comparative study. SCS technology is from a previous generation of single-lead systems limiting the potential flexibility for reprogramming and patient compliance. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 24 {24} | TenVaarwerk (1999)^{15} | Multi-center retrospective cohort study of patients treated with SCS for refractory Angina Pectoris over a 10-year period to determine morbidity and mortality characteristics 517 patients, 14% identified as having Insulin Dependent Diabetes Mellitus (IDDM) Median follow-up of 23 months | Percentage of patients with IDDM in cohort was 14%. IDDM patients were relatively over-represented in the population who died and under-represented in the population who survived. -Died = 20% -Survived = 13% -p = 0.05 Multi-variate analysis significantly correlated IDDM with mortality | Relevance: Report of SCS in a population where a co-factor of diabetes could be described related to safety. Limitations: Within study comparison was not a prospective group allocation factor. The population was not PDN patients and of a group where 100% presented with an intractable cardiovascular disease condition. | | --- | --- | --- | --- | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 25 {25} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | de Vos (2009)^{16} | Prospective observational study of pain relief and microcirculatory function in PDN patients treated with SCS 11 subjects 6-month primary endpoint and 30-month follow-up | 2 lead/extension failures with revisions 1 mild infection treated with antibiotics 1 death described to be unrelated to SCS | Relevance: Use of Medtronic SCS system. Prospective pilot study that led to a larger multicenter RCT Limitations: Small, single-center study without comparator group. Use of single 4-contact lead system. | | Mekhail (2011)^{17} | Single-center retrospective case series to review indications and complications of SCS to treat Failed Back Surgery Syndrome (FBSS), Complex Regional Pain Syndrome (CRPS), Peripheral Vascular Disease (PVD), visceral pain, neuropathy over a 5-year period 707 patients (8% with diabetes diagnosis) Mean follow-up of 3 years and 5 months, range from 3 months to 7 years | Overall infection rate: 4% Infection rate of diabetic population: 9% p = 0.188 chi-square | Relevance: Large case series that allowed for analysis of the co-factor of diabetes as a predictor of infection, concluding no statistical association. Long-term follow-up included Limitations: Potential inclusion bias in retrospective design. Smaller diabetic population may have reduced ability to detect difference in infection rate. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 26 {26} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | **Pluijms (2012^{18}; 2015^{19}), Slangen (2013^{20}; 2014^{21}), van Beek (2015^{22}; 2018^{23})** | Multi-center cohort of subjects included in a prospective single-study and a RCT of SCS to treat PDN with analyses of predictors of success. Patients were pooled from all implanted subjects reported in Pluijms, 2012 and Slangen, 2014 48 subjects 5-year follow-up | 13 subjects with implantable neurostimulator (INS) replacement due to battery depletion, 5 of those subjects had 2 replacements (18 total) 10 subjects reporting pocket pain with 1 leading to revision due to persistent pain, without complete resolution of pain 9 subjects reporting uncomfortable stimulation 6 subjects were explanted due to loss of therapeutic effect. 5 lead migrations with revision 4 lead failures with replacement 2 infections leading to explant 1 dural puncture and CSF leak during trial procedure leading to subdural hematoma and subsequent death | Relevance: Use of Medtronic SCS systems. Long-term follow-up of a cohort of patients included in a single arm study as well as those treated as part of a multi-center RCT of subjects with PDN treated with SCS, including control arm subjects who crossed over to the treatment arm. Long-term follow-up of 5 years. Limitations: Lack of individual patient data to determine the number of adverse events in each patient, other than for battery replacement at the expected end-of-service of devices | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 27 {27} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | de Vos (2014)^{24} | RCT, Parallel design with 2:1 allocation comparing SCS + conventional medical practice vs conventional medical practice to treat of PDN 60 Subjects (40:20) 6 months primary endpoint on pain measures | Procedure related adverse events: 2 pain at INS 2 required additional lead placed to cover painful area 1 each of lead migration, infection during trail period, coagulopathy resulting in prolonged hospitalization Non-study related (potentially due to underlying condition): SCS group: 2 infections causing unstable glucose 1 femur fracture 1 cardiac arrest Control group: 2 infections 1 each of Carotid artery stenosis, Myocardial infarction, atrial fibrillation episode, coronary bypass surgery | Relevance: Provides detailed safety information, including relatedness, from subjects with PDN treated with SCS. Limitations: SCS system used from another manufacturer, though with equivalent characteristics. Limited follow-up of 6 months. Lack of individual patient data to determine the number of adverse events in each patient | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 28 {28} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | **Bir (2016)**^{25} | Retrospective review of SCS patients treated for FBSS or chronic back pain examining the predictors of revision of the SCS system 141 patients Follow-up: Median 31.5 months (range=3-166) | Revision Free Survival curves plotted for non-diabetic vs diabetic patients and there was no significant difference detected (p=0.98) | Relevance: Large review that allowed for analysis of the co-factor of diabetes as a predictor of all cause system survival concluding no significant impact of the co-factor. Limitations: Potential inclusion bias in retrospective design, Not specific to PDN | | **Hoelzer (2017)**^{26} | Multi-center cohort study reviewing infection rates and risk factors associated with SCS over a 7-year period in patients treated for FBSS, CRPS, Post-Herpetic Neuralgia, and other chronic pain conditions 1,960 permanent implants 777 surgical revisions 2,737 total patients (461 patients with diabetes) 12-month follow up window | Surgical Site Infection (SSI) rate of 2.45% SSI rates for diabetic state: -Yes: 1.99% -No: 2.54% -p = 0.49 | Relevance: Large review that allowed for analysis of the co-factor of diabetes as a predictor of surgical site infection, concluding no significant difference. Limitations: Potential inclusion bias in retrospective design, Not specific to PDN | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 29 {29} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | **Falowski (2019)**^{27} | Retrospective analysis of the payer databases over a 5-year period to characterize infection risk factors in chronic pain patients treated with SCS based on demographics, comorbidities, and clinical characteristics 5,563 with initial INS 1,052 replacement INS 6,615 patents in total (1,663 patients with diabetes) 12-month follow-up window | Overall infection rate of 3.11% Proportions of population of initial implants with/without infection: -Type 1 Diabetes Mellitus (DM) = 4.07%/3.32% (p = 0.5904) -Type 2 DM = 24.02%/22.02% (p = 0.4551) Logistic Regression for Infection Within 12 Months: -Type 1 DM -Odds ratio: 1.335 -p = 0.4391 -Type 2 DM -Odds Ratio: 1.124 -p = 0.6121 | Relevance: Analysis of predictors of infection by multiple factors concluding that diabetes was not a predictor of surgical site infection. Payer database likely reliable source as few events would go unrecorded. Limitations: Payer database limited data to implanted subjects, excluding the opportunity for trial exposure. | | **Galan (2020)**^{28} | Sub-analysis of PDN patients from a prospective cohort of peripheral neuropathy patients treated with 10 kHz SCS 8 subjects 12 months follow-up | 8 Non-serious adverse events in 3 subjects of which 2 were study-related: seroma and pain in extremity 3 serious adverse events in 3 subjects of which 1 was study related: wound dehiscence | Relevance: Cohort of PDN patients treated with an SCS system reporting detailed adverse event data. 12-months of follow-up Limitations: Data from other manufacturer where therapy delivery would be unlikely to provide information related to overstimulation events. Small cohort size. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 30 {30} | Cohort (Authors and Years) | Summary of Study Design | Relevant Safety Data | Relevance and Limitations | | --- | --- | --- | --- | | **Antonovich (2021)**^{29} | Retrospective review of chronic pain patients treated with SCS comparing reoperation rates associated with either percutaneous or paddle leads. 271 patients, 65 with a diagnosis of diabetes | 65 patients indicated a diagnosis of diabetes (22.34%) A diagnosis of diabetes was not associated with reoperation (univariate Hazard Ratio = 0.70; p = 0.197). | Relevance: Large contemporary data set describing safety outcomes analyzing diabetes as a co-factor, concluding that it was not statistically associated with re-operation Limitations. Single center retrospective study could allow for inclusion bias | | **Petersen (2021)**^{30} | Multi-center, randomized (1:1) trial comparing the treatment of 10 kHz SCS to conventional management of PDN 216 subjects (103 control and 113 SCS with 104 exposed to at least trial stimulation) 6 months follow-up | 18 adverse events in 14 subjects treated with SCS Study related AEs: 3 Infection 2 Wound dehiscence 2 Explants 1 each of impaired healing, device extrusion, incision site pain, IPG discomfort, lead migration, contact dermatitis, utricaria, radiculopathy, uncomfortable stimulation, gastroesophageal reflux, myalgia, arthralgia, hyporeflexia | Relevance: Safety data from large multi-center RCT in PDN patients comparing outcomes to the standard of care. Provided detailed adverse event information including related and unrelated events. Limitations: Data from other manufacturer where therapy delivery would be unlikely to provide information related to overstimulation events, though one is reported. Data from individual subjects unavailable to determine multiple events in individual subjects. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 31 {31} **Table 5: Reports on effectiveness of SCS to treat PDN** | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | **Tesfaye (1996)^{12} and Daousi (2005)^{13}** | Prospective observational study of SCS to treat PDN with a double-blind test stimulation period and pain ratings of background and peak pain with the stimulator on or off 10 subjects, 8 receiving implant followed for clinical performance outcomes Follow-up: 3 and 6 months and end of study with a median of 14 moths and a range=9-20 months. (Tesfaye, 1996) Patients were then followed-up at 3 and 7 years after the study end. (Daousi, 2005) | Trial success: 80% (8/10) Percent of subjects with pain relief and continued SCS use (n=10): 6 mos: 60% 3.3 years: 60% 7.5 years: 40% (100% of surviving implanted patients) Magnitude of pain relief as % difference in median pain score between stimulation ON and OFF, at 6 months: 'Background pain': 58% 'Peak pain': 59% No change in sensory thresholds, nerve conduction, or HbA1c | Relevance: The earliest report of a prospective study specifically examining the use of SCS to treat PDN. Relatively long follow-up Limitations: Small size with limited number surviving for longest time-point. Non-comparative study. SCS technology is from a previous generation of single-lead systems and externally powered neurostimulators, limiting the potential flexibility for reprogramming and patient compliance. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 32 {32} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | de Vos (2009)^{16} | Prospective observational study of pain relief and microcirculatory function in PDN patients treated with SCS 11 subjects 6-month primary endpoint and 30-month follow-up | Trial success: 82% Subjects with ≥50% pain relief (n=11) 6 mo = 55% 12 mo = 64% 30 mo = 64% Subjects with ≥30% pain relief (n=11) 6 mo = 73% 12 mo = 73% 30 mo = 73% Average pain relief 6 mo = 55.8% (n=9) 12 mo = 70.1% (n=9) 30 mo = 70.1% n=9) | Relevance: Use of Medtronic SCS system. Prospective pilot study that lead to a larger multicenter RCT Limitations: Small, single-center study without comparator group. Use of single 4-contact lead system. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 33 {33} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | de Vos (2014a)^{31} | Single-arm study of chronic pain patients treated with SCS comparing traditional SCS to another programming approach. 48 subjects, 12 with PDN Mean duration of treatment for PDN group: 1.8 years | Average pain relief at follow-up: 60% | Relevance: Publication provided a subset of subjects with PDN and compared to a novel programming method. Data from baseline and standard SCS programming showed meaningful pain relief. Limitations: Single center study with small sample of subpopulation. Detail on baseline pain score collection was limited. Possible selection bias by selecting already implanted subjects. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 34 {34} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | de Vos (2014b)^{24} and Duarte (2016)^{32} | RCT, Parallel design with 2:1 allocation comparing SCS + conventional medical practice vs conventional medical practice to treat of PDN 60 Subjects (40:20) 6 months primary endpoint on pain measures (de Vos, 2014) and Quality of Life (Duarte, 2016) | Trial success: 93% Primary endpoint of proportion of subjects reporting ≥ 50% pain relief at 6 months: SCS: 63% Control: 5% p < 0.001 Average pain relief at 6 months -SCS 57.5% -Control: 0% EuroQoL EQ-5D (0-1 scale) SCS: 0.39 improvement Control: 0.00 improvement EQ-5D VAS (0-100) SCS: 12-point improvement Control: 7-point improvement | Relevance: RCT of standard SCS programming to treat PDN compared to conventional treatment. SCS programming consistent with standard SCS. Demonstrated robust effectiveness and significant average pain relief. Significant improvements in EQ-5D measures related to Quality of Life Limitations: SCS system used from another manufacturer, though with equivalent characteristics. Limited follow-up of 6 months. Lack of individual patient data to perform additional analysis. No blinding which could result in biased outcome measures. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 35 {35} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | **Pluijms (2012^{18}; 2015^{19}) and Slangen (2013)^{20}** | Prospective, single center, single-arm study of SCS to treat PDN. Pain relief was the primary measure. (Pluijms, 2012). Heat-evoked potentials and manual sensory testing were measured (Pluijms 2015) 15 subjects (11 implanted with SCS system) 3, 6, and 12-month follow-up (Pluijms 2012) and through 36 months (Slangen, 2013) | Trial success: 73% Subjects with treatment success as measured by ≥50% pain relief in day or nighttime pain or PGIC rating of ‘much improved or ‘very much improved’ (n=15): at 12 months: 67% Daytime pain relief at 12 months: 51.7% Implanted subjects with treatment success as measured by ≥50% pain relief in day or nighttime pain or Patient Global Impression of Change (PGIC) rating of ‘much improved or ‘very much improved’ (n=11): 12 months: 91% 24 months: 55% 36 months: 68% Subjects with improved EQ-5D 12 mo: 64% 24 mo: 55% 36 mo: 64% No differences were found between responders and non-responders in heat-evoked potentials or sensory testing | Relevance: Use of Medtronic SCS systems. Pilot study to support later RCT. Showed meaningful pain relief and sustained effects to 36 months. Limitations: Small, single-center study. Lack of individual patient data to perform further analysis. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 36 {36} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | Slangen (2014)^{21} and Van Beek (2015)^{22} | Multi-center, randomized (3:2) trial comparing SCS + Best Medical Treatment (BMT) vs BMT to treat PDN 36 subjects (22:14) 6-month primary endpoint (Slangen, 2014) 24-month follow up (Van Beek, 2015) | SCS trial success rate: 77% Primary endpoint of subjects with treatment success as measured by ≥50% pain relief in day or nighttime pain or PGIC rating of ‘much improved or ‘very much improved’: SCS: 59% Control: 7% p = 0.009 Pain reduction at 6 months: SCS: 44% Control: 0% EQ-5D utility score change at 6 months: SCS: 0.25 improvement Control: 0.00 improvement Implanted subjects with treatment success as measured by ≥50% pain relief in day or nighttime pain or PGIC rating of ‘much improved or ‘very much improved’: 3 mo: 94% 6 mo: 76% 9 mo: 76% 12 mo: 71% 24 mo: 65% | Relevance: Use of Medtronic SCS systems. RCT of subjects with PDN treated with SCS, including control arm subjects who crossed over to the treatment arm. Long-term follow-up of 2 years. Demonstrated robust effectiveness and meaningful pain relief. Limitations: Though appropriately powered based on pilot study, was small in size. Lack of individual patient data to perform additional analyses. No blinding which could result in biased outcome measures. Improvement seen with SCS treatment did not reach levels of significance. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 37 {37} | Cohort (Authors and Years) | Summary of Study Design | Effectiveness Data | Relevance and Limitations | | --- | --- | --- | --- | | **Van Beek (2018)**^{23} **-Combined cohort from Pluijms 2012 and Slangen 2014** | Multi-center cohort study of SCS to treat PDN with analyses of predictors of success. Patients were pooled from all implanted subjects reported in Pluijms 2012 and Slangen 2014 48 subjects 5-year follow-up | Subjects with treatment success as measured by ≥50% pain relief in day or nighttime pain or PGIC rating of ‘much improved or ‘very much improved’: 12 mo: 86% 24 mo: 71% 36 mo: 77% 48 mo: 67% 50 mo: 55% Pain score reduction (NRS) for daytime (d) or nighttime (n) pain: 12 mo: (d) 43%; (n) 42% 24 mo: (d) 39%; (n) 39% 36 mo: (d) 43%; (n) 42% 48 mo: (d) 37%; (n) 34% 60 mo: (d) 36%; (n) 31% Kaplan-Meier survival analysis showed 80% of implanted subjects still used the SCS system after 5 years. Higher Michigan Diabetic Neuropathy Score (MDNS) was associated with failure and higher baseline nighttime pain was associated with success. | Relevance: Use of Medtronic SCS systems. Long-term follow-up of a cohort of patients included in a single arm study as well as those treated as part of a multi-center RCT of subjects with PDN treated with SCS, including control arm subjects who crossed over to the treatment arm. Long-term follow-up of 5 years. Demonstrated a high degree of treatment success in implanted subjects through long term follow-up. Provided analysis on predictor of success based on baseline severity of PDN Limitations: Lack of individual patient data to perform additional analyses. No control group after control arm crossed over to SCS treatment. Loss to follow-up over 5 years represents some missing data that could bias conclusions. | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 38 {38} Table 6. Selected Meta-analyses on SCS to treat PDN | Author/Title | Methods Summary | Results | | --- | --- | --- | | Raghu et al. (2020)^{33} Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta-Analysis | MEDLINE and Embase were searched through 10 January 2020. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences. The Cochrane risk of bias tool was used to assess bias. PROSPERO registration: CRD42019135591 | Mean difference in pain score reduction (0-100 scale) of 37.84 (95% CI 28.83 to 46.85; I^{2} = 0%). Pooled mean difference for EQ-5D = 0.16 (CI 0.02 to 0.30; I^{2}=0%) and EQ-VAS = 11.21 (CI 2.26 to 20.16) Risk of bias: “Both RCTs had a low risk of bias in multiple categories. However, allocation concealment and blinding to outcome were unclear, and the nature of SCS necessitates a high risk of performance bias.” | | Duarte et al. (2021)^{34} Spinal cord stimulation for the management of painful diabetic neuropathy: a systematic review and meta-analysis of individual patient and aggregate data | MEDLINE, CENTRAL, and Embase were searched from inception until 21MAY2020. Two reviewers independently screened titles and abstracts and full-text publications were again reviewed independently. Cochrane risk of bias tool (RoB 2.0) was used to assess bias. The primary outcome was pain intensity at the last follow-up time point available. PROSPERO registration: CRD42020204390 | Mean difference in pain score reduction (0-10 scale) of 3.13 (95% CI 4.19 to 2.08; I^{2} = 0%) Risk of bias: “Both RCTs were judged to have a low risk of bias for the domains of the process of randomisation, deviations from intended interventions, and level of missing outcome data. However, both RCTs were judged to have a high risk of bias for outcome measurement as these were open label trials.” | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 39 {39} # D. Safety and Effectiveness Results # 1. Safety Results # Clinical practice guidelines on the perioperative care of diabetic patients Recommendations on the perioperative care of diabetic patients were extracted from the individual publications. Recommended precautions frequently included preoperative screening for patients with a history of comorbidities or poor glycemic control. The level of glycemic control, as reflected by HbA1c (%, or mmol/mol), varied and it was commonly described as having no strong consensus. Several guidelines set a threshold of an HbA1c level of 8% as a point to consider delaying surgery, if it was necessary to ensure that the patient has optimized their glycemic control. The most common recommendations were for surgical timing in the morning to minimize fasting time and management of insulin and medications in the perioperative period. Many recommendations are applicable to care provided by anesthesiologists during intra-operative management of hyperglycemic or hypoglycemic states. The guidelines cited specific complications to which diabetic patients are known to be predisposed. Delayed wound healing, infection, cardiovascular events (including myocardial infarction, stroke, and deep vein thrombosis), and general morbidity or mortality were most commonly referenced. From the guidelines, citations describing the incremental risks were reverse traced to primary sources. The sources described rates of events in the diabetic population as well as the relative risk levels (described in Odds or Hazard Ratios). Sources were screened for similarity of populations studied as compared to SCS (elective, orthopedic or spinal surgery, etc.). Most noted perioperative events were more likely to occur in diabetic patients, with Odds Ratios ranging from 1.52 to 6.07. Several reports described the increased odds of infection. Overall, diabetic patients are approximately twice as likely to experience infection. Delayed wound healing likely contributes to this increased risk by being over 6 times more likely in a patient with an HbA1c greater than 8%.35 Myocardial infarction was identified in univariate analysis as potentially being more likely but did not reach significance in multivariate analyses. The likelihood of stroke was elevated in the same cohort (OR = 3.42; 95% CI = 1.87 to 6.25; p < 0.001).35 Slangen et al. (2014) reported one subject death following a dural puncture and subsequent CSF leak leading to a cranial subdural hematoma.21 Ha et al. (2016) reported data from craniotomy procedures concluding that diabetic patients may be at higher risk of CSF leak (Univariate regression model; p = 0.021).36 Though a Multivariate regression model did not find significant relation between diabetes and CSF leak (Odds Ratio = 1.82; p = 0.448).36 The more invasive nature of craniotomy relative to SCS lead placement somewhat limits the translation of this PMA P840001: FDA Summary of Safety and Effectiveness Data Page 40 {40} concern to SCS procedures. The report in the literature on SCS to treat PDN and the univariate association warrants consideration. Wang et al. (2014) reported increased incidence of subdural hematoma in diabetic patients (log-rank test, p < 0.0001).37 Cox proportional hazard modeling resulted in an adjusted Hazard Ratio = 1.63. The analysis considered all causes including traumatic and non-traumatic events initiating the subdural hematoma. The authors hypothesized that the prevalence of cardiovascular disease and subsequent use of anti-coagulants as well as renal disease may contribute to increase in bleeding tendency or that brain atrophy and subsequent stretching of bridging veins increases the likelihood of vessel tearing as explanations for this increase in relative risk. Selected references are included in Table 7. The table also includes the risk of fluctuation in blood glucose in response to an adverse event as described by de Vos et al. (2014).24 PMA P840001: FDA Summary of Safety and Effectiveness Data Page 41 {41} Table 7. Perioperative complications and relative risk in diabetic patients | Generalized Events | Observed Rate in Diabetic Population (source, intervention, rate) | Relative Risk for Diabetic Population | | --- | --- | --- | | Delayed wound healing | Han et al. (2013)^{38}, Total Knee Arthroplasty, Wound complication rate = **6.6%** | Han et al. (2013): OR HbA1c > 8 = 6.07 | | Infection: surgical site, systemic, pneumonia | Golden et al. (1999)^{39}, Coronary artery surgery, Infection rate: **24.3%** (SSI Leg = 10.9%, SSI sternum = 5.6%) | Golden et al. (1999): progressive trend with blood glucose and OR for infection. OR mean blood glucose (MBG) 207-229 mg/dL=1.17; 230-252 mg/dL =1.86; 253-353 mg/dL=1.72 | | | Brown et al. (2007)^{40}, Lumbar fusion surgery, Infection rate **0.68%** | Brown et al. (2007): OR = 1.52 | | | Anderson et al. (2017)^{41}, Spine surgery, Infection rate for highest risk groups undergoing laminectomy = **2.3%** | Anderson et al. (2017): OR = 2.04 | | | Marchant et al. (2009)^{35}, Total Joint Arthroplasty, Infection rate: **0.38%** in controlled diabetes and **1.18%** in uncontrolled diabetes | Marchant et al. (2009): OR = 2.28 | | Cardiovascular events: stroke, deep vein thrombosis (DVT), myocardial infarction (MI), | Marchant et al. (2009)^{35}, Total Joint Arthroplasty, | Marchant et al. (2009): Myocardial infarction OR = | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 42 {42} | Hemodynamic instability | Myocardial infarction = 0.01% Stroke = 0.2% | 1.54 in uncontrolled diabetics (p>0.05); Stroke OR = 3.42 | | --- | --- | --- | | CSF leak-subdural hematoma | Wang et al. (2014)^{37}, All cause, Rate of subdural hematoma in diabetic population = 2.04/1000 person years | Wang et al. (2014) Adjusted hazard ratio of 1.63 for diabetic patients for subdural hematoma | | | Ha et al. (2016)^{36}, Craniotomy, Rates not specific to diabetic patients | Ha et al. (2016): OR = 1.82 for CSF leak in diabetic patients | | Fluctuation of glucose | de Vos et al. (2014)^{24}, SCS to treat PDN, rate of glucose fluctuation in diabetic patients subsequent to an infection = 5% | N/A - Experienced only by diabetics | PMA P840001: FDA Summary of Safety and Effectiveness Data Page 43 {43} Data on diabetic and specifically PDN patients treated with SCS is included in the following sections. The safety profile of SCS use in diabetic populations appears to be similar as what is observed in non-diabetic patients in most reports, with some exceptions. The similarity in safety profile does not eliminate the fact that diabetic patients are at increased risks for perioperative complications based on broader data collection on similar elective procedures. To address the incremental risks and avoid complications in diabetic patients, safety information in device labeling has been supplemented to include additional warnings and adverse event listings. Additional information includes warnings of the potential for increased frequency or severity of events as well as selecting and managing patients presenting with risk factors or sub-optimal glycemic control. The included recommendations are in line with the most recent American Diabetes Association standards of care on diabetic patients in the hospital setting.$^{42}$ ## Registry data on PDN patients treated with SCS Available data on 67 patients treated with SCS between April 15, 2010 and October 31, 2020 for PDN as a primary or secondary indication are included in the safety analysis. The 67 patients in the PDN analysis set had a median of 15 months of device exposure post-2010, ranging from 0 to 110 months. A total of 51 events related to the device, therapy, or procedure occurred in 22 patients. Adverse events (ex. device site pain, infection, wound healing issues) and device events (lead migration, neurostimulator battery failure, lead fracture) are distinguished, with some events classified as both adverse and device events. Thirty-nine adverse events occurred in 18 patients (27%). Twenty-six device events occurred in 14 patients (21%). Both an adverse event and device event was recorded for 14 of the events. A survival analysis (freedom from event) was conducted by comparing outcomes for the PDN patient population to a non-PDN population enrolled in the Registry (n = 2733). Infection, device site pain, wound problems, cerebrospinal fluid (CSF) leak, lead migration, and lead fracture events were compared. Only infection was shown as having a statistical difference between PDN and non-PDN patients (p = 0.02), with PDN patients having a higher risk of infection (hazard ratio (HR) of 2.8). Data on common adverse events in SCS recorded as part of the Registry are included in Table 8 along with data from published literature. ## Published literature – Safety ### Common Adverse events Studies which included detailed adverse event information were pooled to assess common adverse event occurrences. Table 8 presents study data grouped by PMA P840001: FDA Summary of Safety and Effectiveness Data Page 44 {44} reports of common patient cohorts and by populations defined specifically by PDN or by those reporting on patients with diabetes in general (DM). PMA P840001: FDA Summary of Safety and Effectiveness Data Page 45 {45} Table 8. Common Adverse Events | | n^{a}= | Adverse Event counts (%) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | Infection | Lead migration | Lead failure | Device site swelling or pain | Hematoma/erosion/wound | CSF leak | Uncomfortable stimulation/stimulation issue | | | PDN | PSR | 67 | 5 (7.5) | 11 (16.4) | 4 (6.0) | 5 (7.5) | 1 (1.5) | 1 (1.5) | 5 (7.5) | | | Tesfaye (1996)- Daousi (2005)^{13,12} | 10 | 2 (20) | 2 (20) | 1 (10) | - | 1 (10) | - | - | | | de Vos (2009)^{16} | 11 | 1 (9.1) | | 2 (18.2) | - | - | - | - | | | de Vos (2014)^{24} | 40 | 3 (7.5)^{c} | 1 (2.5) | | 2 (5) | - | - | 2 (5) | | | Pluijms (2012)^{18}- Slangen (2013)^{20} - Slangen (2014)^{21}- van Beek (2015)^{22}-van Beek (2018)^{23b} | 49 | 2 (4.1) | 5 (10.2) | 4 (8.2) | 10 (20.4) | - | 1 (2) | 9 (18.4) | | | Galan (2020)^{28} | 9 | - | - | - | 1 (11) | - | - | - | | | Petersen (2021)^{30} | 104 | 3 (2.9) | 1 (1.0) | - | 2 (1.9) | 4 (3.8) | - | 1 (1.0) | | DM | Petrakis (1999)^{14} | 64 | 2 (3.1) | 2 (3.1) | - | - | - | - | - | | | Mekhail (2011)^{17} | 56 | 5 (8.9) | - | - | - | - | - | - | | | Hoelzer (2017)^{26} | 461 | 9 (2.0) | - | - | - | - | - | - | | | Falowoski (2019)^{27} | 1663 | 59 (3.5) | - | - | - | - | - | - | | Range | | | 2.0%-20% | 1%-20% | 6.0%-18.2% | 1.9%-20.4% | 1.5%-10% | 1.5%-2.0% | 1.0%-18.4% | $^{a}$ Sample size reflects patients or subjects exposed to SCS (at least an SCS trial) as described in the individual reports PMA P840001: FDA Summary of Safety and Effectiveness Data Page 46 {46} # SCS in diabetic populations Published literature describing SCS to treat PDN and published clinical practice guidelines on peri-operative care of diabetic patients provide information on specific inherent risks which may be of concern for diabetic patients when it comes to the delivery and management of SCS therapy. - Infection Data on PDN patients treated with SCS demonstrated a 5.5% (range: 2.9% to 20%) infection rate. In the overall population of diabetic patients included in published literature and the PSR, the infection rate was 3.6%. Data from 3 large retrospective cohorts concluded that either diabetes was not a predictor of infection or there was no statistical difference observed in the infection rate between diabetic and non-diabetic patients.27,26,17 An analysis comparing the infection rate between PDN and non-PDN patients participating in the PSR revealed a significant difference (p = 0.02; HR of 2.8). A recent systematic review of SCS complications across all indications reported an infection rate of 4.9% (range: 2.5%-10%).43 - Wound healing Data on diabetic patients treated with SCS demonstrated 1.7% (range: 1.5% to 10%) rate of issues with wound healing. Delayed wound healing may contribute to infection and the rates may be underestimated due to subsequent appreciation of a more serious adverse event. - Cardiovascular events Several reports of subject or patient death attributed to myocardial infarction (4) or heart failure (1) were included in the available data on SCS to treat PDN.13,24 None were reported to be related to SCS procedures or therapy, though patients with uncontrolled diabetes may have an elevated risk for cardiovascular events in the perioperative period. In an analysis of outcomes in patients undergoing elective orthopedic surgery, patients with poor glycemic control showed a non-significant trend towards greater odds of myocardial infarction and a significantly greater odds of stroke (Odds Ratio 3.42 CI: 1.87-6.25; p < 0.001).35 - Dural puncture and CSF leak Slangen et al. (2014) reported one subject death following a dural puncture and subsequent CSF leak leading to a cranial subdural hematoma.21 Ha et al. (2016) reported data from non-SCS procedures concluding that diabetic patients may be PMA P840001: FDA Summary of Safety and Effectiveness Data Page 47 {47} at higher risk of CSF leak (Univariate regression model; p = 0.021). Though a Multivariate regression model did not find significant relation between diabetes and CSF leak (Odds Ratio = 1.82; p = 0.448).36 Wang et al. (2014) reported increased incidence of subdural hematoma in diabetic patients (log-rank test, p < 0.0001). Cox proportional hazard modeling resulted in an adjusted Hazard Ratio = 1.63.37 • Glycemic control de Vos et al. (2014) reported 2 subjects experiencing fluctuations in blood glucose levels following infections.24 While these were assessed by authors as unrelated to SCS, the physiologic stress of surgery or any adverse event may impact glycemic control. • Mortality and morbidity: Patient deaths and other serious adverse events The cohort described in the PSR data above, there was one death. The event was described as cardiac heart failure and unrelated to SCS. TenVaarwerk et al. published a report on the factors associated with morbidity and mortality in patients treated with SCS for refractory Angina Pectoris.15 The multi- center retrospective studied 517 subjects implanted over a 10-year period, 14% of which were identified as having insulin dependent Diabetes Mellitus (IDDM). A multi-variate analysis significantly correlated IDDM with mortality. Overall, in this cohort, 66% of the patients had experienced myocardial infarction, 68% had three vessel disease, and in 24% the left ventricular ejection fraction (LVEF) was < 40%. The majority of patients had undergone interventional cardiac procedures such as angioplasty or bypass surgery. The benefits of SCS to treat angina may outweigh the risks for this population with intractable pain, though the health status of the population in this report limits the translation of this data to the PDN population. In the 10-subject study reported on in Tesfaye et al. and Daousi et al. there were 3 deaths over the course of 7 year follow up.13,12 The deaths occurred at 2 months, 2 years, and 4 years after implant. All were from myocardial infarction and all had reported effective pain relief up until the time of death. In the 11-subject study published by de Vos et al. (2009), they reported one subject death due to causes unrelated to SCS.16 In the randomized controlled trial (RCT) reported by de Vos et al. (2014), one subject experienced prolonged hospitalization related to the implant procedure due to a coagulopathy.24 The publication also described one subject in the SCS group PMA P840001: FDA Summary of Safety and Effectiveness Data Page 48 {48} with a cardiac arrest (no other detail or comment of subject death) as unrelated to the study procedure. # **SCS-specific events** Device events may be associated with or the cause of certain adverse events. Several reports describe hardware-specific complication rates. - **SCS system survival** Bir et al. (2016) reported on the rates of overall system survival for 141 patients treated at a single center and compared the diabetic population relative to the non- diabetic population. System survival was defined as being free from revision for any reason including device failure, migration, infection, or loss of effect. The revision- free survival time was 35 months for the diabetic population and 43 months for the non-diabetic population. The authors reported no statistical difference between the revision free survival time (log rank p = 0.98).25 Antonovich et al. (2021) conducted a retrospective review of patients treated with SCS for chronic pain and found diabetes was not associated with re-operation (p = 0.197).29 - **Lead migration and lead failure** Lead migration was reported in 5 publications and the PSR. The rate of lead migration reported in these studies ranged from 1% to 20% with an average of 6.2% across all publications that reported events in detail and the PSR. A recent systematic review of SCS complications reported a lead migration rate ranging from 2.1 to 27%, with a mean rate of 15.5%.43 Lead failure was reported in 3 publications and the PSR. The rate of lead failure reported in these studies ranged from 6% to 18.2% with an average of 3.1% across all publications that reported events in detail and the PSR. Lead migration and lead failure were compared in PDN and non-PDN populations within the PSR. No significant difference was found for device survival due to lead migration or lead failure between the two groups. # 2. Effectiveness Results # **Non-compa…