Top News for American Heart Month 2023

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In honor of American Heart Month, held February 2023, get caught up on some of the latest news in stroke as the NeurologyLive® team shares some of our data updates.

In recent months, the NeurologyLive® team has been covering the news on the latest updates in the clinical care of individuals with stroke, including those with acute stroke and post stroke.

For American Heart Month— February 2023—the team has culminated some of the biggest pieces of news to offer updates on new developments in literature about stroke to spread awareness on the prevention and treatment of the condition.

Click here for more coverage of the latest stroke news from NeurologyLive®.

Latest Literature

Clazosentan Fails to Meet Primary End Point in Phase 3 REACT Study of Aneurysmal Subarachnoid Hemorrhage

According to an announcement by Idorsia, initial findings from the phase 3 REACT study (NCT03585270) of clazosenten showed that the agent failed to meet its primary end point of preventing clinical deterioration in patients presenting with aneurysmal subarachnoid hemorrhage (aSAH).1 The primary efficacy end point was the occurrence of clinical deterioration due to delayed cerebral ischemic (DCI) up to 14 days post-study drug initiation. Occurrence of clinically relevant cerebral infarction at day 16, as well as change in modified Raking Scale and Glasgow Outcome Scale-Extended score at week 12, acted as secondary end points for the trial. The trial also had radiological results and clinical end points evaluated by independent committees, blinded to treatment allocation.

REACT was a double-blind, placebo-controlled, parallel-group study that included 409 patients with documented aSAH from a ruptured cerebral aneurysm who were randomly assigned 1:1 to 15 mg/hr intravenous clozaosentan or placebo. Eligible patients were between 18 to 70 years old with World Federation of Neurological Societies grades 1-4 after recovery from the aneurysm-securing procedure and “thick and diffuse clots” on the admission CT scan.

Stroke Risk Increase in Women With Elevated Lifetime Estrogen Exposure

Results from a recent analysis based on the China Kadoorie Biobank cohort study suggest that women with a lower level of estrogen exposure have a decreased risk of ischemic stroke and intracerebral hemorrhage than their counterparts with the highest levels of estrogen exposure.2,3 Comparison of risk among different quartiles of estrogen exposure indicated those in the lowest quartile of reproductive lifespan had a lower risk of total stroke (adjusted HR, 0.95; 95% CI, 0.92-0.98), ischemic stroke (aHR, 0.95; 95% CI, 0.92-0.98), and intracerebral hemorrhage (aHR, 0.87; 95% CI, 0.81-0.94) compared with those in the highest quartile.

The study, which enrolled individuals from 2004-2008, identified 122,939 postmenopausal women without prior stroke at baseline. This cohort had a median age at menarche of 16.0 (IQR, 14.0-17.0) years, a median age at menopause of 49 (IQR, 47.0-51.0) years, and median age at baseline of 58.3 (IQR, 54.0-65.1).

For the purpose of analysis, lifetime cumulative estrogen exposure due to reproductive factors was assessed using reproductive lifespan, endogenous estrogen exposure, and total estrogen exposure. The primary outcome of interest for the study was incidence of stroke, with stroke subtypes serving as secondary outcomes of interest. Investigators pointed out multivariable-adjusted Cox proportional hazards regression models were applied to estimate the adjusted HR for risk of stroke by quartiles of reproductive lifespan, endogenous estrogen exposure, and total estrogen exposure.

Endovascular Brain-Computer Interface Implant Shows Feasibility, Safety in Treating Upper-Limb Paralysis

Findings from the SWITCH study (NCT03834857), the first in-human trial assessing an endovascular brain-computer interface (BCI) implant, showed a favorable safety profile in paralyzed patients with no device-related serious adverse events (AEs) or persistent neurological deficits.4 Investigators concluded that endovascular access to the sensorimotor cortex could be an alternative to placing BCI electrodes in or on the dura by open-brain surgery.

This single-center, prospective study assessed 5 patients with severe bilateral upper-limb paralysis, with follow-up of 12 months. The implanted devices included the Stentrode (Synchron), a 16-electrode sensing device implanted endovascularly, connected by a transvascular lead to an implantable receiver transmitter unit (IRTU) in an infraclavicular subcutaneous pocket. The recording head of the sensing device contained platinum electrodes with a surface area of 0.3 mm2 and an intercontact spacing of 3 mm.

The referred sample included 4 patients with amyotrophic lateral sclerosis (ALS) and 1 with primary lateral sclerosis; however, only 4 patients satisfied all preoperative requirements and went on to receive the implant. The 1 patient was withdrawn from the study because of isolated transverse sinus drainage observed in the preimplant MRI. It had been previously shown that stenosis with contralateral hypoplasia may potentially impede flow; however, this is rather rare, occurring in just 1% of patients in a separate study.

Ticagrelor and Aspirin Combination Most Effective in CYP2C19 Carriers With Low Risk Profile

Post-hoc findings from the CHANCE-2 trial (NCT0407837) showed that the benefit of dual antiplatelet therapy (DAPT) using ticagrelor (Brilinta; AstraZeneca) and aspirin is most effective in carriers of CYP2C19 loss of function (LOF) alleles with minor stroke or transient ischemic attack (TIA) who have low risk profiles, as defined by Essen Stroke Risk Score (ESRS).5

In a cohort of 6412 patients randomly assigned to either ticagrelor and aspirin (n = 3205) or clopidogrel (Plavix; Sanofi) and aspirin (n = 3207), ticagrelor and aspirin use was associated with a reduced risk of new stroke within 90-day follow-up, the primary outcome, in patients at low risk (HR, 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel and aspirin (P = .02). Overall, these findings may help identify patient profiles who may be more suitable for this type of treatment.

On the primary safety analysis, outcome of severe or moderate bleeding did not differ based on risk profile (P = .24 for interaction), though the incidence of total bleeding was greater with ticagrelor and aspirin vs clopidogrel and aspirin among patients with low risk profiles (P <.01). Additionally, secondary outcomes generally went in the same direction as the primary outcome, and analyses in the per-protocol population also yielded similar results. In CHANCE-2, patients received ticagrelor 180 mg on day 1 followed by 90-mg twice daily on days 2 to 90, or clopidogrel 300 mg on day 1 followed by 75-mg daily on days 2 to 90, all while on aspirin 75 to 300 mg on day 1 followed by 75-mg daily for 21 days.

Neurelis Files IND for Potentially First Therapy to Treat Cerebral Cavernous Malformations

Neurelis successfully filed an investigational new drug application (IND) for its rho kinase (ROCK) inhibitor NRL-1049 as a potential treatment for individuals with cerebral cavernous malformations (CCM). The company plans to initiate a study in early 2023 to assess the agent.6

CCM, a disease characterized by abnormally enlarged capillary cavities, most commonly found in the cerebral cortex, brainstem, and spinal cord, currently has no FDA-approved therapeutics to treat the condition. Patients with the condition have typically turned to antiepileptic drugs and surgical interventions to remove lesions; although, most cavernous malformations have been conservatively managed by observing for changes in appearance, recent hemorrhages, or other clinical symptoms.

Familial CCMs, which arise from autosomal dominant mutations in the CCM1, CCM2, and/or CCM3 genes, account for at least 20% of all cases. Despite this, previous research has identified that mutations in these genes cause hyperactivation of the ROCK signaling pathway in brain vascular endothelial cells, which then leads to the loss of endothelial integrity, subsequently causing capillary malformation and eventually, the potential for lesions. In the general population, the prevalence of CCMs accounts between 0.2% to 0.5%; however, this condition accounts for a larger proportion (8% to 15%) of all brain and spinal vascular malformations.

REFERENCES
1. Idorsia announces the results of REACT a phase 3 study of clazosentan in patients following aneurysmal subarachnoid hemorrhage. News release. Idorsia. February 6, 2023. Accessed February 17, 2023. https://www.globenewswire.com/news-release/2023/02/06/2601762/0/en/Idorsia-announces-th%5B%E2%80%A6%5Dpatients-following-aneurysmal-subarachnoid-hemorrhage.html
2. Hou L, Li S, Zhu S, et al. Lifetime cumulative effect of reproductive factors on stroke and its subtypes in postmenopausal Chinese: A prospective cohort study. Neurology. https://n.neurology.org/content/early/2023/02/01/WNL.0000000000206863. Published February 1, 2023. Accessed February 17, 2023.
3. Study design. China Kadoorie Biobank (CKB). https://www.ckbiobank.org/study-resources/study-design. Accessed February 17, 2023.
4. Mitchell P, Lee SCM, Yoo PE, et al. Assessment of safety of a fully implanted endovascular brain-computer interface for severe paralysis in 4 patients: the StentrodeWith Thought-Controlled Digital Switch (SWITCH) study. JAMA Neurol. Published online January 9, 2023. Doi:10.1001/jamaneurol.2022.4847.
5. Wang A, Meng X, Zuo X, et al. Ticagrelor-aspirin vs clopidogrel-aspirin in CYP2C19 loss-of-function carriers with minor stroke or TIA stratified by risk profile. Neurology. Published online December 19, 2022. doi:10.1212/WNL.0000000000201454
6. Neurelis announces filing of its investigational new drug application for NRL-1049, a rho kinase (ROCK) inhibitor with potential to treat cerebral cavernous malformations. News release. Neurelis. January 9, 2023. Accessed February 17, 2023. https://www.prnewswire.com/news-releases/neurelis-announces-filing-of-its-investigational-new-drug-application-for-nrl-1049-a-rho-kinase-rock-inhibitor-with-potential-to-treat-cerebral-cavernous-malformations-301716126.html
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