Clinical trial NCT03145194: TIMES: Ticagrelor vs. Placebo/ Clopidogrel With Aspirin in Anterior STEMI Patients Treated With Primary PCI
Official title: A Randomised Mechanistic Study Comparing the Effects of Different Anti-platelet Combinations (Ticagrelor vs. Placebo/ Clopidogrel) With Aspirin in Patients Presenting With Anterior STEMI Treated With Primary PCI
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: ST Elevation Myocardial Infarction
Lead sponsor: Papworth Hospital NHS Foundation Trust
Sponsor class: OTHER_GOV
Collaborators: name: AstraZeneca
First posted: 2017-05-09
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a single-centred, double blind randomized controlled trial comparing ticagrelor with placebo in clopidogrel and aspirin loaded patients.

Detailed description: The very early benefit of ticagrelor in STEMI is co-mediated by adenosine cardioprotection maintaining/ improving myocardial microcirculatory function, as well as via platelet inhibition or possibly other pleiotropic effects.

Ticagrelor increases circulating adenosine by reducing cellular re-uptake. Adenosine is a cardioprotective agent that utilizes cellular survival kinase pathways that may have beneficial effects on the microcirculation and myocardium in patients presenting with STEMI. Adenosine is currently used as a treatment for no-reflow and improves MVO post-STEMI when administered during PPCI. A recent study of healthy volunteers has confirmed that non-invasive coronary flow is augmented by ticagrelor and that this is mediated by adenosine. The Investigators propose that the very early beneficial effects of Ticagrelor in ACS may be adenosine mediated cardioprotection, rather than only due to an antiplatelet effect. This important research is original and a natural progression of the ticagrelor story. It expands the adenosine hypothesis and mode of action of ticagrelor and addresses a novel cardioprotective/ microcirculatory mechanism of action.

Eligibility criteria: Inclusion Criteria:

1. Provision of informed verbal consent prior to any study specific procedures taking place with written consent confirmed prior to in-patient cardiac MRI.
2. Male or female adult patient aged 18 - 90 years old
3. Anterior STEMI (ST elevation ≥ 2mmHg in contiguous chest leads) with chest pain symptom onset \< 12 hours

Exclusion Criteria:

1. Cardiogenic shock\*
2. Previous anterior myocardial infarction
3. Unfavourable coronary anatomy for PCI: left main / surgical or distal coronary disease
4. Already prescribed Ticagrelor at the time of admission
5. Factors affecting study drug administration/ absorption: vomiting or allergy
6. Concomitant use of potent CYP3A4 inhibitors/ inducers (e.g ketoconazole and rifampicin) or CYP3A4 substrates with a narrow therapeutic window (e.g. cisapride and ergot alkaloids) or simvastatin / lovostatin \>40mg oral dose.
7. Severe bleeding diathesis or current active bleeding\*
8. History of intracranial haemorrhage
9. Moderate or Severe hepatic impairment
10. Severe asthma or bradycardia/ complete heart block (contraindications to adenosine)\*
11. Severe co-morbidity with a life expectancy \< 3 months.
12. Women of child bearing potential (as determined by direct questioning of the patient to confirm and this will be documented in the medical notes).

    * Patients that are found to have any excluding factor (e.g., unfavourable coronary anatomy for PCI) or develop any excluding factor (e.g., vomiting or cardiogenic shock) before the point of final IMR assessment will be discontinued from the study and followed up at discharge and by telephone at 3 and 12 months for adverse event monitoring purposes only.

Primary outcomes:
measure: Index of Myocardial Resistance (IMR)
timeFrame: Baseline to end of PPCI procedure.
Secondary outcomes:
measure: Baseline IMR and change in IMR during PPCI
timeFrame: Baseline to end of PPCI procedure.
measure: ACF and AMR pre/post PPCI
timeFrame: Baseline to end of PPCI procedure.
measure: TIMI flow and TMBG pre/post PPCI
timeFrame: Baseline to end of PPCI procedure.
measure: ST segment resolution
timeFrame: Baseline to end of PPCI procedure.
measure: OCT quantified clot volume pre/post PPCI
timeFrame: Baseline to end of PPCI procedure.
measure: Cardiac troponin - I and CKMB levels at 0, 12 and 24 hours
timeFrame: Baseline to 24 hours.
measure: Cardiac MRI microvascular obstruction between 24-48 hours and infarct size at 3 months
timeFrame: Baseline to 3 months.
Other outcomes:
measure: Creatinine levels (eGRF) at 0, 12 and 24 hours
timeFrame: Baseline to 24 hours.
measure: NYHA Functional Classification and CCS Angina Grading Scale
timeFrame: Discharge to 12 months.
measure: Plasma Ticagrelor levels at the point of final IMR measurement and in-patient Cardiac MRI.
timeFrame: End of PPCI procedure to 24-48 hours.
measure: Plasma Adenosine levels at the point of final IMR measurement and in-patient Cardiac MRI
timeFrame: End of PPCI procedure to 24-48 hours.
measure: Multiplatelet® ADP aggregation assessment of platelet reactivity at the point of final IMR measurement and in-patient Cardiac MRI
timeFrame: End of PPCI procedure to 24-48 hours.
Locations:
city: Papworth Everard
country: United Kingdom
facility: Papworth Hospital NHS Foundation Trust
state: Cambridge
Study officials:
affiliation: Papworth Hospital NHS Foundation Trust
name: Stephen Hoole
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aetesam-Ur-Rahman M, Brown AJ, Jaworski C, Giblett JP, Zhao TX, Braganza DM, Clarke SC, Agrawal BSK, Bennett MR, West NEJ, Hoole SP. Adenosine-Induced Coronary Steal Is Observed in Patients Presenting With ST-Segment-Elevation Myocardial Infarction. J Am Heart Assoc. 2021 Jul 6;10(13):e019899. doi: 10.1161/JAHA.120.019899. Epub 2021 Jun 30.