Study of the Vascular Response to Percutaneous Coronary Intervention in Patients With Non-ST-elevation Acute Coronary Syndromes Using Intravascular Blood Sampling

Study of the Vascular Response to Percutaneous Coronary Intervention in Patients With Non-ST-elevation Acute Coronary Syndromes Using Intravascular Blood Sampling

This interventional study is using the PlaqueTec LBS will enrol participants already undergoing coronary angiography as a component of their standard care for NSTE-ACS. The study will involve no change to medication or overall treatment strategy, but will involve an additional procedure: use of a novel CE-marked coronary artery catheter to obtain spatially-separated intravascular samples for laboratory measurement. As a safety objective and as a component of the required post-marketing surveillance, OCT will be performed before and after deployment of the LBS, and patients will be followed up for a significant period of time by the investigator's post-procedure.

Individual participants will not gain directly from taking part in the study, other than having access to more prolonged follow up than is standard. However, new insights will be gained into the microenvironment surrounding a ruptured plaque in NSTE-ACS, which has the potential to benefit patients with CAD in the future through greater understanding of the effects of current therapy, development of new treatment strategies and methods of assessing the efficacy of those treatment strategies.

Use of the LBS and the associated OCT examinations will require additional angiographic screening and therefore lead to greater exposure to radiation and higher contrast load. This will be closely monitored as per Trust policies in line with IRMER and local radiological guidelines. Patients at particular risk of developing complications from increased exposure to radiation and contrast (eg. those who are pregnant and those with abnormal baseline renal function) will not be included in order to minimise adverse effects.

This clinical protocol will be subject to peer review according to standard local procedures, including independent scientific review by the Scientific Advisory Board of the Clinical Research Facility, Sheffield Teaching Hospitals NHS Foundation Trust; the Clinical Research Office, Sheffield Teaching Hospitals NHS Foundation Trust; and the Research Ethics Committee. The study will be a single-centre study including use of a CE-marked medical device to obtain samples, conducted at Cardiology and Cardiothoracic Surgery Directorate, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust.

Patients with a diagnosis of NSTE-ACS, receiving DAPT with a combination of aspirin and ticagrelor or prasugrel, and listed either for coronary angiography with the intention of proceeding to PCI or for PCI following coronary angiography at a referring hospital, will be approached and their informed consent sought for this study. 18 patients found to have culprit significant proximal epicardial coronary artery stenosis suitable for PCI, meeting all the inclusion and exclusion criteria, will proceed to have platelet function testing and LBS measurements. Blood will be taken from the arterial sheath or guide catheter and baseline platelet function testing will be performed (VerifyNow P2Y12 assay; light transmittance aggregometry with ADP and arachidonic acid as agonists; and serum thromboxane B2 assay). Balloon predilatation prior to stent deployment will be a mandatory requirement for the study. Following balloon predilatation, the LBS will be deployed across the treated lesion and blood sampling will be performed proximal and distal to the lesion at approximately 5 minutes after predilatation. The following assays will be performed on the sampled blood:

1. Plasma levels of soluble markers of thrombosis and inflammation including prothrombin fragments 1 and 2, fibrinopeptide A, soluble P-selectin and thromboxane B2.
2. Platelet surface P-selectin expression
3. Leukocyte surface CD11b expression Blood taken prior to PCI will also be sent to the local laboratory for measurement of the cardiac-specific marker high-sensitivity troponin T and a further venous blood sample will be collected at 6 hours after PCI to measure any rise in troponin in order to correlate this with thrombin generation. A rise of 5 times the upper limit of normal of troponin following PCI in the context of chest pain or diagnostic ECG changes will be used to define peri-procedural myocardial infarction per the Universal Definition of Myocardial Infarction (Thygesen, Alpert et al. 2012).

OCT of the culprit lesion, as well as the coronary artery proximal and distal to this, will be performed before and after the deployment of the LBS to assess any topographical changes to the vessel wall caused by the LBS and provide information on target lesion morphology.

Clinical outcomes will be reviewed and AEs (including MACE) will be recorded at 6 hours, 30 days and 6 months after the procedure. At the 6-hour visit, patients will be assessed by a medically-qualified investigator and have a blood sample collected for troponin T level and ECG performed. At the 30-day visit, patients will receive a full clinical assessment by a medically-qualified investigator, have DAPT compliance assessed, be asked about angina intensity, have any MACE or other AEs recorded and have an ECG. A telephone contact will be made at 6 months after PCI to assess any MACE or other AEs, angina intensity and DAPT compliance.

Inclusion Criteria:

• Aged over 18 years
• Admitted to hospital with non-ST-elevation ACS and plan for either coronary angiography with a view to PCI if appropriate or PCI following coronary angiography at a referring hospital
• Current treatment with aspirin and ticagrelor or, if ticagrelor is not tolerated, prasugrel (DAPT)
• Ability to give informed consent

Exclusion Criteria:

• Treatment with antiplatelet medication apart from aspirin, ticagrelor, prasugrel or clopidogrel in the last 10 days (e.g. dipyridamole, abciximab, tirofiban).
• Planned use of a glycoprotein IIb/IIIa antagonist for the PCI procedure.
• Patients with haemodynamic instability, shock or angiographic evidence of intracoronary thrombus.
• Current use of an oral anticoagulant (e.g. warfarin, dabigatran, rivaroxaban, apixaban).
• Clinically significant liver disease.
• Contraindication or allergy to unfractionated heparin.
• Receiving immunosuppressant medication (eg. cyclosporin, tacrolimus, mycophenolate, azathioprine).
• Administration of doses of low molecular weight heparin or fondaparinux in the 12 hours preceding PCI.
• Known severe left ventricular dysfunction (ejection fraction <30%).
• Culprit lesion in left main coronary artery.
• Women of childbearing potential unless pregnancy has been excluded during the index hospital admission.
• Known serum creatinine above upper limit of local reference range.
• Subjects with known active chronic inflammatory disease, e.g. systemic lupus erythematosus, rheumatoid arthritis, seropositive arthropathies and known seropositivity to HIV, Hepatitis B or Hepatitis C.
• Severely diseased, excessively tortuous or calcified coronary vessels that increase the risk of snaring the LBS.
• Culprit lesion in a coronary vessel with a reference diameter of less than 2.5 mm.
• Need to cross a region of coronary vessel that contains a stent.
• Evidence of ongoing sepsis.
• Receiving a non-steroidal anti-inflammatory drug (NSAID) apart from aspirin, including selective COX2 inhibitors ('coxibs') and including regular or intermittent/as required use.
• Receiving a strong inhibitor of CYP3A4 (eg, ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, or over 1 litre daily of grapefruit juice).
• Receiving simvastatin or lovastatin at doses higher than 40 mg daily.
• Receiving a CYP3A substrate with a narrow therapeutic index (e.g. cyclosporine or quinidine).
• Receiving a strong inducer of CYP3A (e.g. rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital).
• Current or recent (within 30 days) participation in a clinical trial of a drug or device or any other clinical study that might influence the results or safety of the study.
• Any factor precluding ability to comply with follow-up.
• Any other factor judged by the investigator or treating physician to preclude enrolment in the study.