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March 22, 2022; 98 (12) Research Article

Safety and Efficacy of Tenecteplase in Older Patients With Large Vessel Occlusion

A Pooled Analysis of the EXTEND-IA TNK Trials

Vignan Yogendrakumar, Leonid Churilov, Peter J. Mitchell, Timothy J. Kleinig, Nawaf Yassi, Vincent Thijs, Teddy Y. Wu, Darshan G. Shah, Felix C. Ng, Helen M. Dewey, Tissa Wijeratne, Bernard Yan, Patricia M. Desmond, Mark W. Parsons, Geoffrey Alan Donnan, Stephen M. Davis, Bruce C.V. Campbell, on behalf of the EXTEND-IA TNK Investigators
First published January 11, 2022, DOI: https://doi.org/10.1212/WNL.0000000000013302
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Abstract

Background and Objectives Detailed study of tenecteplase (TNK) in patients older than 80 years is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients older than 80 years with large vessel occlusion.

Methods We performed a pooled analysis of the EXTEND-IA TNK randomized controlled trials (n = 502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase 0.90 mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin Scale (mRS) score, all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIH Stroke Score, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.

Results In patients >80 years (n = 137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, adjusted common odds ratio (acOR) 2.70, 95% CI 1.23–5.94) and reduced mortality (acOR 0.34, 95% CI 0.13–0.91) vs 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, acOR 2.28, 95% CI 1.03–5.05) vs alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg. In patients ≤80 years, no differences in 90-day mRS, mortality, or symptomatic ICH were observed among TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg.

Discussion TNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients older than 80 years. No differences among the doses were observed in younger patients.

Trial Registration Information NCT02388061, NCT03340493.

Classification of Evidence This study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.

Glossary

acOR=
adjusted common odds ratio;
aOR=
adjusted odds ratio;
EVT=
endovascular therapy;
EXTEND-IA TNK=
Tenecteplase vs Alteplase Before Endovascular Therapy for Ischemic Stroke;
EXTEND-IA TNK Part 2=
Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischemic Stroke;
IQR=
interquartile range;
LVO=
large vessel occlusion;
mRS=
modified Rankin Scale;
NIHSS=
National Institutes of Health Stroke Scale;
NOR-TEST=
Norwegian Tenecteplase Stroke Trial;
PH=
parenchymal hemorrhage;
TNK=
tenecteplase

The incidence of ischemic stroke increases with age,1,2 with 25%–40% of stroke events occurring in patients aged 80 years and older.1,3,4 Yet this population has been underrepresented in both thrombolytic and endovascular trials.5,6 With the proportion of individuals aged 80 years and older expected to be the fastest growing age group in the developed world over the next 3 decades,7 the frequency of thrombolytic therapy use and mechanical clot retrieval will undoubtedly increase in this age cohort.

Despite earlier concerns and the effect on European treatment guidelines, alteplase has been shown to be effective in patients over the age of 80 years.5 With higher rates of recanalization and growing evidence suggestive of improved clinical outcomes, tenecteplase (TNK) shows increasing promise as the thrombolytic therapy of choice for patients with acute ischemic stroke.8,-,11 However, detailed study of this therapy in patients older than 80 years is limited. Prior cardiovascular studies of TNK indicate an increased risk of intracranial hemorrhage in older patients (≥75 years) when higher doses (0.50 mg/kg) are used.12 However, a subgroup analysis of the Norwegian Tenecteplase Stroke Trial (NOR-TEST) showed no major differences in safety and functional outcomes in older patients (≥80 years) treated with either TNK 0.40 mg/kg or alteplase.13

In this study, we aimed to investigate the association between age and treatment effect and to assess the safety and efficacy of TNK at 0.40 mg/kg and 0.25 mg/kg dosing in patients older than 80 years with large vessel occlusion (LVO) using pooled data from the EXTEND-IA TNK (Tenecteplase vs Alteplase Before Endovascular Therapy for Ischemic Stroke) trials.10,11

Primary Research Question

Are there differences in the safety and efficacy of tenecteplase dosing in older patients with LVO stroke?

Methods

Data availability

All supporting data and methodologic details are available within the article and online-only supplement. Access to the data utilized in this study can be obtained from the study authors upon reasonable request.

Participants

Participants were enrolled in EXTEND-IA TNK and EXTEND-IA TNK Part 2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischemic Stroke).10,11 These 2 studies were multicenter, prospective, randomized trials designed to determine the efficiency of tenecteplase in the context of LVO and administration of endovascular therapy (EVT). Patients with CT angiography–confirmed occlusion of the internal carotid, middle cerebral, or basilar artery were enrolled within 4.5 hours of symptom onset. In the first study, patients were randomized to open-label TNK 0.25 mg/kg or alteplase 0.90 mg/kg prior to initiation of EVT. In part 2, patients were randomized to open-label TNK 0.25 mg/kg or 0.40 mg/kg. Exclusion criteria in both trials included a baseline modified Rankin Scale (mRS) score ≥4, hypodensity in >1/3 of the middle cerebral artery territory, or a history of terminal illness. All patients received CT perfusion imaging at baseline assessment and received either CT or MRI follow-up at 24 hours. All patients received serial clinical assessments up to 90 days poststroke. Patients enrolled into EXTEND-IA TNK were initially required to exhibit a CT perfusion mismatch10; however, this requirement was subsequently removed and not required for enrollment in part 2. There was no upper age limit in either trial. Patients were enrolled from March 2015 to October 2017 (EXTEND-IA TNK) and December 2017 to July 2019 (EXTEND-IA TNK Part 2) in multiple hospitals across Australia and New Zealand. The intention-to-treat populations from both trials were used for this analysis.

Outcomes

Clinical outcomes evaluated in this study include disability level at 90 days via an ordinal analysis of the mRS, freedom from disability (defined as mRS of 0–1 or no change from baseline at 90 days), functional independence (defined as mRS 0–2 or no change from baseline at 90 days), all-cause mortality, and symptomatic intracranial hemorrhage (defined as subarachnoid hemorrhage associated with clinical symptoms or a parenchymal hematoma type 2 combined with at least a 4-point increase in the National Institutes of Health Stroke Scale [NIHSS] score).14 The mRS score assesses poststroke clinical disability and ranges from 0 to 6, with 0 indicating no symptoms; 1, no clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. Imaging outcomes assessed in this study include final modified Treatment in Cerebral Ischemia scores and rates of successful reperfusion at initial angiographic assessment. Angiographic reperfusion was scored pre and post thrombectomy using the expanded Treatment in Cerebral Ischemia scale. Both clinical and imaging outcome assessments were performed by blinded clinicians.

Statistical Analysis

Fisher exact test, Mann-Whitney U, Kruskal-Wallis, and analysis of variance were used as appropriate when evaluating baseline patient characteristics. All reported p values are 2-sided with p < 0.05 regarded as statistically significant. We compared the treatment effects of TNK 0.40 mg/kg, TNK 0.25 mg/kg, and alteplase 0.90 mg/kg in individual age strata predefined as >80 and ≤80 years. The 80-year cutoff was based on its prior use in multiple studies, including a past assessment of NOR-TEST data. Treatment effects were adjusted for baseline NIHSS, age, and time from symptom onset to arterial puncture (selected a priori) via mixed effects proportional odds (90-day mRS, mRS 5–6 merged together) and binary logistic regression models (freedom from disability, functional independence, mortality), with individual studies as random effects. We adjusted for age within the ≤/>80 strata given the expected residual strong prognostic effect of age within those strata. These within-strata estimates are presented with respective 95% CIs using TNK 0.40 mg/kg as the main reference and the p values from the treatment-by-age interaction analysis (see below). We also report a comparison between TNK 0.25 mg/kg and alteplase.

In order to investigate treatment-by-age interactions, we used mixed effects regression models (proportional odds [90-day mRS; mRS 5–6 pooled together] and binary [freedom from disability, functional independence, mortality]) with individual studies as random effects and treatment, baseline NIHSS, age, time from symptom onset to arterial puncture, and multiplicative treatment-by-age interaction terms as independent variables. All reported p values for interaction are 2-sided with p < 0.05 regarded as significant, with no multiplicity correction. For all ordinal models, the proportional odds assumption was assessed using the Brandt test.

We preplanned a sensitivity analysis to assess the aforementioned outcomes with patients with symptomatic intracranial hemorrhage and parenchymal hemorrhage excluded. We also conducted an analysis of 90-day mRS adjusting for baseline mismatch volume (in lieu of baseline NIHSS) in a separate model. Additional analysis of secondary clinical outcomes, adjusting for baseline mismatch and core volume in separate models, was also performed. Statistical analysis was performed using SPSS v27.0 (IBM) and STATA v16 (StataCorp).

Standard Protocol Approvals, Registrations, and Patient Consents

Local research ethics board approval was obtained at all EXTEND-IA TNK enrolling sites. Written informed consent was obtained from the participant or a legal representative before enrollment, except in jurisdictions allowing deferral of consent for emergency treatment, in which case consent was obtained at a later time point to continue participation.

Results

Cohort Characteristics

A total of 502 patients were included in our primary analysis (202 patients from EXTEND-IA TNK; 300 patients from EXTEND-IA TNK Part 2). Between the 2 trials, 251 patients (50%) were randomized to TNK 0.25 mg/kg, 150 (30%) were randomized to TNK 0.40 mg/kg, and 101 (20%) were randomized to alteplase 0.90 mg/kg. Age distributions among the 3 treatment groups were similar (eFigure 1, links.lww.com/WNL/B753) and no significant differences in other baseline characteristics were observed (eTable 1, links.lww.com/WNL/B753). All patients were randomized and administered thrombolysis within 4.5 hours of stroke onset. Sixteen (3%) patients received EVT outside of the 6-hour window due to prolonged interhospital transfer.

A total of 137 (27%) patients were older than 80 years at time of randomization and treatment. Baseline characteristics stratified by age grouping (>80 years, ≤80 years) are outlined in eTable 2, links.lww.com/WNL/B753. The median age of patients in the >80 years cohort was 86 years (interquartile range [IQR] 84–90; oldest patient enrolled was 98 years). A higher proportion of patients in this age group were female and higher rates of hypertension, baseline glucose, previous stroke/TIA, anticoagulant use, and cardioembolic etiology were observed. Workflow processes were noted to be slower in this age group, with delays in times to thrombolysis (median time 139 minutes [IQR 110–170] vs 128 minutes [IQR 99–169]; p = 0.03) and arterial puncture (median time 190 [IQR 151–262] vs 175 minutes [IQR 137–235]; p = 0.02). No significant difference was observed in the site of primary vessel occlusion. Baseline ischemic core volume was lower (median 5 mL [IQR 0–26] vs 13 mL [IQR 0–35]; p < 0.01). In exploratory univariate analysis, no major differences in patient characteristics were observed among treatment groups within each age cohort (Table 1).

View this table:
Table 1

Baseline Characteristics of Patients Stratified by Age Threshold and Treatment Dosing

Older Than 80 Years Cohort

Older patients treated with TNK 0.25 mg/kg had a median mRS score of 3 at 90 days (IQR 1–5), while patients treated with TNK 0.40 mg/kg and alteplase had median mRS scores of 4 (IQR 3–6) and 4 (IQR 2–6), respectively (Figure 1A). Adjusting for relevant covariates, TNK 0.25 mg/kg was associated with improved mRS scores at 90 days, compared to TNK 0.40 mg/kg (adjusted common odds ratio [acOR] 2.70 [95% CI 1.23–5.94]) and alteplase (acOR 2.28 [95% CI 1.03–5.05]) (Table 2). No difference in 90-day mRS was detected between alteplase and TNK 0.40 mg/kg. Our findings were consistent for the primary outcome and freedom from disability in a separate model that adjusted solely for baseline mismatch (eTables 3 and 4, links.lww.com/WNL/B753). The association between TNK 0.25 mg/kg and alteplase remained significant in models that adjusted for both mismatch and baseline NIHSS; however, the association between 0.25 mg/kg and 0.40 mg/kg TNK dosing was no longer statistically significant (p = 0.08; eTable 3, links.lww.com/WNL/B753). The associations among 0.25 and 0.40 mg/kg TNK dosing and standard dose alteplase in our remaining secondary outcomes were not significant when adjusted for baseline mismatch and core in separate models (eTable 4, links.lww.com/WNL/B753). Overall, only a third of patients age >80 were either free from disability or functionally independent at 90 days (eTable 5, links.lww.com/WNL/B753). The proportion of patients with freedom from disability and functional independence was highest in those treated with TNK 0.25 mg/kg. This difference was found to be statistically significant when compared to patients treated with alteplase (freedom from disability: 42% vs 17%; adjusted odds ratio [aOR] 8.54 [95% CI 1.83–39.79]; functional independence: 43% vs 32%; aOR 4.11 [95% CI 1.06–15.90]) (Table 2). Mortality, occurring in 30% of the older cohort, was highest in patients treated with TNK 0.40 mg/kg (41%) and alteplase (34%). TNK 0.25 mg/kg was associated with reduced mortality (aOR 0.34, 95% CI 0.13–0.91) vs TNK 0.40 mg/kg. Comparing TNK 0.25 mg/kg and 0.40 mg/kg, significant treatment-by-age interactions were observed for 90-day mRS (ordinal) and freedom from disability (Figure 2), but no treatment-by-age interaction was observed for mortality. Comparing alteplase and TNK 0.40 mg/kg, no treatment-by-age interactions were observed.

Figure 1
Figure 1 mRS Scores at 90 Days Stratified by Treatment in Patients >80 Years and in Patients ≤80 Years

(A) Patients >80 years. Tenecteplase 0.25 mg/kg was associated with modified Rankin Scale (mRS) shift (mRS 5–6 pooled together), adjusting for baseline National Institutes of Health Stroke Scale, age, and time from symptom onset to arterial puncture, when compared to tenecteplase 0.40 mg/kg (median 3 vs 4, adjusted common odds ratio [acOR] 2.70, 95% CI 1.23–5.94) and alteplase (median 3 vs 4, acOR 2.28, 95% CI 1.03–5.05). No significant differences were observed between alteplase and tenecteplase 0.40 mg/kg (median 4 vs 4, acOR 1.18, 95% CI 0.47–2.95). (B) Patients ≤80 years. No significant differences were observed between tenecteplase 0.25 mg/kg and tenecteplase 0.40 mg/kg (median 1 vs 1, acOR 0.80, 95% CI 0.52–1.23), alteplase and tenecteplase 0.40 mg/kg (median 1 vs 1, acOR 0.64, 95% CI 0.38–1.09), or tenecteplase 0.25 mg/kg and alteplase (median 1 vs 1, acOR 1.25, 95% CI 0.76–2.06) in ordinal analysis of the mRS (mRS 5–6 pooled together), adjusting for baseline National Institutes of Health Stroke Scale, age, and time from symptom onset to arterial puncture.

View this table:
Table 2

Clinical Outcomes Stratified by Treatment and Age Threshold

Figure 2
Figure 2 Treatment Effect Forest Plots Comparing Alteplase 0.90 mg/kg and Tenecteplase 0.25 mg/kg to Tenecteplase 0.40 mg/kg, Stratified by Age Threshold

Treatment effects are adjusted for baseline National Institutes of Health Stroke Scale, age, and time from symptom onset to arterial puncture. Freedom from disability defined as a modified Rankin Scale (mRS) score of 0–1 or no change from baseline. Functional independence defined as mRS score of 0–2 or no change from baseline. acOR = adjusted common odds ratio; aOR = adjusted odds ratio; TNK = tenecteplase; tPA = tissue plasminogen activator.

Symptomatic intracranial hemorrhage was observed in 4 older patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg (Table 3). All patients aged >80 who had a symptomatic intracranial hemorrhage and 5 out of 7 who had a parenchymal hemorrhage (PH) died within the period of follow-up. In a prespecified sensitivity analysis excluding patients with symptomatic intracranial hemorrhage or PH, the difference in mortality between TNK 0.25 mg/kg and 0.40 mg/kg was no longer statistically significant (eTable 6, links.lww.com/WNL/B753). However, TNK 0.25 mg/kg continued to be associated with improved mRS scores at 90 days when compared to TNK 0.40 mg/kg (acOR 2.37 [95% CI 1.05–5.39]) and alteplase (acOR 2.81 [95% CI 1.23–6.45]). Rates of successful reperfusion at initial angiographic assessment did not significantly differ among the 3 treatment groups (27% [TNK 0.25 mg/kg] vs 29% [TNK 0.40 mg/kg] vs 10% [alteplase]; Table 4). There was no significant difference in follow-up core volumes among the different treatment groups (eTable 5, links.lww.com/WNL/B753).

View this table:
Table 3

Posttreatment Hemorrhage Rates Stratified by Treatment Status and Age

View this table:
Table 4

Imaging Outcomes Stratified by Treatment and Age Threshold

Younger Than or Equal To 80 Years Cohort

Patients treated with TNK 0.25 mg/kg had a median mRS score of 1 (IQR 0–3) at 90 days, patients treated with TNK 0.40 mg/kg had a median mRS score of 1 (IQR 0–3), and patients treated with alteplase had a median mRS score of 1 (IQR 1–4). No differences in 90-day mRS were observed among TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase (Figure 1B). Rates of freedom from disability and functional independence were higher in this cohort (ranging from 53% to 69%) compared to the >80 years cohort and the percentage of patients achieving functional independence was comparable among all 3 treatment groups. Mortality and symptomatic intracranial hemorrhage were less frequent than in the older cohort and were also comparable among all 3 treatment groups (Tables 2 and 3). Rates of successful reperfusion at initial angiographic assessment did not significantly differ among the 3 treatment groups (18% [TNK 0.25 mg/kg] vs 16% [TNK 0.40 mg/kg] vs 10% [alteplase]; Table 4) but were lower than that observed in the >80-year cohort (24% vs 16%; p = 0.03; eTable 5, links.lww.com/WNL/B753).

Classification of Evidence

This study provides Class II evidence that tenecteplase 0.25 mg/kg given before EVT in patients >80 years old with LVO stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.

Discussion

In a pooled analysis of 502 patients with LVO stroke, the 0.25 mg/kg dose of TNK was associated with reduced mortality and improved clinical outcomes when compared to the 0.40 mg/kg dose or 0.90 mg/kg alteplase dosing in patients >80 years. The proportions of patients free from disability or achieving functional independence were also higher in patients treated with TNK 0.25 mg/kg. Treatment-by-age interactions for 90-day mRS (ordinal) and freedom from disability were observed between TNK 0.25 mg/kg and 0.40 mg/kg. In patients ≤80 years of age, the rates of freedom from disability, functional independence, and mortality were comparable among all 3 groups.

Rates of favorable clinical outcomes were significantly lower in the >80-year cohort compared to those ≤80 years of age. This is consistent with the universal prognostic effect of age,15,-,17 although the treatment effect in older stroke patients with LVO was preserved in randomized trials.18 The proportion of patients with mRS 0–2 (36%) or mortality (30%) in the >80-year cohort were similar to the EVT arm of the HERMES collaboration (mRS 0–2 30%; mortality 28%) and were higher than the control arm (mRS 0–2 14%; mortality 45%). Of note, rates of successful recanalization prior to the start of clot retrieval were substantially higher in the >80 years cohort (eTable 5, links.lww.com/WNL/B753). However, slower workflow processes (time to lysis and time to puncture) were also observed in this cohort and may have contributed to the higher rates of recanalization at initial angiographic assessment observed, by allowing more time for thrombolysis to dissolve the clot.

From a safety perspective, TNK 0.40 mg/kg was associated with an increased risk of mortality, symptomatic hemorrhage, and parenchymal hematoma. Based on our sensitivity analysis, the increased mortality seen with TNK 0.40 mg/kg dosing was largely explained by the higher rates of hemorrhage and is in keeping with previous cardiovascular literature that suggested an increased risk of bleeding in patients treated with 0.50 mg/kg doses of TNK. The rates of symptomatic hemorrhage in our analysis are also in keeping with an analysis of older stroke patients from the NOR-TEST trial.13

From an efficacy standpoint, TNK 0.25 mg/kg was associated with improved clinical performance when compared to TNK 0.4 mg/kg or alteplase. The reasons for this are unclear. Analysis of radiologic markers showed no differences in follow-up core volumes or rates of successful reperfusion on initial angiographic assessment among the 3 treatment groups. The 3 groups were also comparable at baseline and an analysis of 90-day mRS models adjusting for baseline mismatch volume showed consistency in our findings. The findings of our study could be attributed to a limited sample size and potential type I error. However, the presence of significant interaction across the whole cohort argues against this. Ultimately, the findings of this study are hypothesis-generating and further investigation will be required. Future analysis that looks at collateral status and measures of angiographic techniques (e.g., number of passes, devices used) is warranted.

This study has several limitations. First, the generalizability of our findings is limited to patients with LVO stroke. Furthermore, patients in the >80 years cohort had a notably lower baseline ischemic core volume at the time of randomization and treatment. This may represent a selection bias and as such, the cohort used in our analysis may not be fully representative of the general population in that age group. Further analysis of TNK in additional cohorts will be required to ensure our findings are consistently observed. In addition, although age–treatment interactions were observed between TNK 0.25 mg/kg and 0.40 mg/kg, this study was not formally powered to assess changes among subgroups. As such, an interaction assessment between alteplase and TNK 0.40 mg/kg requires more study with a larger sample size.

Among patients >80 years with LVO stroke, the 0.25 mg/kg dose of TNK was associated with reduced mortality and improved long-term clinical outcomes compared to 0.40 mg/kg or 0.90 mg/kg alteplase. The increased mortality seen in patients who received the 0.40 mg/kg dose may be attributed to higher rates of symptomatic intracranial hemorrhage. Our findings suggest that the 0.25 mg/kg dose of TNK may be the preferred dose for patients >80 years of age with small ischemic cores in whom endovascular procedure is considered reasonably indicated.

Study Funding

Dr. Yogendrakumar is supported by the Canadian Institute of Health Research and the University of Melbourne.

Disclosure

V. Yogendrakumar and L. Churilov report no disclosures relevant to the manuscript. P.J. Mitchell reports receiving travel support from Stryker and Microvention and institutional research support from Stryker and Medtronic. T.J. Kleinig and N. Yassi report no disclosures relevant to the manuscript. V. Thijs reports receiving personal fees and travel support from Boehringer Ingelheim, Bayer, Pfizer/Bristol-Myers Squibb, Amgen, and Medtronic outside the submitted work. T.W. reports no disclosures relevant to the manuscript. D.G. Shah reports receiving personal fees and travel support from Boehringer Ingelheim and personal fees from Bayer and Medtronic outside the submitted work. F. Ng, H.M. Dewey, T. Wijeratne, P. Desmond, and B. Yan report no disclosures relevant to the manuscript. M.W. Parsons reports receiving travel support from Boehringer Ingelheim and research collaboration with Apollo Medical Imaging outside the submitted work. G.A. Donnan reports personal fees from Allergan, Amgen, Bayer, Boehringer Ingelheim, Pfizer, and Servier outside the submitted work. S.M. Davis reports receiving personal fees from Bayer, Boehringer Ingelheim, Tide Pharmaceuticals, and Medtronic and grants from the National Health and Medical Research Council of Australia outside the submitted work. B.C.V. Campbell reports no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Appendix Authors

Table

Appendix 2 Coinvestigators

Table

Footnotes

  • Received May 26, 2021.
  • Accepted in final form December 27, 2021.

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If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

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Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
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