Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05769894 |
| Other study ID # |
RHMCAR0622 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2023 |
| Est. completion date |
August 1, 2024 |
Study information
| Verified date |
March 2023 |
| Source |
University Hospital Southampton NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Non-cardiac acute and chronic inflammatory conditions are associated with high risk of acute
myocardial infarction.
Specifically, there are reports of high prevalence of AMI and cardiac death in chronic
conditions such as Rheumatoid arthritis, chronic gum disease, psoriasis and Chronic airway
disease. Furthermore, there are intriguing temporal links between acute non-cardiac
conditions, including fractured neck of femur and admission for chest infection in the
elderly and subsequent risk of AMI within the next few weeks. Finally, a more recent
association has been reported between COVID vaccination and acute thrombotic events.
In Summary, a link between acute non-cardiac inflammatory conditions and subsequent AMI in a
near term envelope is established, but unexplained, and circumstantial evidence so far
suggests a possible mechanism in terms of dynamic alteration in platelet reactivity. It is
this concept we wish to explore further in the proposed set of experiments.
Our experiments may provide some insight into a potential mechanism of such an association,
which could have implications for future tailored therapeutic interventions.
We will recruit 5 groups of patients, consistent with the data produced previously and the
literature regarding disease models of non-cardiac inflammations. Aiming to recruit 20
patients per group with 100 candidates in total. Groups including:
1. Fracture neck of femur.
2. Patients >70 years age admitted with chest infection.
3. Healthy volunteers receiving fourth COVID booster vaccine.
4. Patients admitted with AMI within 6 weeks of (fractured neck of femur, chest infection
Rheumatoid arthritis flare up, exacerbation of psoriasis and exacerbation of
inflammatory bowel disease).
5. AMI secondary to stent thrombosis.
Study will be undertaken within the Cardiothoracic unit at University Hospital Southampton,
the sponsor will be UHS Research and Development Department, UHS.
Description:
BACKGROUND
Inflammation and Platelets
Cardiovascular disease (CVD) is the leading cause of death worldwide. Specifically, acute
myocardial infarction (AMI) and acute ischaemic stroke are common causes of morbidity and
mortality and are responsible for substantial healthcare costs. Whilst the underlying
pathophysiology of atherosclerosis is now better understood as a chronic inflammatory
process, the exact precipitants for the acute inflammation responsible for the acute event
are still not fully explained. It has become clear that platelets play a key role in the
pathophysiology of both atheroma formation and acute thrombus formation in AMI and stroke.
Specifically, platelet activation is an integral component of initiation and amplification of
the local vascular inflammatory response in these conditions. It is for this reason that
routine antiplatelet therapy represents a mainstay of treatment for patients with coronary
atheroma and especially for those treated with intracoronary stents.
Evidence for inter- and intra-individual variability in response to antiplatelets: dynamic
reactivity
However, previous work from our group and others indicates that the response of individuals
to both aspirin and P2Y12 inhibitors is idiosyncratic, so that some individuals may be
relatively resistant to aspirin as well as clopidogrel, prasugrel and ticagrelor.
Specifically, we have previously shown that patients on P2Y12 inhibitors for coronary stents
with high on treatment platelet reactivity have elevated risk of stent thrombosis , and that
individual responses can be modified using tailored therapy. Furthermore, our group has
previously shown that the response to both aspirin and P2Y12 inhibitors is dynamic. Thus,
there is a rebound Adenosine Diphosphate (ADP) response after clopidogrel is withdrawn in
patients with drug-eluting stents. With regard to aspirin responses, we have reported that
the response to arachidonic acid stimulation is variable within individuals, has some
interaction with P2Y12 inhibitors, and that there appears to be a cyclo-oxygenase-dependent
and -independent pathway for AA-induced platelet activity. Our previous data also suggest
that the most commonly used near patient VerifyNow platelet test overestimates the response
of patients to clopidogrel.
The WEST Group: Novel Assessments of Platelet Priming & Reactivity- Biomarkers of Individual
Thrombotic Risk?
The research group led by Dr West has developed novel techniques for using (a) droplet
microfluidics to assess hyper-reactivity of isolated platelets and (b) apply advanced
single-platelet RNA sequencing methods to define an RNA signature for priming. These
techniques have been subject to initial validation and show great promise as candidate
biomarkers for predicting individual susceptibility to platelet-mediated thrombotic events
such as acute myocardial infarction (AMI). For full background and previous data see
Appendix.
This methodology is therefore complementary to our Thromboelastography (TEG)based assessment
of platelet reactivity phenotype variability: we can validate the candidacy of the West
method as biomarkers of thrombotic risk in these experiments.
Justification for our research question
For many reasons, no attempt is made in routine clinical practice to measure either the
specific response of individuals to their antiplatelet drugs or the status of a patient's
platelet reactivity at any moment in time. The development of tests that allowed both of
these measurements to be made routinely could plausibly facilitate personalised detection and
modification of high risk of bleeding or thrombotic events. The dynamic nature of an
individual's platelet reactivity, and the possible contribution to acute thrombotic events is
the focus for this series of experiments. Whilst it is not yet clear how the acute plaque
erosion or rupture that precipitates AMI is initiated, the link to an acute inflammatory
episode is apparent. Furthermore, an association has been demonstrated, described in detail
below, between a number of non-cardiac acute and chronic inflammatory conditions, and
subsequent risk of AMI. Specifically, there are reports of high prevalence of AMI and cardiac
death in chronic conditions such as rheumatoid disease, chronic gum disease, psoriasis,
chronic airways disease. Furthermore, as described below, there are intriguing temporal links
reported between acute non-cardiac conditions, including fractured neck of femur and
admission for chest infection in the elderly, and subsequent risk of AMI within the next few
weeks. Finally, a more recent association has been reported between COVID vaccination and
acute thrombotic events.
It is plausible that the "non-cardiac" inflammatory condition and/or event is, in actual
fact, part of a disease process that incorporates dynamic changes in the arterial vascular
bed and platelet reactivity, thereby providing the substrate for acute MI.
.
THEORETICAL FRAMEWORK Non-cardiac Inflammatory Conditions and Acute MI: known associations.
CVD and chest infection:
The annual incidence of community-acquired pneumonia (CAP) is 0.5-1% in United Kingdom,
22-42% of which requires hospitalization. The mortality rate of hospitalised patients with
CAP is 5-14%, with higher mortality rates among elderly patients older than 84 years old
(>50%).
Community acquired pneumonia is associated with raised inflammatory markers including CRP
(>21.9 mg/dl), Pro-calcitonin and IL-6 (>169 pg/ml), with higher levels predicting treatment
failure and mortality.
Furthermore, raised inflammatory markers were detected (CRP, TNF-alpha) in patients with
viral upper respiratory tract infections.
Acute respiratory tract infection is associated with increased risk of acute myocardial
infarction. Specifically, the first 28 days following respiratory tract infection, carries
higher risk of cardiovascular events. In a case series study of 53709 patients with first or
recurrent myocardial infarction, significant rise in MI incidence was noticed following acute
respiratory tract infection with the highest rates being 3 days post infection.
Of interest, high on Treatment Platelet Reactivity was detected in patients with viral upper
respiratory tract infection.
Studies assessing the link between MI and respiratory tract infection were mostly based on
assessing GP records and questionnaires (history taking). Measuring levels of inflammatory
markers during episodes of respiratory tract infection leading to MI was not tested.
Fractured Neck of Femur:
Hip fracture in the elderly population represents a substantial clinical and financial burden
on our healthcare system, with high rates of morbidity and mortality. The mortality rate is
9% at 30 days post hip fracture and 33% at 1 year. A common complication of hip fractures is
perioperative myocardial infarction. In one study, a Troponin rise was detected in 35.5% of
patients and non-ST elevation Myocardial Infarction (NSTEMI) was more common than ST
Elevation Myocardial Infarction (STEMI) in this cohort of patients. (23 vs 7) A significant
troponin rise is a strong predictor of mortality in this patient group: a level above 0.04
μg/l is linked with six-fold risk of death. Highest troponin rise was specifically detected
in the fourth post-operative day in the mortality group, compared to no significant rise in
the alive group, with overall 1 year mortality detected in 37% of patients associated with
Peri-operative troponin rise. 27,28 The mechanism behind the increased rate of myocardial
infarction is not clear from current literature, but the suspicion is that there is a link to
systemic inflammation induced by the fracture. There are weak data that some such patients
may be hyporesponders to clopidogrel.
Rheumatoid arthritis flare up:
Rheumatoid arthritis (RA) affects approximately 1% of the adult western population. It is
considered an independent risk factor for ischemic heart disease, with increased mortality
due to accelerated coronary artery atherosclerosis.For example, rheumatoid arthritis was
associated with a 38% increased incidence of myocardial Infarction compared to the general
population in one series. The well described inflammatory process inherent to RA flare up,
and the link to enhanced platelet reactivity, has been shown in a small study. Specifically,
increased platelet reactivity to ADP only was noted in rheumatoid active group.
Major vascular surgery:
The Southampton group has previously described dynamic variability in platelet reactivity
using TEG. Specifically, using TEG AUC 15 to assess 40 participants undergoing elective major
vascular surgery (MVS) on aspirin, The investigators described a reduction in AA- and
ADP-induced clotting in association with the acute vascular inflammatory reaction to surgery,
with rebound reactivity (i.e., higher than baseline) at 3 months post op. The dynamic nature
of these changes in platelet reactivity lends circumstantial support to the concept that this
could play a role in pathological ischaemic events in susceptible individuals.
COVID vaccine:
The coronavirus disease 19 (COVID-19) pandemic has caused over 5 million deaths across the
globe since 2019. COVID-19 infection is associated in some cases with thrombocytopenia due to
platelet consumption, Disseminated Intravascular Coagulopathy (DIC) and thrombotic
microangiopathy.
COVID-19 vaccines were approved in late 2020, with 5 billion individuals vaccinated so far.
Increasing data have shown rare links between vaccines and thrombotic complications including
cerebral sinus thrombosis and myocardial infarction. This may be related to the
well-established systemic inflammatory reaction induced by the vaccine. Vaccine-induced
immune thrombosis and thrombocytopenia (VITT) was identified in a small group of vaccinated
individuals. In the few cases of acute coronary syndrome (ACS) post COVID-19 vaccination a
cause-effect relation was not definitively established.
In summary, a link between acute non-cardiac inflammatory conditions and subsequent AMI in a
near term envelope is established, but unexplained, and circumstantial evidence so far
suggests a possible mechanism in terms of dynamic alteration in platelet reactivity. It is
this concept that we wish to explore further in the proposed set of experiments.
RESEARCH QUESTION/AIM(S)
This study aims to assess the association between non-cardiac inflammatory conditions
involving a vascular inflammatory reaction and dynamic platelet reactivity as determined
using TEG6s device and two novel techniques for using (a) droplet microfluidics to assess
hyper-reactivity of isolated platelets and (b) apply advanced single-platelet RNA sequencing
methods to define an RNA signature for priming.
If our hypothesis is proven, our study will have demonstrated an association between (a) the
presence, and possibly extent of, a dynamic change in individual platelet reactivity and
blood clotting and (b) the concurrent vascular inflammatory status in a variety of
non-cardiac inflammatory conditions.
Summary of study design:
- Suitable candidates meeting the eligibility criteria for participation in the study will
be identified and approached by our research team during their hospital stay or
vaccination hub visit (for COVID booster candidates).
- A member of the research team will explain the aim of the study, benefits, risks, and
burdens with the potential participant. Candidates will be given sufficient time to
decide if they would like to participate in the study.
- A written informed consent will be explained and signed by the candidate.
- First blood sample will be taken following consent, with further blood samples at 24,
48, 72 hours then 1 week or 1 month later depending on the group.
- All blood samples will be analysed as follows (i) After 30 mins of sampling, for
platelet reactivity testing using the TEG 6s device, (ii) Single platelet/microfluidics
analysis and (iii) Further samples will be sent for inflammatory markers testing.
- Participation in the study and follow up will end after the final follow up visit when
final blood samples are collected.
- Data will be pseudonymised and analysed before being submitted to a peer-review journal.
The investigators will recruit 5 groups of patients, consistent with the data produced
previously and the literature regarding disease models of non-cardiac inflammation. Details
of blood testing and general inclusion and exclusion are summarised below.
In all cases, blood sampling will be for both assessment of platelet reactivity using TEG6S
and for blood inflammatory markers (CRP, IL6, TNF alpha and CD40)
1. Group 1: Fractured neck of femur (n=20). Trauma and Orthopaedics wards and the Emergency
department will be screened for new admissions with fractured neck of femur proven by
X-ray on admission, thereby identifying 20 participants according to eligibility
criteria.
Suitable patients will be approached about the study and given an information sheet.
Later, when they have had enough time to consider, they will be enrolled if they are
happy to provide written informed consent.
Blood samples will be taken on the ward on admission, 24, 48 and 72 hours from admission
and at 1 month.
Blood will be collected in 4 tubes on each occasion. (1 x2ml 3.2% sodium citrate
vacutainer, 1 x 6ml lithium heparin vacutainer. 2 x 5ml SST tubes for Inflammatory
markers.) A detailed description of this is laid out below.
2. Group 2: Patients > 70 years age admitted with chest infection (n=20).
The Emergency department, Acute Medical Unit and medical wards will be screened for
eligible participants whose primary diagnosis is chest infection (Acute bronchitis or
Pneumonia). Aiming to recruit 20 participants.
Acute Bronchitis is a lower respiratory tract infection causing inflammation in the
bronchial airways It is a clinical diagnosis characterised by a cough with no evidence
of pneumonia. The chest X-ray can be normal.
Pneumonia is an infection of the lung tissue in which the air sacs in the lungs become
filled with microorganisms, fluid and inflammatory cells, affecting the function of the
lungs. 39 Patients will be selected according to symptoms, clinical diagnosis +/- Chest
X-ray findings (Pneumonia only).
Suitable patients will be approached about the study and given an information sheet.
Later, when they have had enough time to consider, they will be enrolled if they are
happy to provide written informed consent.
Blood samples will be taken on the ward on admission, 24, 48 and 72 hours from admission
and at 1 month.
Blood will be collected in 4 tubes on each occasion. (1 x 2ml 3.2% sodium citrate
vacutainer, 1 x 6ml lithium heparin vacutainer. 2 x 5ml SST tubes for Inflammatory
markers.) A detailed description of this is laid out below.
3. Group 3: Healthy volunteers receiving a COVID Booster vaccine. (n=20). Aiming to recruit
20 participants due to have a COVID vaccine at Southampton General Hospital. We are
aiming to recruit 20 healthy volunteers meeting the criteria as per study eligibility.
Information sheet will be given to participant and they will have sufficient time to
consider participating or not in the study.
Blood samples will be taken directly after injection of COVID booster dose. Participants
will be invited to attend 24-, 48-, and 1-week post booster injection to our research
office on Cath lab day unit for blood sampling.
Blood will be collected in 4 tubes on each occasion. 1x 2ml 3.2% sodium citrate
vacutainer, 1 x 6ml lithium heparin vacutainer. 2 x 5ml SST tubes for Inflammatory
markers.
4. Group 4: Patients admitted with AMI within 6 weeks of:
1. Fractured neck of femur
2. Chest Infection
3. Rheumatoid arthritis flare up
4. Exacerbation of psoriasis
5. Exacerbation of inflammatory bowel disease
Screening will include patients admitted with Type 1 or Type 2 MI or myocardial injury,
as defined by the 4th Universal Definition, if they are within 6 weeks of one of the
inflammatory conditions listed above.40 Suitable patients will be approached about the
study and given an information sheet. Later, when they have had enough time to consider,
they will be enrolled if they are happy to provide written informed consent.
Blood samples will be taken on the ward on admission, 24, 48 and 72 hours from admission
and at 1 month.
Blood will be collected in 4 tubes on each occasion. (1 x 2ml 3.2% sodium citrate
vacutainer, 1 x 6ml lithium heparin vacutainer. 2 x 5ml SST tubes for Inflammatory
markers.) A detailed description of this is laid out below.
5. Group 5: AMI secondary to stent thrombosis (n=20).
Eligible patients will have been admitted with definite stent thrombosis according to the
Academic Research Consortium definition. 41 Stent thrombosis is a complete occlusion of the
artery secondary to thrombus inside the stent. ARC (Academic research consortium) has
identified stent thrombosis detected by angiography as Definite stent thrombosis (ST). They
also categorised stent thrombosis as early (up to 30 days from deployment), or late (30 days
to 12 months from deployment).
Suitable patients will be approached about the study and given an information sheet. Later,
when they have had enough time to consider, they will be enrolled if they are happy to
provide written informed consent.
Blood samples will be taken on the ward on admission, 24, 48 and 72 hours from admission and
at 1 month.
Blood will be collected in 4 tubes on each occasion. (1 x 2ml 3.2% sodium citrate vacutainer,
1 x 6ml lithium heparin vacutainer. 2 x 5ml SST tubes for Inflammatory markers.) A detailed
description of this is laid out below.
