Two Cases Showing That Cilostazol Administration Leads to an Increase in Cerebral Blood Flow and Has a Positive Effect on Rehabilitation

Didn't your competent? doctor create a protocol on its' use a long time ago? NO? Then why are you seeing an incompetent doctor? And why is the board of directors still employing an incompetent doctor?

In my opinion competent doctors are up-to-date on ALL stroke research! No excuses allowed!

• cilostazol (19 posts to August 2013)

 

Two Cases Showing That Cilostazol Administration Leads to an Increase in Cerebral Blood Flow and Has a Positive Effect on Rehabilitation

Shuji Matsumoto • Rintaro Ohama • Takashi Hoei • Ryuji Tojo • Toshihiro Nakamura

Published: March 18, 2024

DOI: 10.7759/cureus.56376 

  Peer-Reviewed

Cite this article as: Matsumoto S, Ohama R, Hoei T, et al. (March 18, 2024) Two Cases Showing That Cilostazol Administration Leads to an Increase in Cerebral Blood Flow and Has a Positive Effect on Rehabilitation. Cureus 16(3): e56376. doi:10.7759/cureus.56376

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Abstract

Cilostazol is a drug that has both antiplatelet and vasodilatory effects. To examine the effects of cilostazol on cerebral blood flow and rehabilitation following stroke, cilostazol was administered to two patients with chronic atherothrombotic cerebral infarction. In both patients, cilostazol administration effectively increased cerebral blood flow and promoted rehabilitation. Therefore, cilostazol was considered to be a useful agent for improving the clinical condition of patients suffering from chronic cerebral infarction. Further clinical studies on the effective use of cilostazol for rehabilitation in stroke patients are needed.

Introduction

Although the mortality rate as a result of stroke is declining, the incidence of stroke itself is increasing. As a result, the number of patients with chronic cerebral infarction is also rising, such that the clinical management of this condition is likely to become a major future health issue. The global number of deaths from stroke is projected to increase from 2.04 million to 3.29 million between 1990 and 2019 and to 4.9 million by 2030 [1].

There is now widespread evidence that antiplatelet drugs are an effective treatment for atherothrombotic cerebral infarction [2], but there are currently no indices as to what types of antiplatelet drugs are most effective or at what stage they should be administered. In addition to an antiplatelet effect [3] due to cyclic guanosine monophosphate (cGMP)-inhibited phosphodiesterase, cilostazol also reportedly has pleiotropic and vasodilatory effects [4,5], improves vascular endothelial function [6] and suppresses vascular smooth muscle growth [7]. Cilostazol reportedly enhances cerebral blood flow in cases of chronic cerebral infarction [8]. However, its effects on physiological functions, the performance of activities of daily living (ADL), and cognitive function have not been investigated previously.

We administered cilostazol to two patients with chronic atherothrombotic cerebral infarction and evaluated the effects of the drug on cerebral blood flow and rehabilitation.

More at link.

Combination of Two Common Cariovascular Drugs Could Improve Outcomes in Lacunar Stroke

Well then write up a proposed protocol on this and get it distributed to all stroke hospitals in the world AND ENSURE staff doctors get trained in its' use. 

Combination of Two Common Cariovascular Drugs Could Improve Outcomes in Lacunar Stroke

Two commonly used cardiovascular medications were safe and well tolerated by patients who had experienced a small vessel stroke, according to results from the open-label, phase 2, randomized Lacunar Intervention Trial-2 (LACI-2) published May 24 in JAMA Neurology.

The trial also showed signs that the drug combination could potentially improve cognitive outcomes in lacunar stroke, although larger trials will be needed to confirm these findings.

LACI-2, the second largest trial ever in lacunar stroke, was designed to assess the feasibility, drug tolerability, safety, and effects of one year of treatment with isosorbide mononitrate (ISMN) and cilostazol on vascular, functional, and cognitive outcomes in patients with this type of stroke.

Lacunar stroke, which occurs in the small penetrating arteries deep within the brain, causes approximately 25 percent of ischemic strokes and is associated with significant morbidity and mortality, including major physical and cognitive disabilities. There is no proven treatment to improve outcomes after a lacunar stroke.

“There appeared to be some potential benefits that will need to be confirmed in a larger phase 3 trial," lead author Joanna M. Wardlaw, MD, FAHA, said at a presentation of the LACI-2 preliminary results during the American Stroke Association's International Conference in February 2023.

“We saw good hints of efficacy, particularly for isosorbide mononitrate on reducing recurrent stroke and cognitive impairment, and we also found that both medications together seemed to work synergistically, rather than counteracting any benefit," said Dr. Wardlaw, professor of applied neuroimaging, honorary consultant neuroradiologist, head of neuroimaging sciences, and director of Edinburgh Imaging at Edinburgh University in Scotland. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes. So, we cautiously hope that these medications may have wider implications for other types of small vessel disease."

Study Details

Between February 2018 and May 2022, the LACI-2 investigators enrolled 363 adults who had experienced lacunar stroke from 26 stroke centers across the United Kingdom. In addition to their standard prescribed stroke medications, study participants were randomized to a year in one of four treatment groups: 40 to 60 mg/day of oral ISMN alone, 200 mg/day of oral cilostazol alone, both medications, or neither medication. 

Participants in the LACI-2 trial had characteristics typical of lacunar ischemic stroke, including being younger compared with all patients with stroke; additionally, “more were men, few strokes had embolic sources, and patients had low rates of dependence and death (1.3 percent) but high rates of cognitive impairment (58.9 percent)."

Participants with indications for, or contraindications to, one study drug could be randomized to the other drug.

At one year, 358 of those initially enrolled were still participating in the study, with 95 percent of participants taking at least half of medication doses, meeting the study's feasibility outcome. The trial also met safety criteria, with relatively few adverse events.

Although the trial was not powered to evaluate efficacy, the composite efficacy outcome—which included vascular events, dependence, cognition, and death—showed signs of benefit with either of the drugs alone and a significantly lower rate with the combination compared with neither drug (48.6 percent vs. 69.6 percent). Overall, the absolute reduction in participants with any cognitive impairment was 18.7 percent (46.7 percent with ISMN-cilostazol and 65.4 percent with neither drug).

Individually, although it did not reduce the composite outcome, ISMN reduced recurrent stroke or transient ischemic attack (TIA)—2.2 percent with ISMN vs. 8.3 percent without; p=0.01)—and improved quality of life (p=0.03), reduced global Stroke Impact Scale (p=0.005), reduced global clinical outcomes (p=0.004), reduced cognitive impairment (p=0.008), and tended to reduce dependence. The absolute reduction in participants with any cognitive impairment was 10.4 percent (54.4 percent with ISMN and 64.8 percent without ISMN).

Cilostazol alone did not reduce the composite outcome, recurrent stroke, or TIA, nor did it improve quality of life or global clinical outcome. It did reduce dependence (with a modified Rankin Scale score of 3 to 6: 8.8 percent with cilostazol vs. 17.3 percent without; p=0.006). Cilostazol did not reduce cognitive impairment but tended to improve mood, as measured by the Zung depression scale (p=0.06).

“This is a great study and great news for the field of small vessel disease," said Jose Rafael Romero, MD, associate professor of neurology and a member of the Stroke Unit at Boston University Chobanian & Avedisian School of Medicine, which has  several ongoing clinical trials for acute stroke treatment and secondary prevention.

“There is a strong signal that there could be more targeted treatment for these patients, not only in stroke risk reduction but [also] with an apparent effect on cognitive outcomes. Small vessel disease is a major underlying cause of dementia, and I would argue that every type of dementia has some component of small vessel disease, so the public health impact of interventions like these can be enormous."

The successful achievement of the study's safety endpoint is strengthened by the fact that the two drugs were administered in addition to standard of care, including single or dual antiplatelet therapy. “In combination with those drugs, cilostazol and ISMN did not increase the risk of major bleeding and showed a safe profile, which makes these findings even stronger," Dr. Romero said.

The LACI-3 trial is now preparing to address many of these questions, and other trials are also being proposed to funders around the world.

“I'm very optimistic about these findings," Dr. Romero said. “I think they are likely to lead us toward a big change for the treatment of small vessel disease in a very positive way."

Look for more in-depth discussion in an upcoming issue of Neurology Today.

Disclosures

Dr. Romero had no disclosures.

Examining first treatment for strokes linked to dementia

Since you already have dementia when you get this stroke you'll have to hope like hell that your doctors are up-to-date on this treatment because you won't be able to inform them of this. Or better yet ask your doctor now to follow this since results are not expected for 5 years.

Examining first treatment for strokes linked to dementia

People who experience a type of stroke linked with nearly half of all dementias could be treated for the first time by repurposing two cheap and common drugs, a trial shows.

Researchers found that isosorbide mononitrate and cilostazol, which are already used to treat other heart and circulatory diseases, can safely improve the debilitating outcomes people experience after lacunar stroke.

The two drugs, which were found to be even more effective when used in combination, could be available as a treatment for lacunar strokes within five years, if the results are confirmed in further trials, experts say.

Lacunar strokes affect at least 35,000 people in the UK each year. They are caused by cerebral small vessel disease, where small blood vessels deep within the brain become damaged and stop working properly. Small vessel disease is also a common cause of cognitive impairment and dementia.

The strokes can be distressing as people may develop problems with their thinking and memory, movement, and even dementia. There are currently no specific effective treatments.

The trial, led by the Universities of Edinburgh and Nottingham and the UK Dementia Research Institute, involved 363 people who had experienced a lacunar stroke.

As well as their standard stroke prevention treatment, for one year participants took either isosorbide mononitrate or cilostazol individually, both drugs together, or neither.

The trial, funded by the British Heart Foundation, investigated cilostazol and isosorbide mononitrate as they possibly improve the function of the inner lining of blood vessels, which researchers believe play a role in small vessel disease.

Participants that took both drugs were nearly 20 per cent less likely to have problems with their thinking and memory compared to the group that did not take either drug. They were also more independent and reported a better quality of life.

Drug Discovery eBook Compilation of the top interviews, articles, and news in the last year. Download the latest edition

In addition, those who took isosorbide mononitrate were less likely to have had further strokes at one year than those who did not take the drug.

Taken on their own, isosorbide mononitrate also improved thinking and memory skills, and quality of life, while cilostazol improved independence and mood. These effects were strengthened when the two drugs were taken together, researchers say.

The team is now planning to test these drugs in a larger four-year clinical trial, which they hope to start by the end of 2023. They are also looking to test whether the drugs are effective in different conditions linked to small vessel disease, such as vascular cognitive impairment and dementia.

Now we understand more about what is triggering these small vessel strokes to attack the brain, we've been able to focus our efforts on treatments that can put a halt to this damage. We need to confirm these results in larger trials before either drug can be recommended as a treatment. However, as these drugs are already widely available for other circulatory disorders, and inexpensive, it shouldn't take too long to move our findings from research into everyday clinical practice."

Joanna Wardlaw, Professor and Chair, Applied Neuroimaging, University of Edinburgh

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said: "These promising findings provide a long-awaited positive step towards the first treatments becoming available for lacunar strokes, offering much needed hope for thousands of people. Lacunar strokes are not the only way that cerebral small vessel disease can affect someone. These findings also open new avenues of research into other conditions related to small vessel disease, such as vascular dementia."

Source:

University of Edinburgh

Journal reference:

Wardlaw, J. M., et al. (2023) The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial. JAMA. doi.org/10.1001/jamaneurol.2023.1526.

Two cardiovascular drugs may help improve outcomes for patients who experienced small vessel stroke

Hell didn't your doctor do anything with all this earlier research?

• isosorbide mononitrate (4 posts to November 2015)

• cilostazol (16 posts to August 2013) 

Is your incompetent doctor and stroke hospital going to ensure this gets further human testing? NO? Then you don't have a functioning stroke doctor or hospital. I'd suggest firing the whole lot, starting with the board of directors, the rot starts at the top.

 

Two cardiovascular drugs may help improve outcomes for patients who experienced small vessel stroke

A study of two widely used cardiovascular medications — cilostazol and isosorbide mononitrate — in more than 350 patients confirmed the two medications were well-tolerated and safe for people who have experienced a stroke in a small blood vessel deep in the brain. The results suggest the medications may help improve patient outcomes, according to preliminary late-breaking science presented today at the American Stroke Association's International Stroke Conference 2023. The meeting, held in person in Dallas and virtually Feb. 8-10, 2023, is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Small vessel disease of the brain accounts for about 20% -25% of all ischemic strokes, according to previous research. A lacunar stroke, or small vessel stroke, occurs when the inner lining of the tiny blood vessels inside the brain are damaged, leading to a stroke or dementia.

"Currently, there is no proven treatment to prevent poor outcomes after lacunar stroke, so the ultimate goal with this research is to evaluate if medications with potential modes of action on the inner lining of blood vessels might help improve small vessel function and prevent or slow long-term brain damage after lacunar stroke," said lead study investigator Joanna M. Wardlaw, M.D., FAHA, professor of applied neuroimaging, honorary consultant neuroradiologist, head of neuroimaging sciences and the director of Edinburgh Imaging at Edinburgh University in Edinburgh, Scotland. She is also the foundation chair of the U.K. Dementia Research Institute.

The medications in the study are commonly prescribed for other cardiac conditions. Isosorbide mononitrate is used to treat chest pain by relaxing blood vessels and decreasing blood pressure. Cilostazol improves the flow of blood by relaxing the blood vessels and reducing blood clotting. It is often prescribed for people with peripheral artery disease — a narrowing of the peripheral arteries that carry blood away from the heart to other parts of the body.

This study, called LACunar Intervention Trial 2 (LACI-2), is the second largest ever trial in lacunar stroke. It examined whether such a trial was feasible among people with lacunar strokes and if the medications would be well-tolerated for one year after lacunar stroke. Researchers also analyzed safety and other outcomes, including recurrent stroke, cognitive impairment, dependency, mood and quality of life. This detailed information is needed for the next stage of research - a phase 3 trial, which would include more study participants. Results of the analysis on cognitive status at one year will be presented separately in the same Main Event session on Feb. 9.

From Feb. 2018 to May 2022, researchers enrolled 363 adults who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. The participants were average age 64 years, and 31% were women. All study participants continued to take their usual prescribed medications as per stroke guidelines, including those that reduce blood clotting, lower blood pressure and/or lower cholesterol — all of which may lower the risk of a second or recurrent stroke.

Participants were randomly assigned to one of four treatment groups: 40-60 mg/day of oral isosorbide mononitrate alone; 200 mg/day of oral cilostazol alone; both medications; or neither medication for one year. The participants completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke and heart problems, cognitive tests, symptoms, quality-of-life surveys, and had brain imaging at 12 months.

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The study met its initial goals to determine if a larger trial was feasible and if the medications were safe and tolerable. After one year, 358 of the adults were still participating in the study, with 95% of participants taking at least half of medication doses prescribed for the trial. Safety criteria were also met: four participants died; there were four episodes of bleeding outside of the brain; no excessive falls or dizziness. Some participants experienced mild symptoms (such as headaches), which were expected.

Researchers also saw some potential benefits from the medication groups, including data that indicated the group who took the combined isosorbide mononitrate and cilostazol had a reduction in the amount of assistance they needed with everyday living tasks, a reduction in cognitive impairment and positive impacts on mood and quality of life. Isosorbide mononitrate alone reduced recurrent stroke, cognitive impairment and improved quality of life; cilostazol alone reduced the need for daily assistance.

There appeared to be some potential benefits that will need to be confirmed in a larger phase 3 trial. We saw good hints of efficacy, particularly for isosorbide mononitrate on reducing recurrent stroke and cognitive impairment, and we also found that both medications together seemed to work synergistically, rather than counteracting any benefit. This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes. So, we cautiously hope that these medications may have wider implications for other types of small vessel disease."

Joanna M. Wardlaw, M.D., FAHA, lead study investigator

The study has some limitations, including that it was relatively small at 363 patients and not designed to measure efficacy, thus the results showing effectiveness should be interpreted cautiously. The trial was open label, meaning participants and clinicians were aware of which medication/s and doses they were taking; however, the follow-up staff for the study were unaware of which treatment the patients were assigned. Additionally, the investigators did not collect data on race or ethnicity, and many ethnic groups were suspected to be underrepresented.

Study co-lead author is Philip M. Bath, D.Sc., FAHA, UK Stroke Association Professor of Medicine at the University of Nottingham. The list of authors' disclosures is available in the abstract.

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer's Society, the U.K. Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland and the U.K. National Institutes of Health Research Clinical Research Networks. The work was conducted by the University of Edinburgh and the University of Nottingham.

Source:

American Heart Association

Familiar Drugs Get a Foot in the Door for Small Vessel Stroke Treatment

 So where is the protocol located so stroke patients can tell their stroke hospitals about it? I don't trust stroke hospitals to follow and implement research.

But this came out in May 2019 already! Did your incompetent hospital DO NOTHING WITH IT?

Cilostazol, Isosorbide Mononitrate Show Promise for Lacunar Stroke May 2019

 

Familiar Drugs Get a Foot in the Door for Small Vessel Stroke Treatment

Combined isosorbide mononitrate and cilostazol feasible, well tolerated in these patients

by Nicole Lou, Senior Staff Writer, MedPage Today February 9, 2023

DALLAS -- Drugs that improve endothelial function appeared promising for people with lacunar strokes resulting from small vessel disease (SVD), according to LACI-2 study findings that pave the way for a larger phase III trial.

Individuals taking isosorbide mononitrate and cilostazol together for a year following lacunar ischemic stroke had a significant reduction in the combined outcome of recurrent stroke, myocardial infarction, functional dependency, death, and cognitive impairment (48.6% vs 69.6% for controls not on either drug, adjusted HR 0.58, 95% CI 0.37-0.92).

While isosorbide mononitrate and cilostazol individually had no effect on the combined endpoint, isosorbide mononitrate in particular had a significant association with reduced recurrent strokes at 12 months (2.2% vs 8.3%, P=0.014), reported Joanna Wardlaw, MD, a neuroimaging specialist at the University of Edinburgh in Scotland, during the American Stroke Association's International Stroke Conferenceopens in a new tab or window (ISC).

What's more, safety events were rare in LACI-2. Extracranial hemorrhages were recorded in 1.1% of the cohort, intracranial hemorrhages in 0, and deaths in 1.1%. Moreover, there was no evidence of drug-drug interaction between isosorbide mononitrate and cilostazol.

Study findings suggest potential for a specific treatment for lacunar strokes, which account for up to a quarter of all ischemic stokes and are related to SVD of the brain. Affected patients are often left with cognitive impairment despite low dependency and stroke recurrence, according to Wardlaw.

Indeed, cognitive impairment was the major contributor to outcomes in the trial. As was the case with LACI-2's composite clinical result, only combination isosorbide mononitrate and cilostazol -- not either drug alone -- managed to reduce the risk of cognitive impairment, according to fellow LACI-2 investigator Philip Bath, DSc, a stroke specialist at the University of Nottingham in England.

"It is great to see that the combination treatment is safe and potentially effective ... It is exciting to see stroke prevention in small vessel disease moving forward," commented Shadi Yaghi, MD, a vascular neurologist at Brown University and Rhode Island Hospital in Providence, who was not involved with the study.

"It is difficult to draw conclusions, however, about the underlying pathophysiology of lacunar stroke based on the study, as cilostazol has also been suggested to be effective in patients with intracranial atherosclerosis as well," Yaghi cautioned in an email to MedPage Today.

It is believed that the intrinsic problem of lacunar strokes is tissue damage and impaired vasodilation in the small vessel endothelium. This is the rationale behind the hypothesis that endothelium-stabilizing drugs like isosorbide mononitrate and cilostazol might improve function and reduce damage.

Both drugs are widely available and inexpensive. Isosorbide mononitrate is a nitrate used to treat and prevent ischemic heart disease with no long-term data in stroke or cognition. Cilostazol is an antiplatelet and vasodilator preferred in Asia to prevent stroke.

Proving the benefit of the two agents will require a larger phase III trial. This LACI-3 trial is in preparation, Wardlaw told the ISC audience.

LACI-2 was conducted as a 2×2 factorial trial that had 363 adults randomized to one of four treatments for 1 year: 25-mg oral isosorbide mononitrate twice a day, 100-mg oral cilostazol twice a day, both medications, or neither medication. Doses were increased over 4 weeks to test tolerability.

Recruitment occurred at 26 stroke centers throughout the U.K. Eligible participants had a lacunar stroke and showed independent function. The cohort had a median age of 64 years, and approximately 31% were women. Groups were well balanced after randomization.

Nearly 90% of participants had a visible index infarct on imaging, the vast majority lacunar, with only 3% involving the middle cerebral artery or posterior cerebral artery.

Most patients were on antiplatelets (97%) and antihypertensives (76%) at baseline. Contraindications to either trial drug were noted in 12%.

LACI-2's overall results and cognition findings were consistent across prespecified subgroups.

The trial was nevertheless not powered for efficacy and subgroup analysis, and its data may be considered hypothesis-generating due to lack of adjustment for multiplicity. Other limitations included the open-label nature of the study and the issue of missing cognition data.

"We saw good hints of efficacy, particularly for isosorbide mononitrate on reducing recurrent stroke and cognitive impairment, and we also found that both medications together seemed to work synergistically, rather than counteracting any benefit," Wardlaw said.

"This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes. So, we cautiously hope that these medications may have wider implications for other types of small vessel disease," she added.

• 

  Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

Disclosures

The study was funded primarily by the British Heart Foundation, with support from the U.K. Alzheimer's Society, the U.K. Dementia Research Institute, the Stroke Association, the Leducq Foundation, NHS Research Scotland, and the U.K. National Institutes of Health Research Clinical Research Networks.

Wardlaw and Yaghi had no disclosures.

Bath reported ties to CoMind, DiaMedica, Phagenesis, and Roche.

Primary Source

International Stroke Conference

Source Reference: opens in a new tab or windowWardlaw JM, et al "Cilostazol, isosorbide mononitrate and their combination to prevent recurrence and dependency in patients with small vessel stroke: the Lacunar Intervention Trial-2 (LACI-2)" ISC 2023.

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Two cardiovascular medicines were well-tolerated for small vessel stroke

Is your doctor and stroke hospital going to ensure this gets further human testing? NO? Then you don't have a functioning stroke doctor or hospital. I'd suggest firing the whole lot, starting with the board of directors, the rot starts at the top. 

Two cardiovascular medicines were well-tolerated for small vessel stroke

American Stroke Association International Stroke Conference – Late-Breaking Science Presentations LB4 and LB12

Research Highlights:

• No standard medical therapy exists for a stroke occurring in a small vessel in the deep areas of the brain — called a lacunar stroke.
• A preliminary study of two common cardiovascular medications, cilostazol and isosorbide mononitrate, suggests these two medications were safe and well-tolerated by adults who have experienced small vessel stroke, when taken alone or together.
• A larger, more extensive study is planned to examine the effectiveness of the medications in treating the complications of small vessel stroke.

Embargoed until 11:40 a.m. CT/12:40 p.m. ET Thursday, Feb. 9, 2023

DALLAS, Feb. 9, 2023 — A study of two widely used cardiovascular medications — cilostazol and isosorbide mononitrate — in more than 350 patients confirmed the two medications were well-tolerated and safe for people who have experienced a stroke in a small blood vessel deep in the brain. The results suggest the medications may help improve patient outcomes, according to preliminary late-breaking science presented today at the American Stroke Association’s International Stroke Conference 2023. The meeting, held in person in Dallas and virtually Feb. 8-10, 2023, is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Small vessel disease of the brain accounts for about 20% -25% of all ischemic strokes, according to previous research. A lacunar stroke, or small vessel stroke, occurs when the inner lining of the tiny blood vessels inside the brain are damaged, leading to a stroke or dementia.

“Currently, there is no proven treatment to prevent poor outcomes after lacunar stroke, so the ultimate goal with this research is to evaluate if medications with potential modes of action on the inner lining of blood vessels might help improve small vessel function and prevent or slow long-term brain damage after lacunar stroke,” said lead study investigator Joanna M. Wardlaw, M.D., FAHA, professor of applied neuroimaging, honorary consultant neuroradiologist, head of neuroimaging sciences and the director of Edinburgh Imaging at Edinburgh University in Edinburgh, Scotland. She is also the foundation chair of the U.K. Dementia Research Institute.

The medications in the study are commonly prescribed for other cardiac conditions. Isosorbide mononitrate is used to treat chest pain by relaxing blood vessels and decreasing blood pressure. Cilostazol improves the flow of blood by relaxing the blood vessels and reducing blood clotting. It is often prescribed for people with peripheral artery disease — a narrowing of the peripheral arteries that carry blood away from the heart to other parts of the body.

This study, called LACunar Intervention Trial 2 (LACI-2), is the second largest ever trial in lacunar stroke. It examined whether such a trial was feasible among people with lacunar strokes and if the medications would be well-tolerated for one year after lacunar stroke. Researchers also analyzed safety and other outcomes, including recurrent stroke, cognitive impairment, dependency, mood and quality of life. This detailed information is needed for the next stage of research – a phase 3 trial, which would include more study participants. Results of the analysis on cognitive status at one year will be presented separately in the same Main Event session on Feb. 9.

From Feb. 2018 to May 2022, researchers enrolled 363 adults who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. The participants were average age 64 years, and 31% were women. All study participants continued to take their usual prescribed medications as per stroke guidelines, including those that reduce blood clotting, lower blood pressure and/or lower cholesterol — all of which may lower the risk of a second or recurrent stroke.

Participants were randomly assigned to one of four treatment groups: 40-60 mg/day of oral isosorbide mononitrate alone; 200 mg/day of oral cilostazol alone; both medications; or neither medication for one year. The participants completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke and heart problems, cognitive tests, symptoms, quality-of-life surveys, and had brain imaging at 12 months.

The study met its initial goals to determine if a larger trial was feasible and if the medications were safe and tolerable. After one year, 358 of the adults were still participating in the study, with 95% of participants taking at least half of medication doses prescribed for the trial. Safety criteria were also met: four participants died; there were four episodes of bleeding outside of the brain; no excessive falls or dizziness. Some participants experienced mild symptoms (such as headaches), which were expected.

Researchers also saw some potential benefits from the medication groups, including data that indicated the group who took the combined isosorbide mononitrate and cilostazol had a reduction in the amount of assistance they needed with everyday living tasks, a reduction in cognitive impairment and positive impacts on mood and quality of life. Isosorbide mononitrate alone reduced recurrent stroke, cognitive impairment and improved quality of life; cilostazol alone reduced the need for daily assistance.

“There appeared to be some potential benefits that will need to be confirmed in a larger phase 3 trial,” Wardlaw said. “We saw good hints of efficacy, particularly for isosorbide mononitrate on reducing recurrent stroke and cognitive impairment, and we also found that both medications together seemed to work synergistically, rather than counteracting any benefit. This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes. So, we cautiously hope that these medications may have wider implications for other types of small vessel disease.”

The study has some limitations, including that it was relatively small at 363 patients and not designed to measure efficacy, thus the results showing effectiveness should be interpreted cautiously. The trial was open label, meaning participants and clinicians were aware of which medication/s and doses they were taking; however, the follow-up staff for the study were unaware of which treatment the patients were assigned. Additionally, the investigators did not collect data on race or ethnicity, and many ethnic groups were suspected to be underrepresented.

Study co-lead author is Philip M. Bath, D.Sc., FAHA, UK Stroke Association Professor of Medicine at the University of Nottingham. The list of authors’ disclosures is available in the abstract.

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the U.K. Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland and the U.K. National Institutes of Health Research Clinical Research Networks. The work was conducted by the University of Edinburgh and the University of Nottingham.

Statements and conclusions of studies that are presented at the American Heart Association’s scientific meetings are solely those of the study authors and do not necessarily reflect the Association’s policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association’s scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

The Association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific Association programs and events. The Association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers and health insurance providers and the Association’s overall financial information are available here.

Additional Resources:

• Multimedia is available on the right column of release link https://newsroom.heart.org/news/two-cardiovascular-medicines-were-well-tolerated-for-small-vessel-stroke?preview=517678de4cc8e0163d68d15cafafce57
• AHA health information: Types of Heart Medications
• AHA News story: Having ideal heart health may lessen the risk for brain vessel disease (Aug. 2022)
• Research article published in the Journal of the American Heart Association: Small‐Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions (Feb. 2019)
• For more news at ASA International Stroke Conference 2022, follow us on Twitter @HeartNews #ISC23.

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Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials

So you found benefits. Where is the protocol located and what is your plan to deliver it to all stroke hospitals?

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials

Mojtaba Dayyani

,

Behnam Sadeghirad

,

James C. Grotta

,

Samira Zabihyan

,

Saba Ahmadvand

,

Yuting Wang

,

Gordon H. Guyatt

and

Sepideh Amin-Hanjani

Originally published31 Mar 2022https://doi.org/10.1161/STROKEAHA.121.035699Stroke. 2022;53:1993–2005

Abstract

Background:

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials.

Methods:

We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence.

Results:

We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53–1.00]; moderate certainty; absolute risk reduction (ARR), −3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07–1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14–12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22–0.68]; high certainty; ARR, −16.65%), nicardipine (OR, 0.48 [95% CI, 0.24–0.94]; moderate certainty; ARR, −13.70%), fasudil (OR, 0.55 [95% CI, 0.31–0.98]; moderate certainty; ARR, −11.54%), and magnesium (OR, 0.66 [95% CI, 0.46–0.94]; high certainty; ARR, −8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia.

Conclusions:

Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan.

Registration:

URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.

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Dual antiplatelet therapy with cilostazol in stroke patients with extracranial arterial stenosis or without arterial stenosis: a subgroup analysis of the CSPS.com trial

Can you at least write up a provisional protocol on this  and get it delivered to all stroke hospitals? YOUR RESPONSIBILITY  since we have fucking failures of stroke associations that do nothing for survivors.

Dual antiplatelet therapy with cilostazol in stroke patients with extracranial arterial stenosis or without arterial stenosis: a subgroup analysis of the CSPS.com trial

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Shinichiro Uchiyama, Kazunori Toyoda, Satomi Okamura, ...

First Published June 28, 2022 Research Article 

https://doi.org/10.1177/17474930221112343

Article information

Abstract

Background: 

We previously reported that dual antiplatelet therapy (DAPT) with cilostazol was superior to aspirin or clopidogrel for the prevention of recurrent stroke and vascular events in a subgroup analysis of intracranial arterial stenosis in the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com), a randomized controlled trial.

Aims: 

We conducted another subgroup analysis to investigate the benefit of DAPT with cilostazol in patients with extracranial arterial stenosis (ECAS) and those without arterial stenosis.

Methods: 

We compared the risk of recurrent ischemic stroke, vascular events, and major bleeding between DAPT with cilostazol plus aspirin or clopidogrel and aspirin or clopidogrel alone in patients with ischemic stroke between 8 and 180 days before starting trial treatment and extracranial arterial stenosis (ECAS) or without arterial stenosis.

Results: 

The median follow-up period was 1.4 years. The risk of recurrent ischemic stroke (hazard ratio [HR]; 1.04, 95% confidence interval [CI]; 0.42-2.57) and vascular events (HR; 0.97, 95% CI; 0.42-2.24) did not differ between the both groups for the 253 patients with ECAS, whereas they were lower (HR; 0.36, 95% CI; 0.18-0.74 and HR; 0.47, 95% CI; 0.26-0.85, respectively) in the DAPT group for the 944 patients without arterial stenosis. The risk of major bleeding did not differ between the groups in patients with ECAS (HR; 0.58, 95% CI; 0.05-6.39) or without arterial stenosis (HR; 0.79, 95% CI; 0.27-2.26).

Conclusions: 

DAPT with cilostazol might be beneficial for prevention of recurrent stroke and vascular events in patients without arterial stenosis but not in those with ECAS.

Keywords

Antiplatelet therapy, Clinical trial, Ischaemic stroke, Stenosis, Asia, Prevention

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Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trial

You better plan on not having this type of stroke, your stroke medical world seems to KNOW NOTHING CONCRETE on how to treat this. Better wait 50 years before you have this stroke.

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trial

Mojtaba Dayyani

,

Behnam Sadeghirad

,

James C. Grotta

,

Samira Zabihyan

,

Saba Ahmadvand

,

Yuting Wang

,

Gordon H. Guyatt

and

Sepideh Amin-Hanjani

Originally published31 Mar 2022https://doi.org/10.1161/STROKEAHA.121.035699Stroke. 2022;0:STROKEAHA.121.035699

Abstract

Background:

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials.

Methods:

We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence.

Results:

We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53–1.00]; moderate certainty; absolute risk reduction (ARR), −3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07–1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14–12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22–0.68]; high certainty; ARR, −16.65%), nicardipine (OR, 0.48 [95% CI, 0.24–0.94]; moderate certainty; ARR, −13.70%), fasudil (OR, 0.55 [95% CI, 0.31–0.98]; moderate certainty; ARR, −11.54%), and magnesium (OR, 0.66 [95% CI, 0.46–0.94]; high certainty; ARR, −8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia.

Conclusions:

Nimodipine and cilostazol are likely(So you don't know for sure. JUST FUCKING SAY YOU KNOW N OTHING!) the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan.

REGISTRATION:

URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.

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Delayed treatment with cilostazol key to preventing stroke recurrence

Is your hospital implementing this?

Delayed treatment with cilostazol key to preventing stroke recurrence

By Robert Herpen, MA

Source/Disclosures

ADD TOPIC TO EMAIL ALERTS

Commencing long-term dual antiplatelet therapy with cilostazol no less than 15 days after stroke proved to be a stronger method of secondary stroke prevention than standard monotherapy, according to study results published in Neurology.

“Early initiation of dual antiplatelet therapy (DAPT), within 30 days of stroke, using ticagrelor and aspirin, compared to aspirin alone, was proven to decrease the risk of the composite of stroke or death, but this combination increased severe bleeding,” Kazunori Toyoda, MD, PhD, of the department of cerebrovascular medicine at the National Cerebral and Cardiovascular Center in Japan, and colleagues wrote. “In addition, the effect at the second month or later has not been explored.”

Source: Adobe Stock

Seeking to determine whether recurrent ischemic stroke risk was affected by the timing of dual medication vs. monotherapy administration after stroke onset, researchers conducted a subanalysis of a randomized controlled trial, in which 1,879 patients between 8 and 180 days after stroke onset received either aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. The participants were divided into three groups, based on the initiation of trial treatment after stroke onset: 498 started either dual therapy or monotherapy between 8 and 14 days (8-14D), 467 between 15 and 28 days (15-28D) and 914 between 29 and 180 days (29-180D). The primary outcome for treatment was initial recurrence of ischemic stroke, with severe or life-threatening bleeding a secondary outcome.

The investigation revealed that dual therapy significantly reduced recurrence of ischemic stroke compared with monotherapy in both the 15-28D group (annualized rate 1.5% vs. 4.9%, respectively; aHR = 0.34; 95% CI, 0.12-0.95) and the 29-180D group (1.9% vs. 4.4%; aHR = 0.27; 95% CI, 0.12-0.63), but recurrence was roughly equal among the 8-14D group (4.5% for both; aHR = 1.02; 95% CI, 0.51-2.04).

Further, researchers found that incidence of severe or life-threatening bleeding was comparable between dual therapy and monotherapy participants across all three randomized groups.

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“Long-term DAPT using cilostazol was more effective for secondary prevention of non-cardioembolic stroke than monotherapy in high-risk patients who started the medication 15 days or later after stroke onset without increasing hemorrhage risk,” Toyoda and colleagues wrote. “The finding suggests the feasibility of a seamless DAPT strategy after stroke, switching from (aspirin + clopidogrel) in the acute to subacute stage to (cilostazol + aspirin) or (cilostazol + clopidogrel) at 15 days or later. Clinical studies to prove this strategy would be needed.”

 

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial

Is this enough to get written in a protocol and distributed to all stroke hospitals? Or will it fall by the wayside since we have fucking failures of stroke associations  doing nothing to get research into the real world? And once again waste time and money?

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial

Haruhiko Hoshino

,

Kazunori Toyoda

,

Katsuhiro Omae

,

Noriyuki Ishida

,

Shinichiro Uchiyama

,

Kazumi Kimura

,

Nobuyuki Sakai

,

Yasushi Okada

,

Kortaro Tanaka

,

Hideki Origasa

,

Hiroaki Naritomi

, … See all authors

Originally published18 Aug 2021https://doi.org/10.1161/STROKEAHA.121.034378Stroke. ;0:STROKEAHA.121.034378

Abstract

Background and Purpose:

Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified.

Methods:

In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents.

Results:

A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258–0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206–2.588]).

Conclusions:

The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients.

REGISTRATION:

URL: http://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

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Cilostazol for secondary stroke prevention: systematic review and meta-analysis

Did your doctor do ANYTHING AT ALL with these earlier pieces of research on Cilostazol including one on cognitive improvement?  Or is your doctor DOING NOTHING to recover your 5 lost years of brain cognition from your stroke?

• cilostazol (8 posts to August 2013)

 The latest here:

Cilostazol for secondary stroke prevention: systematic review and meta-analysiss

1. Choon Han Tan1,
2. Andrew GR Wu2,
3. http://orcid.org/0000-0002-2764-2869Ching-Hui Sia3,
4. http://orcid.org/0000-0003-3659-1650Aloysius ST Leow4,
5. Bernard PL Chan4,
6. http://orcid.org/0000-0002-8976-5696Vijay Kumar Sharma2,4,
7. http://orcid.org/0000-0002-4249-0402Leonard LL Yeo2,4,
8. http://orcid.org/0000-0003-1824-9077Benjamin YQ Tan2,4

1. Department of Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3. Department of Cardiology, National University Heart Centre, Singapore
4. Division of Neurology, Department of Medicine, National University Health System, Singapore

1. Correspondence to Dr Leonard LL Yeo; leonard_ll_yeo@nuhs.edu.sg

 

Author affiliations

1. Department of Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3. Department of Cardiology, National University Heart Centre, Singapore
4. Division of Neurology, Department of Medicine, National University Health System, Singapore

1. Correspondence to Dr Leonard LL Yeo; leonard_ll_yeo@nuhs.edu.sg

 

Abstract

Background Stroke is one of the leading causes of death worldwide. Cilostazol, an antiplatelet and phosphodiesterase 3 inhibitor, has not been clearly established for ischaemic stroke use. We aim to determine the efficacy and safety of cilostazol for secondary stroke prevention.

Methods MEDLINE, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov were searched from inception to 25 September 2020, for randomised trials comparing the efficacy and safety of cilostazol monotherapy or dual therapy with another antiplatelet regimen or placebo, in patients with ischaemic stroke. Version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to assess study quality. This meta-analysis was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results Eighteen randomised trials comprising 11 429 participants were included in this meta-analysis. Most trials possessed low risk of bias and were of low heterogeneity. Cilostazol significantly reduced the rate of ischaemic stroke recurrence (risk ratio, RR=0.69, 95% CI 0.58 to 0.81), any stroke recurrence (RR=0.64, 95% CI 0.54 to 0.74) and major adverse cardiovascular events (RR=0.67, 95% CI 0.56 to 0.81). Cilostazol did not significantly decrease mortality (RR=0.90, 95% CI 0.64 to 1.25) or increase the rate of good functional outcome (Modified Rankin Scale score of 0–1; RR=1.07, 95% CI 0.95 to 1.19). Cilostazol demonstrated favourable safety profile, significantly reducing the risk of intracranial haemorrhage (RR=0.46, 95% CI 0.31 to 0.68) and major haemorrhagic events (RR=0.49, 95% CI 0.34 to 0.70).

Conclusions Cilostazol demonstrated superior efficacy and safety profiles compared with traditional antiplatelet regimens such as aspirin and clopidogrel for secondary stroke prevention but does not appear to affect functional outcomes.(You mean you missed the earlier research I referred to?) Future randomised trials can be conducted outside East Asia, or compare cilostazol with a wider range of antiplatelet agents.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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http://dx.doi.org/10.1136/svn-2020-000737