PROTECT-U: Prospective Randomized Open-label Trial to Evaluate risk factor management in patients with Unruptured intracranial aneurysms. Feb 24th, 2021

Dp1

Mervyn Vergouwen, MD PhD, stroke neurologist
University Medical Center Utrecht, Utrecht, The Netherlands
Email: m.d.i.vergouwen@umcutrecht.nl

The PROTECT-U trial is a randomized controlled trial that investigates if a treatment strategy, consisting of aspirin in combination with intensive blood pressure treatment, decreases the risk of growth or rupture of an intracranial aneurysm. The trial is currently recruiting patients in Germany and the Netherlands, and will soon start patient recruitment in Canada and Finland as well. Currently (February 2021), 211 patients have been
included. We aim to include 776 patients and are looking for additional funding to successfully complete the trial. The study protocol has been published,1 and more detailed information can be found at www.protect-u-trial.com. Below, we give a short synopsis of the trial.

 

Background:
The prevalence of unruptured intracranial aneurysms (UIAs) in adults is 3%, which means that in Europe more than 2 million persons have an UIA.2 Most UIAs are detected incidentally, for example if head imaging is performed because of headache or trauma. UIAs can remain clinically silent or grow, during which they are at increased risk of rupture, or immediately rupture without growth. Aneurysm rupture results in subarachnoid hemorrhage (SAH). The prognosis of this type of stroke is poor: 40% dies within three months after the bleeding and most survivors have long-term disability or cognitive impairment.

In UIA patients, preventive neurosurgical or endovascular treatment is an effective means to eliminate the risk of aneurysmal SAH and hereby increase the number of life years with high quality of life. However, both treatment modalities carry a 5-8% risk of serious treatment complications.3

The risk of rupture can be estimated based on patient-related and aneurysm-related risk factors.4 In many UIA patients, the risk of treatment complications does not outweigh the risk of rupture. These patients presently remain untreated. Apart from smoking, the most important modifiable risk factors in the pathogenesis of aneurysm growth and rupture are hypertension and aneurysm wall inflammation.4,5,6 Thus, pharmaceutical strategies which target these modifiable risk factors of UIA growth and rupture especially for low-risk UIAs could be an appealing and novel treatment option.

Rationale for the PROTECT-U trial:
Despite numerous studies on the importance of these risk factors, to date no randomized controlled trial targeting their modification has been initiated for UIA patients. A randomized, open-label trial on intensive versus standard blood pressure (BP) reduction (targeted systolic BP <120mmHg versus systolic BP <140mmHg, respectively) in a total of 9,361 patients at increased risk for cardiovascular disease was stopped prematurely at 3.3 years of median follow-up because of a lower incidence of the primary outcome event (myocardial infarction, other coronary syndromes, stroke or death from other cardiovascular causes) in the intensive treatment group (1.65% versus 2.19% per year, hazard ratio 0.75%; 95% CI 0.64-0.89), without an effect on overall incidence of adverse events (Level IB evidence).7 It remains unclear if a lower blood pressure target in patients with an UIA decreases the risk of growth and rupture.

The relevance of aneurysm wall inflammation in the pathogenesis of aneurysm rupture has been underlined by data on the protective effect of acetylsalicylic acid (ASA, Aspirin) on the anti-inflammatory effect on aneurysm wall inflammation and thus protective effect on aneurysm rupture in a nested case-control study of UIA patients.5,6 In a cohort of 1,691 UIA patients, those treated with ASA for other indications had lower odds for UIA rupture in the multivariable analysis (OR 0.27; 95% CI 0.27-0.67) (Level IIB evidence).6 A small phase I trial randomizing patients to ASA treatment or treatment as usual showed a reduction of radiological and histological aneurysm wall inflammation as surrogates for rupture (Level IIb evidence).5 In case aneurysm rupture occurs during ASA treatment, ASA use is not associated with more severe hemorrhage or worse outcomes.

In view of the similarity of risk factors between UIAs and cardiovascular diseases, there is strong a rationale to investigate the beneficial effect of intensive BP treatment and ASA on aneurysm growth or rupture. Because the short-term risk of rupture is rather low in patients with small aneurysms, a randomized trial with rupture as the main primary outcome measure is unfeasible. We therefore combined aneurysm rupture with aneurysm growth as the primary endpoint, since UIA growth occurs more often and is an established surrogate for aneurysm rupture (Level II a evidence).8

Primary aim of the PROTECT-U trial:
To assess the hypothesis that an intervention with acetylsalicylic acid (100 mg/day) in combination with intensive blood pressure treatment (targeted systolic blood pressure below 120 mm Hg, monitored with a blood pressure measuring device) reduces the risk of intracranial aneurysm rupture or growth, compared with standard care (i.e. no acetylsalicylic acid, blood pressure management according to guidelines which usually advise treatment if systolic blood pressure exceeds 140 mm Hg, no blood pressure measuring device).

Study design:
The PROTECT-U trial has a PROBE design (prospective, randomized, open-label trial with blinded outcome assessment). Inclusion criteria are: 1) Patient with an intradural, saccular unruptured aneurysm in whom it is decided not to intervene with preventive endovascular or neurosurgical repair of the aneurysm and who are monitored on a regular basis for aneurysm growth; 2) 18 years or older; 3) Last aneurysm imaging with either CTA/MRA/DSA within the last 3 months. The primary endpoint is aneurysm rupture or growth (increase in any aneurysm diameter by ≥1mm) on serial imaging (either two MR or CT angiographies) at 3 years follow-up.

References:

  1. Vergouwen MDI, et al. Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol. Int J Stroke. 2018;13:992-998.
  2. Vlak MH, et al. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: A systematic review and meta-analysis. Lancet Neurol. 2011;10:626-636.
  3. Algra AM, et al. Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis. JAMA Neurol. 2019;76:282-293.
  4. Greving JP, et al. Development of the phases score for prediction of risk of rupture of intracranial aneurysms: A pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13:59-66.
  5. Hasan DM, et al. Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: Preliminary results. J Am Heart Assoc. 2013;2:e000019.
  6. Hasan DM, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke; a journal of cerebral circulation. 2011;42:3156-3162.
  7. Group SR, et al. A randomized trial of intensive versus standard blood-pressure control. The New England journal of medicine. 2015;373:2103-2116.
  8. Dasenbrock HH, et al. The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage: A nationwide inpatient sample analysis. J Neurosurg. 2016:1-11.
  9. Backes D, et al. Phases score for prediction of intracranial aneurysm growth. Stroke; a journal of cerebral circulation. 2015;46:1221-1226.

 

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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.

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    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.

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    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
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    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
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    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.

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    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.
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    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

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