WILL lOWer Dose Aspirin be Better With Rivaroxaban in Patients With Chronic Coronary Syndromes?

Characterisation of a Novel Regimen of Very Low-dose Aspirin Combined With Rivaroxaban in Patients With Chronic Coronary Syndromes: WILL lOWer Dose Aspirin be Better With Rivaroxaban in Patients With Chronic Coronary Syndromes?

The trial is a pharmacodynamic study to determine the effect of a novel regimen of aspirin 20 mg BD plus rivaroxaban 2.5 mg BD on haemostasis, fibrin clot dynamics, inflammatory markers, platelet function and arachidonic acid metabolites when compared to standard regimens of aspirin 75 mg OD and aspirin 75 mg OD plus rivaroxaban 2.5 mg BD.

In a randomised open-label three-period crossover design, patient participants receiving aspirin 75 mg OD for secondary prevention of IHD will be randomised 1:1 to receive one of two sequences of aspirin: aspirin 75 mg OD, then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD, then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD; or aspirin 75 mg OD, then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD, then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD.

At the end of each 14(-2) day medication period, they will attend a study visit at which blood and urine samples will be obtained, and bleeding time measured, before and 2 hours after the last dose of IMP of the treatment period. The samples will be tested for fibrin clot dynamics; inflammatory markers and cytokines; prostanoids; and platelet function.

Participants will be transitioned back to standard-of-care aspirin 75 mg OD at the end of the third treatment period and followed up by telephone call 14(-2) days later.

Recruitment Potential participants will be identified through review of the records of the South Yorkshire Cardiothoracic Centre and/or by referral by their clinical team.

Specifically, participants may be approached in the following ways:

1. An invitation letter sent by post in combination with a copy of the participant information sheet. There will be a reply slip which they can return by post, and there will be contact details (telephone and email) for the research team to allow them to respond by these methods too.

2. Directly by telephone. In this case, should they be happy to learn more, they will be sent a copy of the invitation letter, participant information sheet and reply slip by post or email, depending on their preference. If they agree to attend for study screening, they will communicate this to the research team by returning the reply slip by post or email, or by contacting the research team directly using the contact details provided to them.

3. Directly in clinics within the Cardiology and Cardiothoracic Surgery Directorate at Sheffield Teaching Hospitals NHS Foundation Trust, upon referral from their clinical team. In this case they will be provided with a copy of the participant information sheet and, if unable to decide whether they wish to attend for screening or not during the clinic visit, will be signposted to the contact details of the research team to provide their response.

   Potential participants who are interested in taking part in the study will then be contacted by the research team to book a screening appointment.

   Screening

   Screening will occur at visit 1. The following study procedures will be performed, after obtaining written consent for the study:

   • Medical history
   • Physical examination
   • Collection of demographic data
   • Vital signs (pulse, blood pressure and temperature).
   • Height, weight and BMI
   • Recording of any concomitant medication
   • Safety blood tests (13.5 ml blood sample for haematology, clinical chemistry and coagulation)
   • Urinalysis (dipstick), plus urinary pregnancy test if female and of childbearing potential. This will also be checked immediately prior to first rivaroxaban exposure at visit 3.
   • Baseline electrocardiogram

   Consent Written, informed consent, using the current version of the approved designated form for this study, will be obtained prior to any study procedures being carried out. This will be explained and obtained by a medically-qualified member of the research team, listed on the delegation log. Participants will have the chance to read the ICF/PIS for as long as they need, and will be able to ask any questions, prior to signing. Minors and those judged to be without the mental capacity to provide informed consent will not be enrolled into the study.

   Participants will remain free to withdraw at any time from the trial, without giving reasons and without prejudicing his/her further treatment, and will be provided with a contact point where he/she may obtain further information about the trial. Samples collected up to the point of withdrawal will only be used after withdrawal if the participant consents for this, otherwise they will be destroyed. However, data collected up to that point will be used for analysis, and this will be explicitly stated in the participant information sheet and consent form.

   The randomisation scheme

   Participants will be randomised to one of the following two treatment sequences, in a 1:1 fashion:

   (A) Aspirin 75 mg OD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD or (B) Aspirin 75 mg OD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD

   Baseline data At visit 1

   • Medical history
   • Physical examination
   • Demographic data
   • Vital signs (pulse, blood pressure and temperature)
   • Weight and BMI
   • Concomitant medication
   • Lab safety parameters (full blood count, urea & electrolytes, liver function tests, clotting screen, dipstick urinalysis, urinary pregnancy test if female and of childbearing potential)
   • Electrocardiogram findings At visit 2
   • Vital signs: pulse, blood pressure and temperature
   • Physical examination

   Visit 1 - Screening (Day -21 to 0)

   Screening of subjects and all study-related procedures will take place in the Sheffield Clinical Research Facility, a specialist environment for the conduct of clinical research. The following assessments and procedures will be performed:

   - Full informed consent, including completion of the informed consent form

   • Inclusion/exclusion criteria (see section 6)
   • Medical history
   • Physical examination
   • Demographic data
   • Vital signs: pulse, blood pressure and temperature
   • Weight and BMI
   • Concomitant medication
   • Lab safety (13.5 ml blood sample for haematology; clinical chemistry & coagulation; urinalysis)
   • Electrocardiogram

   Visit 2 (Day 0) - Randomisation

   • Vital signs
   • Physical examination
   • Reconfirm eligibility criteria met (by a medically qualified member of the study team, see section 6) and no withdrawal criteria met (section 7.10)
   • Randomisation
   • Provided with supply of aspirin (aspirin lysine) for periods 1, 2 and 3 (2 boxes of 30 sachets)
   • Dose-preparation training for aspirin (aspirin lysine) 75 mg OD, including supply of written illustrated instructions
   • Issue with participant information card detailing treatment allocation, restrictions during the study and contact details for the research team

   Period 1: 14 (-2) days - Participants will receive aspirin (aspirin lysine) 75 mg OD, but should withhold their dose on the morning of visit 3 (during which the dose will be taken).

   Visit 3 - Period 1: Day 14 (-2)

   • Vital signs
   • Physical examination
   • Adverse event recording
   • Concomitant medication recorded
   • Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function
   • Bleeding time pre- and 2 hours post dose
   • Urine sample pre- and 2 hours post-dose for prostanoids
   • IMP compliance check for period 1
   • Dispensing of rivaroxaban 2.5 mg tablets for periods 2 and 3 (total 56 tablets)
   • Urine pregnancy test for women of childbearing potential (must not continue to period 2 if positive)
   • Dose-preparation training for aspirin (aspirin lysine) 20 mg BD if allocated to sequence A, including provision of written instructions

   Period 2: 14(-2) days

   Participants will receive their allocated regimen for period 2 for 14(-2) days:

   • If randomised to sequence A they will receive aspirin (aspirin lysine) 20 mg BD plus rivaroxaban 2.5 mg BD in period 2.
   • If randomised to sequence B they will receive aspirin (aspirin lysine) 75 mg BD plus rivaroxaban 2.5 mg BD in period 2.

   Participants should withhold their dose on the morning of visit 4 (during which the dose will be taken).

   Visit 4 : 14(-2) days into period 2 - Physical examination

   • Adverse event recording
   • Concomitant medication recorded
   • Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function
   • Bleeding time pre- and 2 hours post dose
   • Urine sample pre- and 2 hours post-dose for prostanoids
   • IMP compliance recorded for period 2
   • Dose-preparation training for aspirin (aspirin lysine) 75 mg OD if allocated to sequence A or 20 mg BD if sequence B, including provision of written instructions

   Period 3: 14(-2) days

   Participants will receive their allocated regimen for period 3 for 14(-2) days:

   • If randomised to sequence A they will receive aspirin (aspirin lysine) 75 mg OD plus rivaroxaban 2.5 mg BD in period 3.
   • If randomised to sequence B they will receive aspirin (aspirin lysine) 20 mg BD plus rivaroxaban 2.5 mg BD in period 3.

   Visit 5 : 14(-2) days into period 3 - Vital signs

   - Physical examination

   - Adverse event recording

   - Concomitant medication recorded

   - Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function

   - Bleeding time pre- and 2 hours post dose

   - Urine sample pre- and 2 hours post-dose for prostanoids

   - IMP compliance recorded for period 3

   • Collect and return unused medication to pharmacy
   • Transition to standard of care aspirin 75 mg OD, ensuring participant has a supply of this

   Visit 6 : 14(-2) days after visit 5 (Telephone call) - Telephone follow-up for adverse events and concomitant medication

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures

2. Male or female aged greater than 18 years

3. Existing diagnosis of a chronic coronary syndrome:

   (i) History of stable angina or (ii) History of an acute coronary syndrome event >1 year ago or (iii) Previous evidence on imaging of either at least one stenosis >50% in an epicardial coronary artery or a myocardial perfusion defect

4. Receiving single antiplatelet therapy with aspirin 75 mg once daily

Exclusion Criteria:

1. Any history of haemorrhagic stroke or lacunar stroke
2. History of ischaemic stroke or transient ischaemic attack in the last year
3. Heart failure associated with NYHA class III or IV symptoms
4. Estimated glomerular filtration rate <15 ml/min
5. Planned procedure for coronary revascularization
6. Any planned surgery or other procedure that may require suspension or discontinuation of antiplatelet therapy expected to occur within 3 months of randomisation
7. Prior intention by patient or physician to discontinue aspirin within the study period
8. Receiving doses of aspirin other than 75 mg once daily
9. Treatment or planned treatment with antiplatelet medication apart from aspirin (eg. clopidogrel, prasugrel, ticagrelor, dipyridamole, ticlopidine)
10. Current use of a loop, thiazide or potassium sparing diuretic (affects prostanoid assays)
11. Any acute coronary syndrome event, percutaneous coronary intervention or coronary artery bypass grafting within 1 year prior to randomisation
12. Current or planned use of an oral anticoagulant (e.g. warfarin, dabigatran, rivaroxaban [including 2.5 mg BD], apixaban, edoxaban) or parenteral anticoagulant (eg. unfractionated heparin, low molecular weight heparin, bivalirudin)
13. Current or planned use of a GPIIb/IIIa inhibitor (eg. abciximab, tirofiban)
14. Current or planned use of a fibrinolytic agent (eg. tissue plasminogen activator)
15. Requiring or likely to require treatment with a non-steroidal anti-inflammatory drug (NSAID), including COX2 inhibitors, and including regular or intermittent/as required use
16. Current or planned use of a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, cobicistat or over 1 litre daily of grapefruit juice), strong inducer (e.g. rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital), a selective serotonin reuptake inhibitor (SSRI) or selective noradrenergic reuptake inhibitor (SNRI).
17. Clinically significant liver disease, defined as known or suspected diagnosis of hepatic cirrhosis with current Child Pugh class B or C; or elevation of serum alanine transferase or aspartate transferase greater than 3 times the upper limit of the normal range for the processing laboratory.
18. History of alcohol or drug abuse, defined as regular use of an illicit substance for recreational purposes or regular consumption of greater than 50 units (males) or 35 units (females) of alcohol per week, in the last year
19. Co-morbidity associated with life expectancy less than 1 year
20. Any other condition deemed by the investigator to significantly affect haemostasis, coagulation, bleeding risk or ability to comply with the study protocol.
21. Females of child-bearing potential unless negative pregnancy test at screening and willing to use effective contraception (i.e. established use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or barrier methods of contraception with spermicide or sole male partner with prior vasectomy and confirmed absence of sperm in ejaculate) for the duration of treatment with study medication.