The Origin and Role of Thromboembolism in the Pathogenesis of Ischaemic Stroke (TORPIS)

May 15, 2024 updated by: University of Edinburgh
Ischaemic stroke is usually due to occlusion of a cerebral artery by thrombus. However, it is often difficult to identify the source of thrombus, or to confirm thrombus as a cause of ischaemic stroke. Moreover, it is debated whether thrombosis plays any role in certain types of stroke such as lacunar stroke. In preliminary studies, the investigators have evaluated a novel clinical grade thrombus-specific radiotracer, 18F-GP1, which has a high specificity for the glycoprotein IIb/IIIa receptor on activated platelets. The investigations have demonstrated that 18F-GP1 is highly sensitive to in vivo thrombus formation and demonstrates avid binding to thrombus associated with myocardial infarction, pulmonary embolism and aortic bioprosthesis. This study will use this imaging approach to define the role and origin of thrombus in patients with ischaemic stroke, cryptogenic stroke and lacunar stroke.The investigators will also assess its added clinical value in assessing patients with ischaemic stroke.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Stroke remains the second leading cause of death and the commonest cause of dependency in adults worldwide. The majority of strokes (80%) are due to cerebral ischaemia with a minority caused by subarachnoid (5%) or intracerebral (15%) haemorrhage.

Some stroke classification systems are based on the presumed mechanism, such as the Trial of Org 10172 in Acute Stroke Treatment (TOAST), the Causative Classification System (CCS) and the Atherosclerosis Small Vessel Disease Cardiac Source Other cause Dissection (ASCOD) classifications. These systems assign individual patients to cardioembolic, atherothromboembolic, lacunar (due to intrinsic disease of the cerebral perforating arterioles), other, or uncertain causes of stroke. However, a substantial proportion of patients (up to 25%) remain in the 'undetermined' category, because they have several potential overlapping causes, are incompletely investigated or are 'cryptogenic' where no cause has been identified.

Cryptogenic Stroke:

Cryptogenic stroke may have an embolic origin, supported by a pattern of brain infarction typically seen in patients with a definite embolic source: mainly cortical and affecting multiple vascular territories. In a systematic review, 1 in 6 ischaemic strokes were cryptogenic (~17%; range 9 to 25%) and in the Oxford Vascular Study of 2555 patients with a first ischaemic stroke, 1 in 3 were cryptogenic. Unfortunately, these patients have a high risk of recurrent ischaemic stroke (~25% at 5 years) that is comparable to those with known causes of stroke, indicating the need for better understanding and treatment of cryptogenic stroke. Two large randomised controlled trials compared direct oral anticoagulant therapies with aspirin to prevent stroke recurrence in patients with cortical cryptogenic strokes, testing the hypothesis that many of these strokes were due to an unidentified cardioembolic source (particularly paroxysmal atrial fibrillation). However, anticoagulant therapies were not superior to aspirin in preventing recurrent stroke and carried an increased risk of bleeding. Thus, the optimal preventative strategy in patients with cryptogenic stroke remains open for further exploration, and likely requires better patient stratification (i.e. selecting out those with occult thromboembolism) and understanding of its pathogenesis.

Lacunar Stroke:

As well as the uncertainty existing around causes and management of cryptogenic stroke, the aetiology and best management remains poorly understood in another common and important subtype of stroke, lacunar stroke. Lacunar stroke accounts for 25% of all ischaemic strokes and most haemorrhagic strokes in patients aged over 65 years, but the understanding of its pathophysiology remains limited. Epidemiological studies indicate that emboli are uncommon in lacunar ischaemic stroke. While it is physically possible for emboli to enter the lenticulostriate arteries, laboratory studies suggest that this is infrequent. Some larger lacunar infarcts in the basal ganglia may be due to atheromatous occlusion of a lenticulostriate artery or an embolus entering a lenticulostriate artery from the middle cerebral artery. However, in the few studies where embolic sources were actively sought, the percentage of patients with lacunar stroke and a source of emboli was only 11%. Cryptogenic stroke definitions sometimes exclude patients with brain imaging showing lacunar (small subcortical) infarctions, but this means that embolic sources may be missed through presumed non-embolic causes of lacunar stroke. Given that management of cardioembolic stroke is quite different to that for atherothromboembolic stroke and that intrinsic small vessel disease appears to need an alternative management strategy, there is an urgent unmet clinical need to determine the actual underlying cause of an ischaemic stroke in many patients.

Determining Stroke Aetiology and Treatment:

The mechanisms underlying ischaemic stroke can be divided into cardio-embolic (including paradoxical embolism, such as deep vein thromboses crossing patent foramen ovale), artery-to-artery atherothrombotic embolism, extra- or intra-cranial large artery atherosclerosis with acute superimposed occlusion, intrinsic small vessel disease (lacunar) and arterial inflammation.

Following acute stroke, patients undergo diagnostic brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). CT or MRI angiography may identify a point of medium to large arterial obstruction or atheromatous ipsilateral carotid stenosis as a likely source of embolism, but they are commonly unable to show small emboli or to visualise directly the origin of the thromboembolus. Patients will also undergo clinical investigations to identify potential causes of stroke including blood pressure measurement, clinical biochemistry, electrocardiogram, echocardiography, and carotid and vertebral artery imaging to identify treatable symptomatic carotid stenosis or other pathologies such as dissection, usually with Doppler ultrasound, CT or MRI angiography or prolonged electrocardiogram monitoring. In younger patients (<65 years) or where other aetiologies are suspected, additional investigations may include genetic or metabolic screens and echocardiography. Most patients will be commenced on lifelong anti-platelet, statin and antihypertensive therapies. If atrial fibrillation or flutter is detected, they will be considered for anticoagulant treatment with direct oral anticoagulants or warfarin therapy. Patients thought likely to have an embolic stroke but in whom no embolic or other relevant source is found, are considered at this point to have cryptogenic stroke, and currently, they receive the same treatment as for non-cardioembolic stroke. Given their high risk of stroke recurrence, it raises the question as to whether a new imaging technique could identify stroke aetiology and the origin of thromboembolism, thereby improving patient management.

Positron emission tomography and computed tomography:

Positron emission tomography combined with CT (PET-CT) fuses anatomical with functional imaging which can be tailored to a specific disease process depending on which radiotracer is used. Recently, the investigators have used the tracer 18F-sodium fluoride to study microcalcification in a range of cardiovascular disease processes, successfully highlighting disease activity in coronary artery plaque, carotid artery plaque, abdominal aortic aneurysms and calcific aortic stenosis. However, such techniques can be applied to other pathophysiological processes depending on the properties of the radiotracer. The great strength of PET is its exquisite sensitivity and ability to detect even small areas of disease activity.

Platelet Biology and 18F-GP1:

The activation and deposition of platelets are major contributors to human thrombus formation, especially in the arterial circulation. The glycoprotein IIb/IIIa receptor is expressed on activated platelets and is key in the fibrin-crosslinking process of platelet aggregation. It is also the target for anti-platelet therapy used in routine clinical practice for high-risk percutaneous coronary intervention. The thrombus tracer, 18F-GP1, is a derivative of elarofiban and has a high and specific binding affinity for the activated glycoprotein IIb/IIIa receptor. In studies of Cynomolgus monkeys, 18F-GP1 binds to acute venous and arterial thrombi. It has recently undergone preliminary human clinical studies confirming it is a highly sensitive method of identifying in vivo arterial and venous thrombosis. The investigators have undertaken preliminary studies using 18F-GP1 and have demonstrated that it has excellent in vivo binding properties which enable detection of intravascular thrombosis in a range of conditions including left ventricular thrombus following myocardial infarction, pulmonary thromboembolism, deep vein thrombosis and coronary thrombosis.

Study Aims:

The aims of this project are to establish the contribution of activated platelets to the mechanism of various subcategories of ischaemic stroke. The investigators will establish the frequency and distribution of activated platelets in thromboemboli of patients with ischaemic stroke including those with cryptogenic stroke and lacunar stroke. This will inform the pathophysiology and mechanism of stroke subtypes and establish sources and origins of platelet activation.

Research Hypothesis:

In patients with ischaemic stroke, the investigators hypothesise that non-invasive 18F-GP1 imaging will:

  1. Identify the origin and contribution of activated platelets to thromboembolism in patients with ischaemic stroke.
  2. Establish the frequency and distribution of activated platelets in subtypes of ischaemic strokes.
  3. Have the potential to influence management of patients with stroke.

Rationale for Study:

  1. Origin and source of thromboembolism: To date, some techniques and clinical assessments make assumptions about the source of thromboemboli. Moreover, an important proportion of patients have no clear source of embolism or cause for their stroke. For example, strokes that occur patients in atrial fibrillation are often assumed to have thrombus from the atrial appendage or a valve. However, it is unknown whether this is the situation in all cases and what is the contribution of activated platelets to thromboembolic events.
  2. Cerebrovascular thrombosis in cryptogenic and lacunar strokes:In a substantial percentage of acute strokes, there is real uncertainty regarding the presence or contribution of activated platelets and thrombosis to cerebral infarction. This is the case for patients with cryptogenic stroke and especially for lacunar stroke. Indeed, there is debate regarding the contribution of activated platelets and embolic or in situ thrombus (the latter might be an endstage event on a damaged arteriolar endothelium) to lacunar strokes and this has been hard to resolve because of the difficulties of visualising activated platelets and thrombus at multiple locations with current non- invasive image techniques. This study will assess patients with cryptogenic and lacunar strokes to establish the evidence of whether activated platelets and thrombosis plays a role, and if so, in what proportion of patients this occurs and whether there are any dominant associated clinical features.

Study Type

Observational

Enrollment (Estimated)

120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United Kingdom
      • Edinburgh, United Kingdom
        • Recruiting
        • Clinical Research Facility
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

120 patients following acute ischaemic stroke

Description

Inclusion Criteria:

  • Males and females ≥18 years old
  • Diagnoses of acute ischaemic stroke (within 21 days of symptom onset) as per American Heart and Stroke Association guidelines

Exclusion Criteria:

  • Inability or unwillingness to provide informed written consent (ie lack capacity)
  • Inability to undergo the scanning protocol including ability to transfer onto the scanner
  • Women of child- bearing potential in whom pregnancy cannot be excluded
  • Contraindication to PET-CT scanning including estimated glomerular filtration rate <30 mL/min/1.73 m2
  • Participation in the study would result in a delay to carotid endarterectomy surgery
  • Known allergy to iodinated contrast or radiotracer
  • Severe or significant comorbidity precluding ability to complete study procedures.
  • Haemorrhagic stroke
  • Contra-indication to Magnetic Resonance imaging for those patients requiring a MRI Head

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Ischaemic Stroke
Diagnostic test: 18F-GP1 PET/CT
Patient will receive 1 18F-GP1 PET/CT
Diagnostic test: Agitated Contrast Echocardiogram
Agitated saline and ultrasound contrast will be performed to assess for intracardiac shunts and left ventricular thrombus.
Diagnostic test: MRI Head
Where necessary, if the CT head is normal or the clinical diagnosis of a stroke is not definite, a research MRI head will be undertaken if this has not already been performed as part of standard care.
Diagnostic test: ECG Monitoring
All patients who do not have evidence of atrial fibrillation or atrial flutter on their 12-lead ECG will undergo an ECG Holter monitor for up to 7 days. This will be part of their standard care. If this has not been arranged by the usual care team this will be performed as a research procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary outcome measure will be the degree and location of platelet activation as determined by the target to background ratio of 18F-GP1.
Time Frame: < 21 days
< 21 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Measuring the presence of platelet activation in cardio-embolic, artery to artery and in situ arterial thrombosis.
Time Frame: < 21 days
< 21 days
Identifying the presence and site of platelet activation in cryptogenic and lacunar strokes.
Time Frame: < 21 days
< 21 days
Identifying sites of platelet activation in patients with atrial fibrillation or atrial flutter.
Time Frame: < 21 days
< 21 days
Correlation and comparison between platelet activation with excised carotid atheroma in patients referred for carotid endarterectomy.
Time Frame: < 21 days
< 21 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Edinburgh

Collaborators

British Heart Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 28, 2023

Primary Completion (Estimated)

August 1, 2024

Study Completion (Estimated)

August 1, 2025

Study Registration Dates

First Submitted

November 23, 2022

First Submitted That Met QC Criteria

November 23, 2022

First Posted (Actual)

December 5, 2022

Study Record Updates

Last Update Posted (Estimated)

May 16, 2024

Last Update Submitted That Met QC Criteria

May 15, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AC21130

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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