LivaNova (United Kingdom)

The RECOVER trial randomized 493 patients with markedly treatment-resistant major depressive disorder to treatment-as-usual with or without active vagus nerve stimulation (VNS Therapy). While the primary outcome measure did not statistically separate the treatment conditions, the field may lack optimal metrics for quantifying symptom improvement in markedly treatment-resistant patients. This study examined the impact of three factors on sensitivity to clinical improvement across the total RECOVER sample and to differences in the effectiveness of the randomized conditions, systematically varying outcome classification (remission, response, and partial response), observation period (3-12months, 6-12months, 10-12months and last observation), and depression rating scale. Effect sizes for detecting therapeutic change across the total sample and the difference in effectiveness between the randomized groups were markedly higher for partial response than response or remission classifications. Longer observation periods produced larger therapeutic effects across the sample, but the effect sizes for the randomized treatment differences were substantially higher in the final 10-12month period. The MADRS showed the least sensitivity to change across the sample and between the treatment groups. Using the partial response classification and the 10-12month observation period, a significant difference between the groups was obtained for 3 of 4 depression scales. The findings derive from a retrospective assessment of alternative outcome metrics. In a large randomized controlled trial of VNS for markedly treatment-resistant depression, the magnitude of therapeutic effects and separation of treatment groups differed as a function of outcome classification, measurement period, and rating scale.

Few treatments are available for individuals with marked treatment-resistant depression (TRD). Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD. This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3-12, with response defined as a ≥50% change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated. Overall, 88.4% of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory-Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology-Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology-Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P=0.004) and QIDS-SR (P=0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30%) on the CGI-I (P<0.001) and QIDS-C (P=0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P=0.035), a known side effect of VNS. No new adverse events were identified. Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD.

Generalized tonic-clonic seizures (GTCS) are considered to be among the most devastating seizures due to increased health risks. Use of device-based therapies, such as vagus nerve stimulation (VNS), is common for those resistant to antiseizure medications and important for those in whom resective surgery is not feasible. Our objective is to investigate whether adjunctive VNS can reduce the frequency of GTCS. Participants were enrolled in an international, multicenter, prospective observational study (CORE-VNS) on seizure and nonseizure outcomes following the implantation of VNS. Participants with GTCS at baseline were selected for analysis. Baseline seizure frequency data and patient-reported outcome measures were collected at 3, 6, 12, 24, and 36 months. This interim analysis compared baseline data to VNS therapy outcomes through 24 months. A total of 115 participants met the inclusion criteria. Following 12 months of VNS, participants experienced a median GTCS reduction of 73.9%, with 37% of participants reporting seizure freedom from GTCS for the 3 months prior to the 12-month follow-up. This outcome remained stable at 24 months, with a median GTCS reduction of 77% and 42.6% of participants reporting seizure freedom for the 3 months prior to the 24-month visit. After 12 months of VNS, the number of participants reporting the postictal severity of their most debilitating seizure as "severe" or "very severe" dropped from 52.8% to 25.3% (21/83). After 24 months of VNS, the percentage of participants reporting these levels of postictal severity was 26.3% (20/76). The participants' drug load did not change significantly during the follow-up. Adverse events were typical of those previously documented in patients with drug-resistant epilepsy (DRE) using VNS. Adjunctive VNS therapy was effective in reducing GTCS frequency in study participants. The sustained and consistent nature of the response further supports VNS as a long-term effective therapy in patients with DRE who have GTCS.

There is a spelling mistake in one of the authors listed in the published version of the paper: "Martin Otler" should be read "Martin Ortler" The original article is corrected.

ObjectiveTo conduct a descriptive assessment of patterns of utilization and cost of healthcare services and pharmacotherapies among patients with drug-resistant epilepsy (DRE) before neurostimulator implantation. MethodsUsing a large United States healthcare claims database, we identified all patients with DRE who were implanted with neurostimulators between January 1, 2012, and December 31, 2019. Patients without an epilepsy diagnosis on their implantation date were excluded, as were those without (1) anti-seizure medication (ASM) dispenses within 12 months of implantation date, and (2) continuous enrollment for the 24-month period before this date. Demographic and clinical characteristics were assessed over the two-year period before implantation, as were patterns of utilization and cost of healthcare services and pharmacotherapy. Care was assessed as all-cause or epilepsy-related, with the latter defined as all medical (inpatient and outpatient) care resulting in diagnoses of epilepsy and all ASM dispenses. ResultsEight hundred sixty patients met all selection criteria. Among these patients, comorbidities were common, including depression (27%), anxiety (30%), and learning disabilities (25%). Fifty-nine percent of patients had ≥1 all-cause hospitalizations; 57% had ≥1 epilepsy-related admissions. Patients averaged 8.6 epilepsy-related visits to physicians’ offices, including 5.1 neurologist visits. Mean all-cause and epilepsy-related healthcare costs during the pre-implantation period were $123,500 and $91,995, respectively; corresponding median values were $74,567 and $53,029. Median monthly all-cause healthcare costs increased by 138% during the 24-month period (from $1,042 to $2,481 in the month prior to implantation); median epilepsy-related costs, by 290% (from $383 to $1,492). ConclusionsThe two-year period before neurostimulator implantation is a long and costly journey. Estimates likely minimize the burden experienced during this period, given that seizure frequency and severity—and corresponding impacts on quality of life—were unavailable in these data. Further research is needed to understand the clinical, economic, and psychological impact of the time between DRE onset and implantation among qualifying patients.

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

IntroductionThe objective was to estimate, from the perspective of a managed care organization in the United States, the budget impact and effect on health outcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy®)] among patients aged ≥ 12 years with drug-resistant epilepsy (DRE) with partial-onset seizures.MethodsAn Excel model was developed to compare the costs of continued anti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. The number of people eligible for VNS was estimated using published prevalence data and an estimate of the percentage of eligible patients currently without VNS. Costs included VNS device, placement, programming, and battery changes; adverse events associated with VNS (cough, voice alteration, device removal resulting from surgical site infection); AEDs; and seizure-related costs affected by seizure frequency, which affects resource utilization (i.e., hospitalizations, emergency department visits, neurologist visits). To estimate the potential savings with VNS due to a reduction in seizure frequency, the budget impact model uses the results of an underlying Markov model to estimate seizure-related costs by seizure frequency. Transitions occurred among four health states, defined by number of seizures per month (i.e., seizure-free, ≤ 1, > 1 to < 10, ≥ 10) on a 3-month cycle based on published clinical trials and registry data.ResultsVNS resulted in an estimated net cost savings, on average, over 5 years, due to the expected reduction in seizure frequency. The initial cost of the VNS device, placement, and programming was estimated to be offset 1.7 years after VNS device placement. Reductions in hospitalizations were the main contributor to the cost savings with VNS.ConclusionsVNS is a proven intervention that offers a long-term solution for patients with DRE by reducing seizure frequency, which leads to lower resource utilization and lower costs.FundingLivaNova PLC.