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All ASPIRIN SUMMARIES

ISSUE Conference 2022 Session 2

Conference 2022 : Session 2 : The place of aspirin in Neurology

Table of Contents

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The place of aspirin in Neurology
Chairpersons Pierre Amarenco (France) and Mathias Endres (Germany)

The place of aspirin in Neurology: Treatment vs Prevention
Peter Rothwell (UK)

Aspirin has been of interest and use in a number of neurological conditions, these are summarised in the article below where aspirin has a clear role in stroke, TIA and migraine prevention but has not been shown to be of benefit in depression, dementia, Parkinson’s disease or motor neurone disease.

In early data from Sir Richard Doll’s British Doctor aspirin cardiovascular (CVD) trial in the 1970s it was observed that daily aspirin reduced the frequency of seeking medical attention for migraine by around 30% in the aspirin versus control group. Aspirin has been found to work well at both low and high doses in migraine prevention an important indication in neurology.

Hippocrates recognised that the early signs seen in what we now call a TIA were warnings of a full stroke.

‘Unaccustomed attacks of numbness and anaesthesia are signs of impending apoplexy’ Hippocrates circa 400 BC

It was years later, in 1951, that Charles Miller Fisher termed these early warnings as a transient ischemic attack (TIA) and described their likely thrombotic aetiology. The Express1 and SOS TIA2 studies led by Peter Rothwell and Pierre Amarenco’s teams in the UK and France found an 80% reduction in the risk of recurrent stroke if aspirin is given acutely.

Despite public education programmes people can still be slow to seek medical attention for TIAs. Aspirin is recommended in UK guidelines and is something that first point of contact health care providers can give or recommend6,7. This is supported in online advice to the general public8.

Offer aspirin (300 mg daily), unless contraindicated, to people who have had a suspected TIA, to be started immediately.’ NICE NG 128 2019

Dr Lawrence Craven, California was the first to note that aspirin reduced MI and also proposed that it might prevent ‘little strokes’ in the 1950s 4,5. Years later the FDA approved aspirin to reduce the risk of stroke after TIA in men in 1980 and post MI in 1985.

In a time-course analysis looking at the effects of aspirin on both the risk and severity of early recurrent stroke after a TIA or ischemic stroke the greater benefit is seen in the first six weeks with less of an impact after 12 weeks3. Low-dose aspirin still works in the long term and analysis of the data if censored at the withdrawal of allocated treatment does show the effect of aspirin use long term. The time course event analysis shows that compliance with therapy is a major issue with the long-term efficacy of aspirin and in both cardiology and neurology this appears to be due to compliance with the drug rather than biology. There are major problems interpreting primary prevention trials due to adherence issues. It takes a lot of motivation to continue over 7-8 years taking a daily medicine when you are unsure if this is the active drug or placebo. It may be that people will adhere better in the real world when they know they are on an active medication shown to prevent disease. There may also be more benefits if primary CVD prevention medications such as aspirin are used at a younger age than currently seen in the clinical trials. Further work from the Antithrombotic Trialist (ATT) collaboration is expected.

When to take low-dose aspirin for stroke prevention is of interest. The risk of stroke increases in the late morning and reduces by late afternoon. Should aspirin be taken in the morning? Blood pressure medication trials have had mixed results and currently there is no data on when the best time might be to take aspirin or how this might impact on other regular medication.

In other areas of neurology, the ASPREE9 trial showed no benefit for aspirin in dementia, and there is no hint from RCTs of an effect with Parkinson’s disease or motor neurone disease. There is no confirmation from trial work that aspirin is helpful in depression. The ASPREE trial looked at depression and found no evidence of an effect of aspirin on incidence of depression in people that didn’t have a history of depression at baseline and no evidence of any benefit in terms of recurrent depression or worsening depression in people that were depressed at baseline.

In summary, neurologists commonly use aspirin for treating migraine. Aspirin is important in the acute phase of a stroke or TIA and should continue in the longer term for the secondary prevention of stroke. There may be a role for aspirin in primary stroke prevention, but current thinking is that it might need to be started at a younger age with good long-term adherence.

Importantly, in routine practice patients adhere to treatment regimens better than in trials, this is because they are on active treatment, with evidence that the drug works and they are motivated to comply with long term therapy.

References

  1. Rothwell PM, Giles MF, Chandratheva A et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet. 2007. 370(9596), 1432-1442
  2. Lavallée PC, Meseguer E, Abboud H et al. A transient ischaemic attack clinic with round-the-clock assess (SOS- TIA):feasibility and effects. Lancet Neurol. 2007 6(11):953-60
  3. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management NICE guideline [NG128]Published: 01 May 2019 Last updated: 13 April 2022
    https://www.nice.org.uk/guidance/ng128/chapter/recommendations
  4. Australian Stroke Foundation Guidelines (downloaded 8/10/2020) https://informme.org.au/en/Guidelines/Clinical-Guidelines-for-Stroke-Management
  5. Transient Ischemic Attack https://www.nhs.uk/conditions/transient-ischaemic-attack-tia/
  6. Craven LL, Ann West Med Surg 1950;4:95-99
  7. Craven LL, M.Valley Med J 1953;75:38-44
  8. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet. 2016 Jul 23;388(10042):365-375. doi: 10.1016/S0140-6736(16)30468-8. Epub 2016 May 18. PMID: 27209146; PMCID: PMC5321490.
  9. Ryan J, Storey E, Murray AM, Woods RL, Wolfe R, Reid CM, Nelson MR, Chong TTJ, Williamson JD, Ward SA, Lockery JE, Orchard SG, Trevaks R, Kirpach B, Newman AB, Ernst ME, McNeil JJ, Shah RC; ASPREE Investigator Group. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology. 2020 Jul 21;95(3):e320-e331. doi: 10.1212/WNL.0000000000009277. Epub 2020 Mar 25. PMID: 32213642; PMCID: PMC745535

Round Table Discussion

Professors’ Scott Kasner (USA), Lawrence Wong (Hong Kong), Peter Rothwell (UK), Pierre Amarenco (France), Mathias Endres (Germany), Carlo Patrono (Italy), Bianca Rocca (Italy) and Dr John Chia (Singapore).

The discussion covered aspirin’s current place in neurology versus cardiology and summarised data for aspirin versus newer drugs but concluded there is no clear evidence or consensus for replacing aspirin in its current position in the guidance.

The advice to take aspirin before assessment in TIA was debated due to the small risk that intercranial bleeding may have caused the event. This risk is very small (less than 1%) and therefore overall, the risk versus benefit of lives saved from taking aspirin immediately is in favour of a benefit. However, immediate aspirin use before brain imaging diagnoses the cause of the stroke is a challenging message to give and is not without some controversy. Where possible using clinical judgement to assess risk factors can be helpful in deciding whether to give aspirin before imaging.
The Chinese Aspirin trial and a recent meta-analysis showed a clear aspirin benefit and as result it is widely used in China and across Asia. This population is also more at risk from haemorrhage and the side effects of aspirin but overall, the balance is in favour of a benefit. There is also more clopidogrel resistance in Asia with about half the population carrying the resistant gene mutation.
The best dosing regimen is still not fully resolved, this in part can be driven by BMI where at higher BMIs a more rapid platelet turnover is observed. Twice daily dosing is one solution in, for example, men with a higher body weight where aspirin is less effective. However, more evidence is needed to be able to offer clear guidance in this area. Weight based dosing is commonly used in paediatrics and it is interesting to explore this area in adults.

 

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Djp

Daniel José Piñeiro

ASSOCIATE
Name
Daniel José Piñeiro
Academic Affiliations:
Full Professor of Medicine, Universidad de Buenos Aires, Argentina Trustee, Board of Trustees, American College of Cardiology
Professional Setting:
My academic experience includes more than 40 years as a practicing medical doctor, teacher, and researcher. I have fulfilled these appointments in settings of vital social engagement and impact, most notably at the Hospital de Clínicas “José de San Martín” of the Universidad de Buenos Aires, a public hospital with high academic recognition. Additionally, I currently hold the position of Full Professor of Medicine at that same University.
Academic Activities:
  • International Meetings Participations: 180
  • Books-Editor: 1
  • Books Chapters: 39
  • Refereed Full Articles: 118 (listed in Pubmed: 29)
  • Refereed Abstracts: 221
  • Editorial Boards: 10
Profesional Associations:
  • 2005 President, Sociedad Argentina de Cardiología.
  • 2011-2013 President, Inter-American Society of Cardiology.
  • 2011-2013 Member (ex-officio), Board of Directors, World Heart Federation
  • 2017-2018 Member (at large), Board of Directors, World Heart Federation
  • 2018-2021 Trustee, Board of Trustees, American College of Cardiology
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Chia

John Chia

Name
John Chia MBBS (Spore), MRCP (UK), FAMS (Spore)
Academic Affiliations:

Adjunct Associate Professor DUKE-NUS Graduate Medical School,
Consultant Oncologist Curie Oncology Singapore,
Visiting Consultant National Cancer Centre Singapore.

Discipline:

Medical Oncology

Scientific Interests:
  • Aspirin as adjuvant therapy in established cancers
  • Adoptive T cell therapy and Dendritic cell vaccines in the treatment of solid tumors
  • Clinical Trial Design and Management
Declaration of Conflicts of Interest:

In the past 3 years, I have received consultant fees from Tessa Therapeutics, Aslan Pharmaceuticals, Novartis, and AstraZeneca.

I received grant support for investigator-initiated research from:

  • National Medical Research Council Singapore
  • Bayer AG

I hold shares in:  Roche, BMS, AstraZeneca, Incyte, Teva Pharmaceuticals, Trillium Therapeutics, Compugen, Arrowhead pharmaceuticals, Emergex, QuantumDx and Halozyme Therapeutics

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Badimon

Lina Badimon

Name
Lina Badimon BSc, PharmD, PhD, FESC, FAHA
Academic Affiliations:
Director of the Cardiovascular Science Program (ICCC) at the Hospital Santa Creu and San Pau, IIB-Sant Pau; CIBER CV. Director of the Cardiovascular Research Chair of the Autonomous University of Barcelona and Director of the UNESCO Chair in Biomedical Sciences Training and Research.
Discipline:
Pharmacology, Cardiovascular Disease
Scientific Interests:
Cardio-metabolic diseases, thrombosis, atherosclerosis and ischemic heart disease
Declaration of Conflicts of Interest:

I received consultant and speakers fees from Amgen, AstraZeneca, Bayer, Lilly and Sanofi.

    Return to Scientific Advisory Board
    Ge

    Junbo Ge

    Name

    Junbo Ge

    Ge Junbo, male, was born in Wulian, Shandong province on Nov. 8, 1962. He is the member of Chinese Academy of Sciences, professor and doctoral supervisor. He received his doctor’s degree of Medicine from German Mayence University in 1993 and now works as the director for Shanghai Institute of Cardiovascular Disease and the Center for Stem Cells and Tissue Engineering, Fudan University. He is also the designate chairman of the Cardiovascular Disease Branch of Chinese Medical Association, council member of the Cardiovascular Angiography and Interventions Association, international consultant of the American Heart Association. In Dec. 2013, he was appointed as the vice president of Tongji University.

    Prof. Ge has been engaged in clinical and scientific research work of cardiovascular disease since 1987, and his research area covers the pathogenesis of coronary heart disease, early diagnosis and treatment plan optimization.

    Return to Scientific Advisory Board
    Langley

    Ruth Langley

    Name
    Ruth Langley PhD, FRCP
    Academic Affiliations:
    Professor of Oncology and Clinical Trials, MRC Programme Leader and Chair of the Cancer Group, MRC Clinical Trials Unit at UCL, honorary consultant in medical oncology at the Brighton and Sussex University Hospital.
    Discipline:
    Medical oncologist; trialist
    Scientific Interests:
    • Aspirin
    • Gastro-oesophageal malignancy
    • Transdermal oestrogen in the treatment of prostate cancer
    • Trials methodology
    Declaration of Conflicts of Interest:
    Has received honorarium from Bayer
    Return to Scientific Advisory Board
    Chan

    Andrew T Chan

    Name
    Andrew T. Chan MD, MPH
    Academic Affiliations:
    Chief, Clinical and Translational Epidemiology Unit, Vice Chair, Division of Gastroenterology, Massachusetts General Hospital, Boston, Co-leader, Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston.
    Discipline:
    Gastroenterology
    Scientific Interests:
    • The role of aspirin in the prevention of colorectal cancer and other cancers
    • The role of the gut microbiome in colorectal cancer and other chronic gastrointestinal diseases, including inflammatory bowel disease and diverticulitis
    • The role of diet and lifestyle in colorectal cancer and other chronic gastrointestinal cancers
    Declaration of Conflicts of Interest:

    AACR Honors Dr. Andrew T. Chan With 2019 AACR-Waun Ki Hong Award

    Click here to find the press release.

    I received consultant Bayer and Pfizer, Inc.

    I received grant support for investigator-initiated research from:

    • National Institutes of Health
    • National Cancer Institute
    • Crohn’s and Colitis Foundation
    • Bayer AG
    Return to Scientific Advisory Board
    Gaziano

    Mike Gaziano

    Name
    J Michael Gaziano MD, MPH
    Academic Affiliations:

    Professor of Medicine, Harvard Medical School; Chief Division of Aging, Brigham and Women’s Hospital; Director of Preventive Cardiology and Director of Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System.
    Discipline: Cardiology and Epidemiology

    Scientific Interests:
    I am a chronic disease epidemiologist with a particular interest in the roles that individual lifestyle choices (diet, exercise, smoking), metabolic factors (obesity, high cholesterol, and hypertension), and biochemical and genetic markers play on the risk of cardiovascular disease and other chronic illnesses. Also, of interest is the impact that vascular disease has on other organ systems, including cognitive dysfunction and renal disease. I have an interest in the design of large-scale trials and observational studies nested in large health care systems using big data analytic techniques.
    Declaration of Conflicts of Interest:

    I received consultant and speaker fees Bayer.

    I received grant support as a principal investigator or co-investigator for research from the VA, DOD, NIH, Merck and Kowa.

    Return to Scientific Advisory Board
    Rothwell

    Peter Rothwell

    PAST – CHAIR
    Name

    Peter M. Rothwell PhD, MD, FRCP, FMedSci

    Academic Affiliations:
    • Action Research Chair of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford;
    • Founding Director, Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford;
    • Wellcome Trust Senior Investigator;
    • Emeritus NIHR Senior Investigator;
    • Theme Leader, Stroke and Vascular Dementia, NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford
    Discipline:
    Neurology and Stroke Medicine
    Scientific Interests:
    • Risks and benefits of aspirin;
    • Primary and secondary prevention of stroke;
    • Effects of blood pressure on the brain.
    Declaration of Conflicts of Interest:
    I received consultant and speakers fees from Bayer AG.
    CarloPatrono

    Carlo Patrono

    CHAIR
    Name
    Carlo Patrono MD, FESC, FRCP
    Academic Affiliations:
    Adjunct Professor of Pharmacology at the Catholic University School of Medicine in Rome (Italy) and at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia (USA).
    Discipline:
    Clinical Pharmacology
    Scientific Interests:
    • Studying platelet activation and inhibition in diabetes mellitus
    • Studying platelet activation and inhibition in myeloproliferative neoplasms
    • Investigating the mechanism of action of low-dose aspirin in preventing colorectal cancer
    Declaration of Conflicts of Interest:

    I received consultant and speakers fees from Acticor Biotech,  Amgen,  Bayer, GlaxoSmithKline,  Tremeau,  Zambon.

    I received grant support for investigator-initiated research from:

    • AIFA (Italian Drug Agency)
    • Bayer AG
    • Cancer Research UK
    • European Commission, FP6 and FP7 Programmes

      Return to Scientific Advisory Board

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