Marco Meglio

Investigators from a study are suggesting that healthcare policies to implement efficient pre-hospital triage and accelerate in-hospital workflow may be needed after they found that any time delay to endovascular therapy (EVT) reduced quality-adjusted life years (QALY) and decreased the economic value of care provided by this intervention.

Markov model analysis performed from US healthcare and societal perspectives over a lifetime horizon showed an average gain of 39 days (95% prediction interval, 23–53 days) of disability-free life for every 10 minutes of earlier treatment with EVT.

For each 10-minute interval of earlier treatment, the net monetary benefit (NMB) increased by $10,593 (95% prediction interval, $5549–$14,847) and by $10,915 (95% prediction interval, $5928–$15,356) from health care and societal perspectives, respectively. The researchers combined weighted QALYs and costs into 1 composite outcome, NMB.

The study concluded 849 patients suffering a large vessel occlusion (LVO) stroke at 65 years of age who were among intervention arms across 7 EVT trials. Wolfgang G. Kunz, MD, associate professor of radiology, Ludwig-Maximilians-Univeristy of Munich, and the HERMES collaborators were among those who conducted the study.

READ MORE: SSRIs Have Mixed Risks, Benefits in Post-Stroke Recovery

Patients also gained an estimated 106 additional days of life in functional independence (95% prediction interval, 64–144 days) when EVT treatment was expedited by 10 minutes. Gained days of life in functional independence represented the additional cumulative time the simulated patient spent in the health states modified Rankin Scale (mRS) score 0–2 across the lifetime projection.

The similar accumulation of costs over time with later treatment were explained by the higher mortality rates, which resulted in proportionally lower acute costs within 90 days, thus equating a shorter overall life expectancy to overall lower long-term costs.

For early treatment within 60 to 119 minutes, EVT led to an average NMB of $425,738 from the health care perspective, adding on average more than $300,000 in care value compared to treatment within 360 to 419 minutes.

Kunz and colleagues also looked at the data from a nationwide perspective for the United States. They found that a median reduction of treatment times by 10 minutes was estimated to grant the annual patients with stroke treated with EVT 2440 additional QALYs (95% prediction interval, 1464–3316). Faster treatment by 10 minutes would increase the NMB of EVT by an estimated $242 million per year from a healthcare perspective (95% prediction interval, $127M–$339M) and $249 million from a societal perspective (95% prediction interval, $135M–$351M).

The sensitivity analyses, which allowed for simultaneous alteration of multiple input parameters, confirmed that each later treatment has an annual continuous effect on QALYs, the percentage of patients living with functional independence, and the cumulative mortality.

Investigators used the age-specific annual death rate of the general population drawn from the United States Life Table. Hazard rate ratios by mRS health states reported by contemporary cohort studies were used to calculate the excess death rate of stroke survivors.

Understanding the outcomes of EVT has been continually examined within the stroke research community. A case-control study published in August slightly contrasted these results, indicating that patients with anterior circulation LVO presenting very late (>16 hours to 10 days) from their last well known (LKW) time 

, despite notions that the therapy can only be effective in a window less than 16–24 hours from LKW.

Age can also play a factor in outcomes of EVT. In Kunz et al, investigators performed analysis on patients with a stroke onset at the age of 65 years. Recently published data from the MR CLEAN registry revealed that 

older age is associated with an increased absolute risk of poor clinical outcome

 in patients with acute ischemic stroke (AIS) treated with EVT, while the relative benefit of successful reperfusion seems to be high.

1. Kunz WG, Hunink MG, Almekhlafi MA, et al. Public health and cost consequences of time delays to thrombectomy for acute ischemic stroke. 

. Published online September 17, 2020. doi: 10.1212/WNL.0000000000010867

2. Kim BJ, Menon BK, Kim JY, et al. Endovascular treatment after stroke due to large vessel occlusion for patients presenting very late from time last known well. 

. Published August 10, 2020. doi: 10.1001/jamaneurol.2020.2804

3. Groot AE, Treurniet KM, Jansen IGH, et al. Endovascular treatment in older adults with acute ischemic stroke in the MR CLEAN registry. 

. Published online June 11, 2020. doi: 10/1212/WNL.0000000000009764

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Patients with later treatment had higher morbidity-related costs over a shorter time span due to their shorter life expectancy, resulting in similar lifetime costs as patients with early treatment.

Late Intervention With Endovascular Therapy Decreases Economic Value of Care

Results from a 2-center ambispective study presented at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, demonstrated that low doses of rituximab (Rituxan; Genentech/Biogen) seem to offer similar effectiveness with better safety profile than high doses when treating multiple sclerosis (MS).

Presented by Luciana Midaglia, MD, neurologist, Vall Hebron University Hospital, and the Multiple Sclerosis Centre of Catalonia, the study compared patients in the Barcelona center (BC; n = 249) who were administered 2 g of rituximab intravenously (IV) during at least 3 cycles, followed by 1 g every 6 months to those in the Girona center (GC; n = 54). In that cohort, 2 g rituximab was administered for at least the first cycle, followed by 500 mg every 6 months.

At baseline, mean annualized relapse rate (ARR) was 0.37 (±0.6) for those in the BC and 0.33 (±0.5) in the GC. At Year 1, ARR decreased to 0.05 (87.5%; 

Remaining stable or improvements on the Expanded Disability Status Scale (EDSS) score was found in 79.4% and 71.4% of progressive MS phenotypes in BC and GC, respectively. Median EDSS at baseline was 5.5 (BC: range, 1–9.0) versus 6.0 (GC: range, 1–8.0).

At Year 1, 2.7% of the BC population had contrast-enhancing lesions (CELs) and 19% reported with new T2 lesions. In comparison, 8% of those in the GC had CELs while 16% had new T2 lesions. At third year, 0% of the GC population documented CELs or new T2 lesions, whereas 12% of the BC reported CELs. Notably, there were 0 cases of CELs reported in the BC at third year.

In the BC, adverse events (AEs) occurred in 14.8% of patients during the first year compared to 4.1% at third year. Researchers noted that there was no difference in the dynamics of CD19% lymphocytes, while immunoglobulin (IgG) values in serum decreased significantly in the BC cohort throughout the first 3 years.

Rituximab, an anit-CD20 monoclonal antibody, has been widely used as an off-label treatment for MS, but has not received FDA approval for this indication. It was first approved in November 1997 and has been indicated for the treatment of chronic lymphocytic leukemia, rheumatoid arthritis, Non-Hodgkin’s lymphoma, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus.

The agent has been often linked in use to treat other MS phenotypes such as myasthenia gravis and neuromyelitis optica spectrum disorder (NMOSD). A study published in May showed that treatment with 

rituximab performs better if initiated earlier

 after the onset of generalized symptoms in those with myasthenia gravis.

 Results from another study of patients with NMOSD suggest that first-line treatment with 

rituximab is more effective in suppressing clinical activity

, independent of the antibody status, compared with mycophenolate mofetil (MMF) and other first-line immunosuppressants.

1. Midaglia L, Alvarez GB, Cedeno RR, et al. Rituximab treatment for MS: an observational multicentric dose comparison. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract PS01.05

2. Stewart J. Rituxan FDA approval history. Drugs.com. drugs.com/history/rituxan.html. Updated September 30, 2019. Accessed Thursday September 24, 2020.

3. Brauner S, Eriksson-Dufva A, Hietala MA, Frisell T, Press R, Piehl F. Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Refractory Generalized Myasthenia Gravis. 

Published online May 4, 2020. doi: 10.1001/jamaneurol.2020.0851

4. Poupart J, Gioivannelli J, Deschamps R, et al. Evaluation of efficacy and tolerability of first-line therapies in NMOSD. Neurology. 2020;94:1-12. doi:10.1212/WNL.0000000000009245.

In the third year of treatment, both dose cohorts did not experience any contrast-enhancing lesions, and only a small population in the Barcelona center showed new T2 lesions.

Low-Dose Rituximab Safe, as Effective as High Dose in MS

A cross-sectional analysis examining the use of midazolam (Nayzilam; UCB) by an emergency medical services (EMS) agency for treatment of adults with status epilepticus showed a significant deviation from evidence-based benzodiazepine use, contributing to the need for rescue therapy and respiratory support.

In total, 2494 cases of status epilepticus in adults were included in the analysis, with 1537 patients given midazolam at any dose (39.4% given 5 mg or more), yielding an administration rate of 62%.

Led by Elan L. Guterman, MD, neurologist, University of California San Francisco, the data showed that undertreatment with midazolam was associated with an increased need for rescue therapy, with 282 (18%) patients needing a second dose.

Those who received rescue therapy were less likely to have received an initial midazolam dose of 5 mg or more, were more frequently tachycardic, had lower Glasgow Coma Scale (GCS) scores, and were evaluated by providers who had seen a higher number of patients with status epilepticus during the study period.

National guidelines state that first-line, evidence-based treatment with midazolam requires administering the medication intramuscularly as a single 10-mg dose, and does not recommend the intranasal, intravenous, or intraosseous route of administration. Notably, no patients included in the study received the guideline-based dose of 10 mg; only 5 patients actually received a dose greater than 5 mg. Intranasal and intravenous injection accounted for 47% and 38.3% of midazolam administration, followed by intramuscular (13.7%) and intraosseous (1%).

Guterman and colleagues wrote that “this finding identifies an important gap in the treatment of status epilepticus and carries important clinical implications if EMS agencies nationally parallel this single site experience. The next challenge will be evaluating the true scope of the problem and identifying effective interventions to correct it.”

Higher midazolam doses were associated with lower odds of needing rescue therapy (odds ratio [OR], 0.8; 95% CI, 0.7–0.9) and were not associated with increased respiratory support, the primary and secondary end point of the study, respectively. In fact, higher doses of midazolam were associated with decreased need for respiratory support after adjustment (OR, 0.9; 95% CI, 0.8–1.0). Notably, receiving a midazolam dose of 5 mg or more was associated with lower odds of needing respiratory support (OR, 0.8; 95% CI, 0.7–1.0).

Respiratory support was ultimately required by 678 of the 1537 (44.1%) patients who received any dose of midazolam, with 517 (33.6%) patients requiring ventilatory support. Those who required respiratory support were more likely to be male, have comorbid alcohol and drug use, were tachycardic, had lower oxygen saturation, had lower GCS scores, and were evaluated by providers who had seen a higher number of total seizure and status epilepticus patients during the study period.

Univariate and multiple logistic regression analysis showed that patients with epilepsy (OR, 1.4; 95% CI, 1.2–1.7) and with a lower GCS score (GCS 8–12: OR, 0.7; 95% CI, 0.5–0.9; GCS 13–15: OR, 0.3; 95% CI 0.2–0.3) were more likely to receive midazolam.

intranasal treatment for acute  intermittent, stereotypic episodes of frequent seizure activity that are distinct from usual seizure pattern in patients with epilepsy 12 years of age and older.

The benzodiazepine, which may be administered in the outpatient setting by a non-healthcare professional in patients actively seizing and where a seizure cluster occurs, is supplied as 2 single-use nasal spray units, each containing a 5-mg dose of midazolam in 0.1-mL solution.

1. Guterman EL, Sanford JK, Betjemann JP, et al. Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. 

Published online September 17, 2020. doi: 10.1212/WNL.0000000000010913

2. UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the U.S. News release.  UCB. May 20, 2019. Accessed September 23, 2020. https://ucb.com/stories-media/Press-Releases/article/UCB-announces-NAYZILAM-midazolam-nasal-spray-now-approved-by-FDA-to-treat-intermittent-stereotypic-episodes-of-frequent-seizure-activity-in-people-living-with-epilepsy-in-the-U-S

Notably, no patients received a dose and route consistent with national guidelines.

Midazolam for Status Epilepticus Underutilized in EMS Setting Despite High Efficacy

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, suggest that fatigue occurs in most patients with relapsing multiple sclerosis (MS) and influences daily functioning.

Presented by Lindsey L. Lair, MD, FAAN, senior Global Medical Affairs Leader-Neuroscience, Janssen Pharmaceuticals, the research aimed to measure MS fatigue and its impact on daily life in a real-world population using a survey that included that relapsing MS (RMS)-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).

On a score range from 0 to 100, higher scores indicated greater severity. Findings from the cohort of 142 patients with RMS revealed that fatigue levels are severe, with a mean FSIQ-RMS symptom domain score of 59.5 during a 7-day period.

Demographic and clinical questionnaires that included disease history and status, sleep, and social and emotional function were completed by the participants along with the FSIQ-RMS, which was administered daily for 7 days. Physical, cognitive/emotional, and coping subdomain scores were 45.1, 44.9, and 50.6, respectively, following the 7-day period.

Walking difficulties and fatigue were recorded as the 2 most impactful symptoms on daily functioning. Notably, 56% of the patient population experienced fatigue prior to MS diagnosis.

In total, 72% of patients were not currently relapsing and had a mean fatigue symptom domain score of 56.2, compared to 68 who had an active relapse. Lair and colleagues also noted that fatigue was rated the most impactful symptom on daily life by those with lower disability.

Patients without depression, which represented 56% of the population, still reported mean fatigue symptom domain scores of 53.7 compared to 67 in those with depression. Among those who reported a sleep disorder, a mean fatigue symptom domain score of 58.1 was recorded in 72% of the population. In contrast, those without a sleep disorder recorded a 63.3 mean fatigue symptom domain score.

The most common triggering factor for fatigue was heat exposure, which occurred in 82% of patients.

Disability and economic burden have both been associated with higher levels of fatigue in patients with MS. 

Another study presented at MS Virtual 2020

 revealed that patients with relapsing-remitting MS who were stratified by high levels of fatigue had greater comorbidity and economic burdens compared to those with MS who had low levels of fatigue.

The data from that study showed that the annualized number of outpatient visits, emergency room visits, and hospitalizations were greater for those with relapsing-remitting MS with high levels of fatigue compared to those with relapsing-remitting MS with low levels of fatigue.

Amy B. Sullivan, PsyD, ABPP, director of Behavioral Medicine at the Mellen Center for MS Treatment and Research at Cleveland Clinic, recently sat down with 

and discussed how she approaches fatigue in MS from a behavioral standpoint. Watch the interview below.

1. Azoulai M, Levy-Heidmann T, Morisseau V, et al. A real-world study characterizing symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis using a novel disease specific scale. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1004.

2. Le H, Ken-Opurum J, Maculaitis M, Sheehan J. Comorbidity and economic burdens of fatigue among patients with relapsing-remitting multiple sclerosis in the United States. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0857.

Patients with lower levels of disability tended to report fatigue as the most impactful symptom in daily life.

Author | Marco Meglio

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