Clinical Trial Inclusion and Impact on Early Adoption of Medical Innovation in Diverse Populations.

BACKGROUND: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations. OBJECTIVES: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval. METHODS: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions. RESULTS: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female). CONCLUSIONS: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations.

Racial disparities in access to DBS: results of a real-world U.S. claims data analysis.

Introduction: Deep brain stimulation (DBS) is an effective and standard-of-care therapy for Parkinson's Disease and other movement disorders when symptoms are inadequately controlled with conventional medications. It requires expert care for patient selection, surgical targeting, and therapy titration. Despite the known benefits, racial/ethnic disparities in access have been reported. Technological advancements with smartphone-enabled devices may influence racial disparities. Real-world evidence investigations can shed further light on barriers to access and demographic disparities for DBS patients. Methods: A retrospective cross-sectional study was performed using Medicare claims linked with manufacturer patient data tracking to analyze 3,869 patients who received DBS. Patients were divided into two categories: traditional omnidirectional DBS systems with dedicated proprietary controllers ("traditional"; n = 3,256) and directional DBS systems with smart controllers ("smartphone-enabled"; n = 613). Demographics including age, sex, and self-identified race/ethnicity were compared. Categorical demographics, including race/ethnicity and distance from implanting facility, were analyzed for the entire population. Results: A significant disparity in DBS utilization was evident. White individuals comprised 91.4 and 89.9% of traditional and smartphone-enabled DBS groups, respectively. Non-White patients were significantly more likely to live closer to implanting facilities compared with White patients. Conclusion: There is great racial disparity in utilization of DBS therapy. Smartphone-enabled systems did not significantly impact racial disparities in receiving DBS. Minoritized patients were more likely to live closer to their implanting facility than White patients. Further research is warranted to identify barriers to access for minoritized patients to receive DBS. Technological advancements should consider the racial discrepancy of DBS utilization in future developments.

Clinical Longevity of 106,462 Rechargeable and Primary Cell Spinal Cord Stimulators: Real World Study in the Medicare Population.

INTRODUCTION: Spinal cord stimulators (SCS) are available with either primary cell (PC) or rechargeable cell (RC) batteries. Although RC systems are proposed to have a battery longevity upward of nine years, in comparison with four years for PC systems, there are few studies of longevity of SCS in the real world. MATERIALS AND METHODS: This was an observational, nonrandomized, retrospective study of Medicare beneficiaries who received neurostimulator implants in the outpatient hospital. This study used Medicare fee-for-service claims data from 2013 to 2020. The clinical longevity of the implantable pulse generator (IPG), defined as the duration from implant until removal for any reason, was compared between PC and RC devices. Life distribution analysis was used to approximate device lifespan. The secondary analysis separated removals into explant or replacements. The statistics were adjusted for relevant clinical covariates. RESULTS: A total of 25,856 PC and 79,606 RC systems were included in the study. At seven years after implant, 53.8% of PC IPGs and 55.0% of RC IPGs remained in use. The life distribution modeling analysis projected a median lifespan of 8.2 years for PC and 9.0 years for RC devices. The rate of explant was lower for PC devices (19.2%) than for RC devices (22.0%, hazard ratio (HR) = 0.96, p = 0.082), whereas the rate of replacements was higher for PC devices (33.7%) than for RC devices (29.5%, HR = 1.31, p < 0.001). An analysis of the battery type used in device replacements showed an increasing adoption of PC devices over time. CONCLUSIONS: This large, retrospective, real-world analysis of Medicare claims data demonstrated that the clinical longevity of neurostimulator devices is similar for PC and RC batteries. In the past, clinicians may have defaulted to RC devices based on the assumption that they provided extended battery life. Considering this longevity data, clinicians should now consider the choice between PC and RC devices based on other individual factors pertinent to the patient experience and not on purported longevity claims.

Reduced Risk of Reoperations With Modern Deep Brain Stimulator Systems: Big Data Analysis From a United States Claims Database.

Objective: There have been significant improvements in the design and manufacturing of deep brain stimulation (DBS) systems, but no study has considered the impact of modern systems on complications. We sought to compare the relative occurrence of reoperations after de novo implantation of modern and traditional DBS systems in patients with Parkinson's disease (PD) or essential tremor (ET) in the United States. Design: Retrospective, contemporaneous cohort study. Setting: Multicenter data from the United States Centers for Medicare and Medicaid Services administrative claims database between 2016 and 2018. Participants: This population-based sample consisted of 5,998 patients implanted with a DBS system, of which 3,869 patients had a de novo implant and primary diagnosis of PD or ET. Follow-up of 3 months was available for 3,810 patients, 12 months for 3,561 patients, and 24 months for 1,812 patients. Intervention: Implantation of a modern directional (MD) or traditional omnidirectional (TO) DBS system. Primary and Secondary Outcome Measures: We hypothesized that MD systems would impact complication rates. Reoperation rate was the primary outcome. Associated diagnoses, patient characteristics, and implanting center details served as covariates. Kaplan-Meier analysis was performed to compare rates of event-free survival and regression models were used to determine covariate influences. Results: Patients implanted with modern systems were 36% less likely to require reoperation, largely due to differences in acute reoperations and intracranial lead reoperations. Risk reduction persisted while accounting for practice differences and implanting center experience. Risk reduction was more pronounced in patients with PD. Conclusions: In the first multicenter analysis of device-related complications including modern DBS systems, we found that modern systems are associated with lower reoperation rates. This risk profile should be carefully considered during device selection for patients undergoing DBS for PD or ET. Prospective studies are needed to further investigate underlying causes.

The Cost of Lost Productivity in an Opioid Utilizing Pain Sample.

BACKGROUND AND AIMS: Chronic pain affects more adults in the United States than any other condition. Opioid medications are widely used in the treatment of chronic pain, but there remains considerable risk and cost associated with their use. This study aims to characterize the effects of opioid prescribing for chronic pain and similar pain conditions on lost productivity in the United States. METHODS: This was a retrospective, longitudinal, observational study of chronic pain patients in 2011-2014. We identified patients with a diagnosis of musculoskeletal pain receiving index prescription for opioids in administrative claims and studied disability absence in a linked health and productivity management database. Patients were grouped as de novo and continued use opioid users before index, and by opioid dose in the year after index. Days of disability were compared before and after index with bootstrapping. Effect of opioid dose group on disability was evaluated with negative binomial regression. Lost productivity cost was compared before and after index. RESULTS: The cohort contained 16,273 de novo and 6604 continued use patients. On average, de novo patients used 24.8 days of disability after index, an increase of 18.3 more days compared to before (p < 0.001). Continued use patients used 30.7 days after index, 9 more days than before (p < 0.001). There was a dose-response relationship between dose group and days of disability in de novo patients (p < 0.001). The weighted-average cost per person of lost productivity was $4344 higher in the year after index compared to the year before. CONCLUSION: Opioid prescriptions for pain patients were associated with significant disability use and lost productivity costs. With the evolution of opioid-prescribing practices, CDC recommendations, and the HHS Pain Management Best Practices, there is opportunity to use alternative pain therapies without the risks of opioid-induced side effects to improve work productivity.

Real-world Adoption of Smartphone-based Remote Monitoring Using the Confirm Rx™ Insertable Cardiac Monitor.

While previous generations of insertable cardiac monitors (ICMs) required a bedside monitor for remote monitoring (RM), the Confirm Rx™ ICM (Abbott, Chicago, IL, USA) utilizes Bluetooth®, Wi-Fi/cellular technology, and a smart device to connect to the RM system. We aimed to characterize compliance, connectivity, and event transmission timing with the Confirm Rx™ ICM RM system. The study cohort included American patients who received the Confirm Rx™ ICM with SharpSense™ technology within three months of release (May-July 2019). Compliance with RM was quantified as the proportion of patients registering the patient app on their smart device and transmitting at least once. Connectivity was measured as the median number of days between consecutive transmissions per patient. Event transmission time was measured from episode detection to availability on the Merlin.net™ RM system (Abbott). Time from transmission until review by a clinician was examined. Values for device connectivity, episode transmission timing, and clinician view times were reported as median [first quartile, third quartile]. Of 5,666 patients who received a Confirm Rx™ ICM, 97% registered their patient app and 92% transmitted data at least once. Among those utilizing RM (aged 66 ± 15 years; 49% female), connectivity occurred every 1.5 [1.2, 2.4] days, or 4.7 times per week. Patient-reported symptoms were transmitted to Merlin.net™ within 2.9 [2.1, 3.8] minutes of event onset and viewed by the clinician within 0.9 [0.4, 3.1] days, while device-detected episodes without symptoms were transmitted within 18.5 [11.2, 36.5] hours and then viewed within 0.8 [0.3, 2.5] days. This real-world study demonstrated excellent patient compliance with the smartphone-based RM paradigm enabled by Confirm Rx™, suggesting the suitability of this technology for future cardiac implantable devices.

The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.

AIMS: The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities. METHODS AND RESULTS: The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014). CONCLUSION: Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

Gain in real-world cardiac resynchronization therapy efficacy with SyncAV dynamic optimization: Heart failure hospitalizations and costs.

BACKGROUND: SyncAV, a device-based cardiac resynchronization therapy (CRT) algorithm, promotes electrical optimization by dynamically adjusting atrioventricular intervals. OBJECTIVE: The purpose of this study was to evaluate the impact of SyncAV on heart failure hospitalizations (HFHs) and related costs in a real-world CRT cohort. METHODS: Patients with SyncAV-capable CRT devices followed by remote monitoring and enrolled in Medicare fee-for-service for at least 1 year preimplant and up to 2 years postimplant were studied. Patients with SyncAV OFF were 4:1 matched to those with SyncAV ON on preimplant HFH rate, demographics, comorbidities, disease etiology, and left bundle branch block. HFHs were determined from the primary diagnosis of inpatient hospitalizations, and the cost for each event was the sum of Medicare, supplemental insurance, and patient payment. RESULTS: After 4:1 propensity score matching, 3630 patients were studied (mean age 75 ± 8 years; 1386 [38%] female), including 726 (25%) patients with SyncAV ON. The pre-CRT HFH rate was 0.338 HFH events per patient-year. Overall, CRT diminished the HFH rate to 0.204 events per patient-year (P < .001). SyncAV elicited a larger reduction in HFH rate (SyncAV ON: hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.41-0.66; P < .001 and SyncAV OFF: HR 0.68; 95% CI 0.59-0.77; P < .001). After 2 years, the HFH rate was lower in the SyncAV ON group than in the SyncAV OFF group (0.143 HFHs per patient-year vs 0.193 HFHs per patient-year; HR 0.70; 95% CI 0.55-0.89; P = .003) and fewer HFHs were followed by 30-day HFH readmissions (4.41% vs 7.68%; P = .003) and 30-day all-cause hospital readmissions (7.04% vs 10.01%; P = .010). The total 2-year HFH-associated costs per patient were lower with SyncAV ON (difference $1135; 90% CI $93-$2109; P = .038). CONCLUSION: This large, real-world, propensity score-matched study demonstrates that SyncAV CRT is associated with significantly reduced HFHs and associated costs, incremental to standard CRT.

Cost-Effectiveness of Dorsal Root Ganglion Stimulation or Spinal Cord Stimulation for Complex Regional Pain Syndrome.

OBJECTIVES: ACCURATE, a randomized controlled trial, compared safety and effectiveness of stimulation of the dorsal root ganglion (DRG) vs. conventional spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS-I and II) of the lower extremities. This analysis compares cost-effectiveness of three modalities of treatment for CRPS, namely DRG stimulation, SCS, and comprehensive medical management (CMM). MATERIALS AND METHODS: The retrospective cost-utility analysis combined ACCURATE study data with claims data to compare cost-effectiveness between DRG stimulation, SCS, and CMM. Cost-effectiveness was evaluated using a Markov cohort model with ten-year time horizon from the U.S. payer perspective. Incremental cost-effectiveness ratio (ICER) was reported as cost in 2017 U.S. dollars per gain in quality-adjusted life years (QALYs). Willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were used to define highly cost-effective and cost-effective therapies. RESULTS: Both DRG and SCS provided an increase in QALYs (4.96 ± 1.54 and 4.58 ± 1.35 QALYs, respectively) and an increase in costs ($153,992 ± $36,651 and $128,269 ± $27,771, respectively) compared to CMM (3.58 ± 0.91 QALYs, $106,173 ± $27,005) over the ten-year model lifetime. Both DRG stimulation ($34,695 per QALY) and SCS ($22,084 per QALY) were cost-effective compared to CMM. In the base case, ICER for DRG v SCS was $68,095/QALY. CONCLUSIONS: DRG and SCS are cost-effective treatments for chronic pain secondary to CRPS-I and II compared to CMM. DRG accrued higher cost due to higher conversion from trial to permanent implant and shorter battery life, but DRG was the most beneficial therapy due to more patients receiving permanent implants and experiencing higher quality of life compared to SCS. New DRG technology has improved battery life, which we expect to make DRG more cost-effective compared to both CMM and SCS in the future.

Effect of High Influenza Activity on Risk of Ventricular Arrhythmias Requiring Therapy in Patients With Implantable Cardiac Defibrillators and Cardiac Resynchronization Therapy Defibrillators.

Influenza is associated with an increased risk of cardiovascular events. Influenza's association with ventricular arrhythmias (VAs) has not been adequately studied. We investigated the relation of seasonal influenza activity with the incidence of VAs requiring therapy in patients with an implantable cardiac defibrillator or cardiac resynchronization therapy defibrillator. We retrospectively studied 163,831 patients with an implantable cardiac defibrillator or cardiac resynchronization therapy defibrillator who were enrolled in the Abbott Medical Merlin.net remote-monitoring network between January 2009 and December 2015. We used cross-correlation to assess the temporal relationship between influenza activity and the incidence of VAs requiring shock or antitachycardia pacing (ATP). We used a generalized linear model to test the possible effect of seasonal influenza activity on the occurrence of VAs requiring shock or ATP treatment, after adjustment for within-patient effects, age, gender, device type, and calendar year. We found a significant correlation between influenza activity and the incidence of VAs requiring shock or ATP treatment. The multivariate generalized linear model showed that during high influenza activity, patients were more likely to have a VA treated with shock (odds ratio = 1.06, p < 0.001) or ATP (odds ratio = 1.06, p < 0.0001). The impact of high influenza activity was most prominent during the years 2014 and 2015. We conclude that high influenza activity is associated with increased risk of VAs requiring therapy.

Atrial fibrillation burden, progression, and the risk of death: a case-crossover analysis in patients with cardiac implantable electronic devices.

AIMS: Atrial fibrillation (AF) is associated with increased mortality, but the temporal relationship between AF burden (AFB) and death among patients with cardiac implanted electronic devices is unknown. We sought to characterize the timing and progression of AFB before death. METHODS AND RESULTS: Using Merlin.netTM remote monitoring (RM) data, we analysed weekly AFB in patients age ≥55 years implanted with dual-chamber pacemaker, implantable cardioverter-defibrillator, or cardiac resynchronization therapy devices whose death was verified in the Social Security Death Index and who had continuous RM from 1 year to 4 weeks preceding death. Atrial fibrillation burden was defined as amount of time per week atrial rate exceeded a set threshold of 180 b.p.m. Case-crossover analysis was used to compare the AFB at every week to 6 control weeks at the start of the year before death. There were 3131 patients meeting analysis criteria (age at death 76 ± 8 years, 70% men). Weekly increase in AFB >6 h was associated with increased odds of death, which was greatest at 4 weeks before death [odds ratio (OR) 2.30, 95% confidence interval (CI) 2.09-2.53; P < 0.001]. Atrial fibrillation progression week-to-week >24 h was associated with the greatest odds of death (OR 12.95, 95% 8.72-19.22; P < 0.001). A combination of AFB >6 h per week and activity <0.5 h per day was associated with an increased odds of death. CONCLUSION: In this large patient cohort, AFB progression accelerated in the weeks leading to death. Continuous monitoring of AFB may help identify device patients who may be at risk for adverse outcomes, including death.

A control-theoretic system identification framework and a real-time closed-loop clinical simulation testbed for electrical brain stimulation.

OBJECTIVE: Closed-loop electrical brain stimulation systems may enable a precisely-tailored treatment for neurological and neuropsychiatric disorders by controlling the stimulation based on neural activity feedback in real time. Developing model-based closed-loop systems requires a principled system identification framework to quantify the effect of input stimulation on output neural activity by learning an input-output (IO) dynamic model from data. Further, developing these systems needs a realistic clinical simulation testbed to design and validate the closed-loop controllers derived from the IO models before testing in human patients. APPROACH: First, we design a control-theoretic system identification framework to build dynamic IO models for neural activity that are amenable to closed-loop control design. To enable tractable model-based control, we use a data-driven linear state-space IO model that characterizes the effect of input on neural activity in terms of a low-dimensional hidden neural state. To learn the model parameters, we design a novel input waveform-a pulse train modulated by stochastic binary noise (BN) parameters-that we show is optimal for collecting informative IO datasets in system identification and conforms to clinical safety requirements. Second, we further extend this waveform to a generalized BN (GBN)-modulated waveform to reduce the required system identification time. Third, to enable extensive testing of system identification and closed-loop control, we develop a real-time closed-loop clinical hardware-in-the-loop (HIL) simulation testbed using the [Formula: see text] microelectrode recording and stimulation device, which incorporates stochastic noises, unknown disturbances and stimulation artifacts. Using this testbed, we implement both the system identification and the closed-loop controller by taking control of mood in depression as an example. RESULTS: Testbed simulation results show that the closed-loop controller designed from IO models identified with the BN-modulated waveform achieves tight control, and performs similar to a controller that knows the true IO model of neural activity. When system identification time is limited, performance is further improved using the GBN-modulated waveform. SIGNIFICANCE: The system identification framework with the new BN-modulated waveform and the clinical HIL simulation testbed can help develop future model-based closed-loop electrical brain stimulation systems for treatment of neurological and neuropsychiatric disorders.

Increased Hospitalizations and Overall Healthcare Utilization in Patients Receiving Implantable Cardioverter-Defibrillator Shocks Compared With Antitachycardia Pacing.

OBJECTIVES: The purpose of this study was to evaluate the effect of these therapies on healthcare utilization in a large patient cohort. BACKGROUND: Antitachycardia pacing (ATP) terminates ventricular tachycardia and avoids delivery of high-voltage shocks. Few data exist on the impact of shocks on healthcare resource utilization compared with ATP. METHODS: PROVIDE (Programming Implantable Cardioverter Defibrillators in Patients With Primary Prevention Indication) was a prospective study of patients who received an implantable cardioverter-defibrillator (ICD) for primary prevention at 97 U.S. centers (2008 to 2010). We categorized the PROVIDE patients by the type of therapy delivered: no therapy, ATP only, or at least 1 shock. All ICD therapies, hospitalizations, and deaths were adjudicated. Cumulative cardiac hospitalizations, risk of all-cause death or cardiac hospitalization, and annual costs were compared between groups. RESULTS: Of the 1,670 patients in PROVIDE, followed up for 18.1 ± 7.6 months, 1,316 received no therapy, 152 had ATP only, and 202 received at least 1 shock. Patients receiving no therapy and those receiving only ATP had a lower cumulative hospitalization rate and were at lower risk for death or hospitalization (hazard ratio: 0.33 [p < 0.001] and 0.33 [p < 0.002], respectively). The cost of hospitalization was $2,874 per patient-year (95% confidence interval: $877 to $5,140; p = 0.002) higher for those receiving at least 1 shock than for those who received ATP only. There was no difference in outcomes or cost between patients receiving only ATP and those without therapy. CONCLUSIONS: Among patients implanted with an ICD for primary prevention, those who received only ATP therapy had reduced hospitalizations, mortality, and cost compared with those who received at least 1 high-voltage shock and had equivalent outcomes to patients who did not require any therapy. (Programming Implantable Cardioverter Defibrillators in Patients With Primary Prevention Indication [PROVIDE]; NCT00743522).

High-resolution local field potentials measured with deep brain stimulation arrays.

OBJECTIVE: Local field potential (LFP) recordings along a deep brain stimulation (DBS) lead can provide useful feedback for titrating DBS therapy. However, conventional DBS leads with four cylindrical macroelectrodes likely undersample the spatial distribution of sinks and sources in a given brain region. In this study, we investigated the spectral power and spatial feature sizes of LFP activity in non-human primate subthalamic nucleus and globus pallidus using chronically implanted 32-channel directional DBS arrays. APPROACH: Subthalamic nucleus and globus pallidus LFP signals were recorded from directional DBS arrays in the resting state and during a reach-and-retrieval task in two non-human primates in naïve and parkinsonian conditions. LFP recordings were compared amongst bipolar pairs of electrodes using individual and grouped electrode configurations, with the latter mimicking the cylindrical macroelectrode configurations used in current clinical LFP recordings. MAIN RESULTS: Recordings from these DBS arrays showed that (1) beta oscillations have spatial 'fingerprints' in the subthalamic nucleus and globus pallidus, and (2) that these oscillations were muted when grouping electrode contacts together to create cylindrical macroelectrodes similar in relative dimension to those used clinically. Further, these maps depended on parkinsonian condition and whether the subject was resting or performing a motor task. SIGNIFICANCE: Development of future closed-loop DBS therapies that rely on LFP feedback will benefit from implanting DBS arrays with electrode sizes and spacings that are more consistent with the dimensions of oscillatory sinks and sources within the brain.

Association of Opioid Usage with Spinal Cord Stimulation Outcomes.

Study Design: Observational study using insurance claims. Objective: To quantify opioid usage leading up to spinal cord stimulation (SCS) and the potential impact on outcomes of SCS. Setting: SCS is an interventional therapy that often follows opioid usage in the care continuum for chronic pain. Methods: This study identified SCS patients using the Truven Health MarketScan databases from January 2010 to December 2014. The index event was the first occurrence of a permanent SCS implant. Indicators of opioid usage at implant were daily morphine equivalent dose (MED), number of unique pain drug classes, and diagnosis code for opioid abuse. System explant was used as a measure of ineffective SCS therapy. Multivariate logistic regression was used to analyze the effect of pre-implant medications on explants. Results: A total of 5,476 patients (56 ± 14 years; 60% female) were included. SCS system removal occurred in 390 patients (7.1%) in the year after implant. Number of drug classes (odds ratio [OR] = 1.11, P = 0.007) and MED level (5-90 vs < 5 mg/d: OR = 1.32, P = 0.043; ≥90 vs < 5 mg/d: OR = 1.57, P = 0.005) were independently predictive of system explant. Over the year before implant, MED increased in 54% (stayed the same in 21%, decreased in 25%) of patients who continued with SCS and increased in 53% (stayed the same in 20%, decreased in 27%) of explant patients (P = 0.772). Over the year after implant, significantly more patients with continued SCS had an MED decrease (47%) or stayed the same (23%) than before (P < 0.001). Conclusions: Chronic pain patients receive escalating opioid dosage prior to SCS implant, and high-dose opioid usage is associated with an increased risk of explant. Neuromodulation can stabilize or decrease opioid usage. Earlier consideration of SCS before escalated opioid usage has the potential to improve outcomes in complex chronic pain.

Association of Antitachycardia Pacing or Shocks With Survival in 69,000 Patients With an Implantable Defibrillator.

AIMS: Antitachycardia pacing (ATP) is an effective treatment for ventricular tachycardia (VT) and can reduce the frequency of shocks in patients with an implantable cardioverter defibrillator (ICD). The association between survival and ATP, as compared to a shock, has not been confirmed in a large patient population. This study aims to determine if patients with an ICD receiving ATP have lower mortality, as compared to those receiving shock. METHODS: Sixty-nine thousand three hundred and sixty-eight patients underwent ICD implantation between October 2008 and May 2013 and were enrolled in the remote monitoring network Merlin.net™ (St. Jude Medical, St. Paul, MN, USA). Patients were categorized into three groups based on the type of ICD therapy received during follow-up: no therapy (N = 47,927), ATP (N = 8,049), and shock (N = 13,392) groups. Survival was determined by linking implant records to the Social Security Death Index. RESULTS: The no therapy (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.56-0.64, P < 0.001) and ATP (HR 0.70, 95% CI 0.64-0.77, P < 0.001) groups were associated with a lower mortality risk than the shock group. These results were unaffected by age, gender, device type, atrial fibrillation (AF) burden, or ventricular rate. ATP was effective in 85% of episodes and ATP effectiveness was dependent on the ventricular rate. CONCLUSIONS: Mortality rates were higher in ICD patients who received only ATP compared to no therapy, but ICD patients who received a shock had higher mortality compared to both groups. Furthermore, the data suggest that age, gender, device type, AF burden, and rate of arrhythmia do not change the trend of higher mortality in patients receiving ICD shock compared to ATP alone.

A Novel Lead Design for Modulation and Sensing of Deep Brain Structures.

GOAL: Develop and characterize the functionality of a novel thin-film probe technology with a higher density of electrode contacts than are currently available with commercial deep brain stimulation (DBS) lead technology. Such technology has potential to enhance the spatial precision of DBS and enable a more robust approach to sensing local field potential activity in the context of adaptive DBS strategies. METHODS: Thin-film planar arrays were microfabricated and then assembled on a cylindrical carrier to achieve a lead with 3-D conformation. Using an integrated and removable stylet, the arrays were chronically implanted in the subthalamic nucleus and globus pallidus in two parkinsonian nonhuman primates. RESULTS: This study provides the first in vivo data from chronically implanted DBS arrays for translational nonhuman primate studies. Stimulation through the arrays induced a decrease in parkinsonian rigidity, and directing current around the lead showed an orientation dependence for eliciting motor capsule side effects. The array recordings also showed that oscillatory activity in the basal ganglia is heterogeneous at a smaller scale than detected by the current DBS lead technology. CONCLUSION: These 3-D DBS arrays provide an enabling tool for future studies that seek to monitor and modulate deep brain activity through chronically implanted leads. SIGNIFICANCE: DBS lead technology with a higher density of electrode contacts has potential to enable sculpting DBS current flow and sensing biomarkers of disease and therapy.

Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator.

OBJECTIVE: Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). APPROACH: Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. MAIN RESULTS: LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects' limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. SIGNIFICANCE: This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject's symptomatology.

Classification of pallidal oscillations with increasing parkinsonian severity.

The firing patterns of neurons in the basal ganglia are known to become more oscillatory and synchronized from healthy to parkinsonian conditions. Similar changes have been observed with local field potentials (LFPs). In this study, we used an unbiased machine learning approach to investigate the utility of pallidal LFPs for discriminating the stages of a progressive parkinsonian model. A feature selection algorithm was used to identify subsets of LFP features that provided the most discriminatory information for severity of parkinsonian motor signs. Prediction errors <20% were achievable using 28 of the possible 206 features tested. For all subjects, a spectral feature within the beta band was chosen through the feature selection algorithm, but a combination of features, including alpha-band power and phase-amplitude coupling, was necessary to achieve minimal prediction errors. There was large variability between the discriminatory features for individual subjects, and testing of classifiers between subjects yielded prediction errors >50%. These results suggest that pallidal oscillations can be predictive biomarkers of parkinsonian severity, but the features are more complex than spectral power in individual frequency bands, such as the beta band. Additionally, the best feature set was subject specific, which highlights the pathophysiological heterogeneity of parkinsonism and the importance of subject specificity when designing closed-loop system controllers dependent on such features.

Modulations in oscillatory frequency and coupling in globus pallidus with increasing parkinsonian severity.

While beta oscillations often occur within the parkinsonian basal ganglia, how these oscillations emerge from a naive state and change with disease severity is not clear. To address this question, a progressive, nonhuman primate model of Parkinson's disease was developed using staged injections of MPTP. Within each parkinsonian state (naive, mild, moderate, and severe), spontaneous local field potentials were recorded throughout the sensorimotor globus pallidus. In the naive state, beta oscillations (11-32 Hz) occurred in half of the recordings, indicating spontaneous beta oscillations in globus pallidus are not pathognomonic. Mild and moderate states were characterized by a narrower distribution of beta frequencies that shifted toward the 8-15 Hz range. Additionally, coupling between the phase of beta and the amplitude of high-frequency oscillations (256-362 Hz) emerged in the mild state and increased with severity. These findings provide a novel mechanistic framework to understand how progressive loss of dopamine translates into abnormal information processing in the pallidum through alterations in oscillatory activity. The results suggest that rather than the emergence of oscillatory activity in one frequency spectrum or the other, parkinsonian motor signs may relate more to the development of altered coupling across multiple frequency spectrums.