Three years of remote electrical neuromodulation (REN) acute treatment for migraine shows consistent effectiveness and no tachyphylaxis phenomenon

Abstract

Objective:

The current study aimed to evaluate the remote electrical neuromodulation (REN) wearable device over 3 years, assessing the potential for tachyphylaxis, consistent effectiveness, overall utilization patterns, and safety.

Background:

Migraine is a highly prevalent chronic neurological disease, especially during peak years of productivity, requiring ongoing management to prevent and reduce its disability. Traditional treatments often face challenges with long-­ term adherence due to waning efficacy, side effects, and medication interactions. REN offers a nonpharmacological approach for acute and preventive migraine treatment.

Methods

This prospective real-­ world cohort study analyzed data from 224 patients with migraine in the United States who consistently treated their migraine attacks with the REN wearable device for 3 years between December 2019 and September 2024. The primary endpoint was defined as lack of tachyphylaxis, aka an increase of no more than 2.5 intensity units on a scale of 100 units between 2 consecutive years, representing a nonclinically meaningful change in treatment intensity over 3 years. Secondary endpoints were consistent effectiveness in at least 50% of treatments and consistent utilization, compared over 3 years. The safety outcome assessed the proportion of users with device-­ related adverse events (dAEs) and the severity and seriousness of the dAEs.

Results:

Over 3 years, there was no clinically meaningful change in treatment intensity, and the average (± standard deviation, SD) change between 2 consecutive years was no more than 2.5 intensity units (1.8 ± 5.5 between years 1 and 2, and 1.4 ± 5.3 between years 2 and 3; p = 0.120, McNemar test for two related dichotomous variables), indicating no tachyphylaxis. Effectiveness endpoints remained consistent over 3 years of treated attacks (generalized linear mixed model of repeated measures categorical data) with no significant differences over the 3 years: 72.1%–76.8% of users reporting pain relief (p = 0.846), 26.8%–28.7% pain freedom (p = 0.966), 65.3%–70.8% functional disability relief (p = 0.749), 31.4%–38.9% functional disability freedom (p = 0.680), 29.0%–37.0% freedom from photophobia (p = 0.590), 37.9%– 49.4% freedom from phonophobia (p = 0.534), and 57.1%–66.7% freedom from nausea/vomiting (p = 0.753). Monthly utilization was consistent, ranging between 8.0 and 8.8 treatments per month, suggesting sustained adherence to therapy (p = 0.337, generalized linear model of repeated measures). Only two (0.9%) expected, nonserious dAEs were reported (mild or moderate localized skin reactions), neither leading to treatment discontinuation.

Conclusion

This study demonstrates the long-­ term safety, consistent utilization, and acute treatment effectiveness, with no tachyphylaxis, in patients with migraine consistently treating with REN for 3 years. This suggests that REN offers an effective, well-­ tolerated, safe, and sustainable long-­ term treatment option for individuals with migraine.

Plain Language Summary

Individuals with migraine often struggle to find long-­ term relief due to medication side effects or reduced effectiveness over time. This study assessed the characteristics of acute treatment of migraine with the remote electrical neuromodulation (REN) wearable device over 3 years of consistent use. The results showed that REN provided consistent relief without the need for a dosage increase over time, and that patients continued using the device regularly over 3 years; thus, the study suggests that REN may be an effective, safe, and sustainable long-­ term treatment option for migraine.

Keywords: drug-­ free, long-­ term, migraine, remote electrical neuromodulation, tachyphylaxis

Introduction

Migraine is a highly prevalent, chronic, neurological disease, affect- ing up to 15% of the global population.1,2 It is characterized by de- bilitating headaches and associated symptoms that can significantly impair an individual's quality of life, productivity, and social func- tioning over decades.3 Migraine usually emerges during adolescence or early adulthood, spanning over an individual's most productive adult years, and even persisting into senior years.3 As such, migraine requires ongoing management throughout a significant portion of a person's life.

Current migraine treatments, including both acute and preventive options, can be effective for many patients; however, medications are often accompanied by considerable adverse events, drug–drug interactions, and demanding dosing and administration schedules, leading to low adherence. Considering the protracted nature of the disease, the potential for disease progression when untreated, and the risk of medication-­ overuse headache (MOH), there is a pressing need for sustainable long-­ term treatments. Ideally, long-­ term interventions should provide consistent relief while avoiding adverse events and MOH, in parallel with preserving quality of life. Another major concern associated with long-­ term migraine management is the potential for tachyphylaxis, the phenomenon in which a treatment's efficacy diminishes over time, requiring either a higher dosage or a change in medication. Relatively few studies have evaluated the long-­ term (over 3 years or more) effects and dosage stability of migraine medications. These showed that therapies can become less effective over time, leading to dose escalation or poor adherence, ultimately followed by a switch to alternative treatments.Other studies have indicated that patients frequently may require numerous preventive and acute medication changes over time, potentially due to waning efficacy.

Remote electrical neuromodulation (REN) is a noninvasive, drug-free, prescribed therapy that has emerged as a long-­ term treatment option for migraine. REN is US Food and Drug Administration (FDA)– cleared for acute and preventive migraine treatment in patients aged 8 years and older. REN delivers low-­ intensity electrical stimulation to specific peripheral nerves, leveraging conditioned pain modula- tion (CPM) to decrease the pain signals of migraine.Prior clinical trials and real-­ world evidence (RWE) studies underscore REN safety and efficacy across diverse populations.A previous study suggested robust long-­ term effectiveness and safety over 1 year of REN treatment, yet multi-­ year data have yet to be analyzed. The current study aimed to evaluate REN usage over a longer period, assessing the potential for tachyphylaxis, consistent effectiveness, utilization patterns, and safety over 3 years of acute treatment by retrospectively analyzing prospective user data. The primary hy- pothesis being tested in this study is that long-­ term consistent use of the REN wearable device for acute migraine treatment does not result in tachyphylaxis, such that there is no clinically meaningful change in stimulation intensity (treatment dosage), defined as an in- crease of no more than 2.5 units between any 2 consecutive years, to obtain a consistent level of effectiveness of outcomes (pain relief, pain freedom, functional disability relief, and functional disability freedom at 2 h) across years 1–3.

Methods

Study design and ethics

The study was a prospective, RWE cohort study of long-­ term users of the REN wearable device across the United States. The study was reviewed by WCG IRB (WIRB-­ Copernicus Group, Puyallup, WA, USA; approval number 20245084), which found that it meets the requirements for a waiver of consent under 21 CFR 50.22. The data were collected between December 2019 and September 2024 in accordance with Good Clinical Practice and the Declaration of Helsinki guidelines. The study was registered with Clini calTr ials. gov (NCT06738056). On Clini caltr ial. gov, the primary endpoint was revised from initially being safety focused device-­ related adverse events (dAEs) to efficacy focused (lack of tachyphylaxis) to better align with the study's main research question. Data analyses were provided by the study sponsor, Theranica (Netanya, Israel).

Participants

Inclusion criteria: (1) patients with migraine aged 12 years and older who were prescribed the REN wearable device as part of their routine treatment, (2) began treating with the REN wearable device between December 2019 and September 2021, and (3) used the REN device for acute or acute and preventive treatment at least once a month over at least 9 months per year for 3 consecutive years. No statistical power calculation was conducted prior to the study. The sample size was based on the available data. Of the 17,967 patients with migraine who began treating with REN during the abovementioned period, all REN users who met the three criteria were included in the study cohort and analyzed (see Figure 1). Users who did not meet at least one criterion were excluded from the analysis.

Study device

The REN wearable device (Nerivio, by Theranica) is a wireless, drug-free, noninvasive stimulation device placed on the upper arm for the treatment of migraine. It has received clearance from the FDA for both acute and preventive management of migraine in individuals aged 8 years and older. The device stimulates small nerves in the skin using a tailored electrical signal, triggering CPM, a natural, endog- enous pain control mechanism.Patients control each 45-­ min treat- ment session using the device's companion mobile application on their smartphone and can go about their daily activities throughout the session. Patients are instructed to adjust the treatment intensity over a scale of 0–100 units via the application to a level that is strong yet nonpainful; this level is equivalent to treatment dosage.

Data collection

This study retrospectively analyzed prospective data collected using the REN mobile application. During the sign-­ up process, patients agreed to the terms of use, consenting to the collection of deidenti- fied data for research purposes. Moreover, patients agreed to pro- vide personal information (age, sex) to be securely stored on a Health Insurance Portability and Accountability Act (HIPAA)–compliant REN server. Treatment variables, including timing, length, and in- tensity were automatically logged into the REN server. Additionally, at the start of each REN treatment, users were prompted to vol- untarily report characteristics of their migraine attack, and again 2 h after acute treatments, they were re-­ prompted to voluntarily re- port attack characteristics and treatment outcomes through in-­ app questionnaires. The collected data included headache pain intensity, presence of associated symptoms, functional impairment, and any additional therapies used concomitantly (see Data S1).

Outcome measures

The outcome measures focused on acute treatments conducted over 3 consecutive years (36 months). For each user, outcome measures were calculated annually. The first 3 full months of treatment in the first year were considered an adaptation period and were excluded from the analyses.

Primary endpoint

Lack of tachyphylaxis

The primary endpoint, lack of tachyphylaxis, was defined as clinically nonmeaningful change in treatment intensity, quantified as an in- crease of no more than 2.5 intensity units between any 2 consecutive years (and a total increase of no more than 5 intensity units across the 3-­ year period). This metric was selected based on years of experience with the REN wearable device. The average treatment intensity was calculated annually for each user to assess the difference between average treatment intensity of 2 consecutive years for each pair of consecutive years. These differences were then transformed into cat- egorical dichotomous variables, indicating whether the change was ≤2.5 (classified as 1) or >2.5 (classified as 0) intensity units. Treatment intensity is equivalent to drug dosage, and as such an increase in treat- ment intensity over time would reflect tachyphylaxis (an increase in the dosage needed to achieve effectiveness).

Post hoc subanalyses of the primary endpoint

Three post hoc sub analyses on the primary endpoint of lack of tachyphylaxis were performed: (1) checking if there was a difference in the change in treatment intensity between the subgroup of participants who also participated in the earlier study, looking at 1-­ year continuous REN treatment, versus participants who did not participate in that earlier study; (2) checking if there was a difference in the change in treatment intensity between subgroups of two treatment patterns types, preventive treatment pattern. which is 12 or more treatments in a month, versus acute treatment pattern, which is less than 12 treatments a month; and (3) sensitivity analysis accounting for all 12 months in the first treatment year versus the main analysis conducted in this study considering the first 3 treatment months as an adaptation period

Secondary endpoints

Long-­ term consistent effectiveness

Pain and functional disability were rated on a 4-­ point scale: severe, moderate, mild, or none. Associated symptoms, including photopho- bia (light sensitivity), phonophobia (sound sensitivity), and nausea/ vomiting were reported as either being present or absent. All were reported voluntarily at the start of treatment (baseline), and at 2 h posttreatment when pain was reported at treatment onset (i.e., re- flecting acute care of a migraine attack). Evaluable treatments for ef- fectiveness analyses were those in which pain, functional disability, or an associated symptom presence were reported at baseline, and reported at 2 h posttreatment, in addition to REN being used as a standalone therapy (no report of medication usage). Patients were considered consistent responders if they showed an improvement from baseline to 2 h posttreatment in the respective reports in at least 50% of their treatments for each endpoint. Consistent effective- ness is the proportion of consistent responders for each effectiveness endpoint per year, which was compared over the 3 years. Seven consistent effectiveness endpoints were assessed:

1. Pain relief: reduction in pain intensity from moderate or ­ severe (baseline score of 2 or 3) to mild or no pain (score of 1 or 0) at 2 h posttreatment.
2. Pain freedom: reduction in pain intensity from moderate or ­ severe (baseline score of 2 or 3) to no pain (score of 0) at 2 h posttreatment.
3. Functional disability relief: reduction in functional disability from moderate or severe (baseline score of 2 or 3) to mildor no disability (score of 1 or 0) at 2 h posttreatment.
4. Functional disability freedom: reduction in functional disability from moderate or severe (baseline score of 2 or 3) to no disability (score of 0) at 2 h posttreatment.
5. Freedom from an associated symptom (photophobia, phono- phobia, nausea and/or vomiting): absence of the associated symptom at 2 h posttreatment for treatments when the symptom was present at baseline.

Long-­ term utilization (adherence)

The average number of monthly treatments per year was calculated per user and compared over the 3 years.

Safety and tolerability

An adverse events (AEs) reporting system was used in the app as well as via the customer support call center. AEs were escalated to the medical team for further care and classification. All AEs reported during the study period were analyzed. The proportion of users with a report of an AE was analyzed and characterized with respect to device-­ relatedness (dAE), severity, and seriousness.

Statistical analysis

Descriptive statistics were used to summarize demographic data and treatment outcomes including average, standard deviation (SD), minimum and maximum values, and 95% confidence intervals. The McNemar test, a nonparametric test for two related dichotomous variables, was used to test the change in intensity levels between following years using the chi-­ square distribution. Post hoc analyses of the primary endpoint compared subgroups (patients who par- ticipated in the previous 1-­ year study vs. those who did not; and participants who treated in a prevention-­ like pattern vs. those who did not; using McNemar tests), and a sensitivity analysis (taking all 12 months of the first treatment year vs. considering the first 3 treatment months as an adaptation period) using t- ­ tests on the dif- ference between pairs of consecutive years.

Generalized linear mixed model (GLMM) was used to compare categorical data of effectiveness rate outcomes over 3 years (the fixed effect), and the assumed structure covariance was diagonal. The GLMM did not include random effect, and the coefficient was set to zero because it was redundant. The Akaike information crite- rion (AIC) was used to assist with selecting the appropriate statis- tical model. The probability distribution was binomial, and the link function was probit for all effectiveness measures. Trend over time for continuous data of average monthly treatments was measured by a GLM repeated measures analysis, including tests for multivar- iate trends and within-­ subjects contrasts. Except for three post hoc analyses of the primary endpoint, all tests were preplanned. A two-­ tailed significance level of p < 0.05 was used. In line with com- mon practice in RWE studies, missing data were handled using a complete case approach; no imputation or extrapolation was per- formed. Analyses were therefore restricted to available data. Data extraction and management were performed using Structured Query Language (SQL) in BigQuery, and statistical analyses were conducted using SPSS version 29.0 (IBM Corp., Armonk, NY, USA).

RESULTS

All patients who met the inclusion criteria of treating monthly for 3 consecutive years were included in the analysis (n = 224). These individuals were 43.8 ± 16.2 (mean ± SD) years of age, 85.7% fe- male, and they performed a total of 64,717 treatments through- out the study period. On average, a user performed 288.9 ± 271.7 (mean ± SD) treatments over the 3-­ year period. Participants treated with the REN wearable for an average of 11.0–11.3 months per year. See Tables 1 and 2.

Primary endpoint: lack of tachyphylaxis

Over 3 years, there was no clinically meaningful change in treat- ment intensity with an increase of no more than 2.5 intensity units on a scale of 100 units between each pair of 2 consecutive years (1.8 ± 5.5 between years 1 and 2, and 1.4 ± 5.3 between years 2 and 3; p = 0.120, McNemar test for two related dichotomous variables),suggesting no occurrence of tachyphylaxis. Average treatment in- tensity increased by a total of 3.2 units from the first to the third treatment year (35.0 ± 16.2; 36.8 ± 17.0; 38.2 ± 18.3; for years 1, 2, and 3, respectively; see Table 2 and Figure 2).

Post hoc subanalyses of the primary endpoint

Three post hoc subanalyses of the primary endpoint of lack of tachyphylaxis were performed. First, we looked at the overlap with the previous 1-­ year study (Synowiec et al.).21 Of the 224 par- ticipants in the current study, 142 (63.4%) participated also in the 1-­ year study. McNemar tests compared the proportion of partici- pants who increased the treatment intensity by ≤2.5 units between each pair of consecutive years in each of the two subgroups. In both McNemar tests, we found no statistically significant differ- ence between the change for each pair of years (p = 0.557 for pa- tients who were not included in the 1-­ year study, and p = 0.174 for patients who were also included in the 1-­ year study).

Second, we looked at the subgroup of patients with a prevention-like treatment pattern (≥12 treatments per month). Of the 224 par- ticipants in the current study, 39 (17.4%) followed a prevention-­ like treatment pattern. McNemar tests compared the proportion of participants who increased the treatment intensity by ≤2.5 units be- tween each pair of consecutive years in each of the two subgroups. In both McNemar tests, we found no statistically significant difference between the change for each pair of years (p = 0.549 for patients who followed a prevention-­ like treatment pattern, and p = 0.193 for patients who treated with an acute-­ like treatment pattern).

Third, we conducted a sensitivity analysis of the primary endpoint, taking all 12 months of the first year, as opposed to treating the first 3 months as an adaptation period and excluding them from analysis. The average (mean ± SD) difference between first 2 years was larger when accounting for all 12 months of the first year (2.54 ± 5.78) than when excluding the first 3 months of treatment as an adaptation pe- riod (1.84 ± 5.53). When including all 12 months of the first year, the difference between pairs of years was significant (p = 0.004), whereas when treating the first 3 months of treatment as an adaptation period, the difference was not significant (p = 0.210), justifying this decision.

Secondary endpoints

Long-­ term consistent effectiveness

Year-­ to-­ year clinical effectiveness did not change across the 3 years in any of the seven post–2 h effectiveness outcomes as determined by a GLMM test for each outcome, suggesting stable effectiveness over years of treatment. Over the 3 years, pain releif was reported by 72.1%–76.8% of users (F(2,205) = 0.167, p = 0.846), pain freedom by 26.8%–28.7% of users (F(2,228) = 0.034, p = 0.966), functional dis- ability relief by 65.3%–70.8% of users (F(2,216) = 0.290, p = 0.749), and functional disability freedom was reported by 31.4%–38.9% of users (F(2,216) = 0.386, p = 0.680) (see Figure 3A). Freedom from associated symptoms was reported by the following percentages of users: 29.0%–37.0% (F(2,180) = 0.530, p = 0.590) for photopho- bia, 37.9%–49.4% (F(2,157) = 0.630, p = 0.534) for phonophobia, and 57.1%–66.7% (F(2,113) = 0.284, p = 0.753) for nausea (see Figure 3B). Annual averages are presented in Table 3 and Figure 3.

Long-­ term utilization (adherence)

The average number of treatments per month remained consistent over time, with a 3-­ year monthly average ranging between 8.0 and 8.8, and no statistically significant differences from year to year as determined by a GLM repeated measures analysis (F(2,446) = 1.090, p = 0.337; see Table 2 and Figure 4).

Safety and tolerability

Only two (0.9%) adverse events were reported, each by a different user. Both were expected, nonserious, dAEs, reported by one par- ticipant at month 12 (mild redness on the arm) and by the other par- ticipant at month 36 (moderate skin rash on the arm) of treatment.Only two (0.9%) adverse events were reported, each by a different user. Both were expected, nonserious, dAEs, reported by one par- ticipant at month 12 (mild redness on the arm) and by the other par- ticipant at month 36 (moderate skin rash on the arm) of treatment.

DISCUSSION

This prospective RWE cohort study followed 224 patients living with migraine who used the REN wearable device consistently for 3 consecutive years. Results suggest that the REN wearable is an ef- fective and safe long-­ term acute treatment for migraine.

First, this study's findings suggest the absence of tachyphy- laxis; users did not require higher device intensities (reflecting REN dosage) to treat their attacks over 3 years. Contrary to sce- narios in which patients with migraine escalate medication doses to maintain efficacy or need to switch medications due to the loss of effectiveness over time,the stable average intensity ob- served here provides clinically meaningful evidence, suggesting that therapeutic effect of REN can be maintained without dose adjustments.

Second, monthly utilization remained consistent over 3 years, in- dicating that users neither substantially increased treatments (e.g., to compensate for waning effectiveness) nor decreased usage (e.g., due to dissatisfaction, inefficacy, adverse events, or poor tolerability). Whereas inclusion criteria required consecutive monthly treatment over 3 years, there was no selection criterion on the actual number of treatments per month. Stable treatment utilization and long-­ term adherence are hard to achieve in migraine management.It is re- ported that only about 50% of patients with migraine adhere to their triptan medication as prescribed.Longitudinal studies of migraine treatments used for 3 or more years are very scarce.The consistent usage patterns found in the current study suggest the REN wearable device is a feasible long-­ term treatment to which patients may ad- here for years beyond the initial months of adaptation.

In addition to stable dose and utilization, acute effectiveness endpoints reflecting relief or freedom from pain and functional dis- ability, as well as freedom from associated symptoms, did not dif- fer significantly from year to year over 3 years. The percentage of users reporting consistent effectiveness per endpoint aligns with previous REN studies, including the pivotal randomized controlled trial (RCT),and short-­ term real-­ world studies.Moreover, this study extends the 1-­ year study on the effectiveness of REN,which showed consistent 2 h pain relief in 74.1% and 2 h pain free- dom of 26.0% of participants, to 3 years. These results not only show that REN effectiveness is stable over years but also it is similar to other acute treatments for migraine reported in the literature. For example, a systematic review and network meta-­ analysis of 133 RCTs shows that 2 h pain relief reported in triptan clinical studies ranged between 42% and 76% of patients, and 2 h pain freedom was 18%–50%.Efficacy of gepants in RCTs was in similar ranges with 2 h pain relief reported by 58.1%–59.3% of patients using rimegep- ant and 62.7% of patients using ubrogepant,and 2 h pain free- dom of 19.6%–21.2% and 21.8%, respectively. The current findings are particularly significant given the protracted nature of migraine,which can require management throughout much of an individual's life.3 Traditional medication-­ based approaches can be effective ini- tially, but as previously stated, adherence often diminishes because of side effects, interactions, and waning efficacy. By contrast, the present results suggest that the benefits from acute therapy do not appear to degrade among users of REN over an extended timeline, as indicated by stable dose, utilization, and effectiveness.

Only two dAEs of localized skin reactions, one mild and one moderate, were recorded. Neither event prompted discontinuation of treatment, and in both cases the users continued REN beyond the scope of the study. These outcomes reinforce earlier studies' findings of the favorable safety profile of REN and further show that it is a sustainable long-­ term solution. Whereas pharmacolog- ical options may show increased side effects over time, leading to low adherence, REN showed consistent safety and tolerability throughout the 3 years. Given the long-­ term nature of migraine man- agement, a consistently low adverse event rate is clinically important for ensuring ongoing patient adherence.

Limitations

Whereas this study provides valuable insights into the long-­ term effectiveness and safety of acute treatment using REN, limitations must be acknowledged. First, the study population consisted of in- dividuals who chose to continue using REN for 3 years, introducing a potential selection bias. The high exclusion rate (98.8%) indicates that only a small fraction of REN users maintained consistent long-term usage. Users who found the device ineffective or had difficulty adhering to the treatment protocol may have discontinued use before the 3-­ year mark. This could lead to a highly selected population with favorable treatment response as well as an overestimation of the de- vice's effectiveness and utilization in the overall migraine population. However, discontinuation rates of prescribed migraine medications are known to be high. A recent 3-­ year claims-­ based cohort study of prescribed migraine medications in the United States shows that only 14.3% continued using the initially prescribed acute treatment they received for 3 years; of those, only 5.1% continued using only that initial treatment.However, the inclusion criteria in that study were much less rigorous than in the current study because patients were included if they had at least one claim over 6 months, without re- questing actual treatment verification, and without requiring month-by-­ month usage. Moreover, the selection process used in the current study also allows us to specifically examine the long-­ term effects of acute treatment using REN in a population that has demonstrated sustained engagement with the therapy, providing valuable insights into its potential for long-­ term management. Furthermore, the stable utilization over the 3 years, which was not an inclusion criterion, sug- gests that REN is well tolerated and perceived as beneficial, which is an important consideration for long-­ term adherence.

Second, reporting in this study was voluntary, meaning that ef- fectiveness endpoints were subject to reporting bias from those users who chose to report over the 3 years. Whereas patient-reported outcomes provide crucial information about the real-­ world impact of migraine treatments on patients' lives, including pain and functional improvement, the voluntary nature of reporting may not accurately reflect the experiences of all users. That said, the con- sistent reporting of positive outcomes over 3 years by a substantial portion of the participants (between 40% and 45%) strengthens the validity of these findings, which are similar to previous short-­ term efficacy reports of REN treatment. This suggests a sustained ben- efit of REN therapy for those actively engaged with the reporting process.

Finally, the focus of this study was the acute treatment of mi- graine attacks with REN, even though the device is also indicated for migraine prevention. Data on the effectiveness of preventive treat- ment over 3 years is not available yet. With that, at an average of 8.4 treatments per month, it can be inferred that our long-­ term users had a substantial burden of migraine, and the use of REN may have contributed to reducing disease severity by treating a large propor- tion of acute attacks effectively.

CONCLUSIONS

This study's analysis of data collected from REN users who treated consistently for 3 years as part of their clinical regimen in a real-world setting enhances the generalizability of previous findings, showing long-­ term stable effectiveness, safety, and utilization, with no evidence of tachyphylaxis in these patients.