Clinical trial NCT03998319: A Study of Low-dose Intracoronary Thrombolytic Therapy in STEMI (Heart Attack) Patients.
Official title: A Randomised Trial to Evaluate the Efficacy of Low-dose Intracoronary Tenecteplase in ST-Elevation Myocardial Infarction (STEMI) Patients With High Microvascular Resistance Post-percutaneous Coronary Intervention (PCI).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: STEMI
Elevated IMR (>32)
Keywords: STEMI
IMR
microcirculation
microvascular obstruction
myocardial infarction
physiology
angioplasty
PCI
thrombolysis treatment
thrombolysis
Lead sponsor: University of Sydney
Sponsor class: OTHER
First posted: 2019-06-26
Enrollment: 445
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-Centre double-blind, placebo controlled randomised phase IIIb clinical trial, stratified and balanced between groups on important prognostic factors.
Primary purpose: OTHER

Brief summary: Heart attacks are caused by a blood clot blocking the blood vessels of the heart, preventing blood getting to the heart muscle. Opening up the artery with a balloon (angioplasty) and a small mesh tube (stent) although life saving can cause this clot to break up and get washed downstream, which can make the heart attack worse. The investigators can measure the amount of damage caused to the microcirculation by calculating the IMR (Index of Microcirculatory resistance).

This can be measured by a wire in the coronary artery with a pressure sensor at the tip. If the IMR is elevated, it is suggestive of extensive microcirculatory damage. A clot dissolving medicine can be administered in the artery to try and reduce the IMR which can reduce damage to the heart muscle and improve outcomes.

Impaired microcirculatory perfusion in patients as a result of ST-elevation myocardial infarction (STEMI) is associated with poor clinical outcomes. This project seeks to identify patients with impaired microcirculatory perfusion after STEMI and to assess whether acute improvement in microcirculatory perfusion in these patients by the use of intracoronary thrombolytic therapy results in improved clinical outcomes.

Detailed description: Patients presenting to the participating hospitals with a heart attack will be approached to participate in the study. After angioplasty has been performed, the IMR will be measured in the infarct related artery. If the IMR is \>32 patients will be randomised to receive intracoronary clot dissolving therapy in the form of low dose tenecteplase (TNK) or water as a placebo. Patients who have an IMR ≤32 will be followed up in a registry. Cardiac enzymes will be measured at baseline and discharge. Randomised participants will receive a cardiac MRI at discharge (3-7 days post primary PCI) and at 6 months post PCI. All participants will be followed up at 30 days, and 6, 12 and 24 months following discharge.

Eligibility criteria: Inclusion Criteria:

1. Adult men and women aged over 18 who present with STEMI within 6 hours of symptom onset. Patients will be eligible if they have symptoms consistent with myocardial ischaemia (chest pain, dyspnoea) for at least 20 minutes accompanied by definite ECGs indicating STEMI as defined by Australian National Heart Foundation (NHF) guidelines
2. Willing and able to comply with all study requirements, including treatment, assessment and clinic visit attendances
3. Able to personally read and understand the Participant Information and Consent Form and provide written, signed and dated informed consent to participate in the study
4. (At time of PCI) Patient has received metallic drug-eluting stent
5. Participant consents to have a 3-7 day (discharge) and 6 month follow up cardiac MRI

Exclusion Criteria:

At the time of screening and/or prior to randomisation, no known;

1. Previous coronary bypass grafting
2. Other residual lesions with ≥50% diameter stenosis in the culprit vessel
3. Prior myocardial infarction in the target territory
4. Presence of contraindications to thrombolytic therapy (including history of stroke and recent brain surgery active internal bleeding; history of cerebrovascular accident; intracranial or intraspinal surgery, or trauma within 2 months; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; and severe uncontrolled hypertension)
5. Presence of contraindications to adenosine infusion for IMR measurement including sinus node disease, moderate to severe bronchoconstrictive disease and second or third-degree atrioventricular (AV) block
6. Diagnosis of metastatic disease
7. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
8. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
9. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.
10. Participation in any investigational study in the previous 30 days

    Other exclusion criteria:
11. (Cardiac MRI cohort only) Presence of contraindications to contrast enhanced MRI including severe claustrophobia, pregnancy, pacemakers, non-MRI compatible aneurysm clips, defibrillators and estimated glomerular filtration rate of \&lt;30mL/min.

    (At time of PCI)
12. Patients who received GpIIb/IIIa treatment prior to IMR measurement
13. Patients who do not undergo primary PCI due to lack of severity of culprit lesion or other reasons.

Primary outcomes:
measure: To compare the number of participants who experience cardiovascular mortality and rehospitalisation for heart failure at 24 months in those given tenecteplase with those given placebo (Cardiac MRI cohort only)
timeFrame: 24 months
measure: To compare MI size as a % of LV mass and intramyocardial bleeding rates in participants at 6 months post PCI in those given low dose tenecteplase with those given placebo.
timeFrame: 6 months after primary PCI procedure.
Secondary outcomes:
measure: Number of participants who experience individual components of the primary endpoint: (a) cardiovascular mortality at 24 months, (b) rehospitalisation for heart failure at 24 months;
timeFrame: 24 months after primary PCI procedure
measure: Number of Major Adverse Cardiac Events (MACE)
timeFrame: 24 months after primary PCI procedure
measure: All-cause mortality
timeFrame: 24 months after primary PCI procedure
measure: Number of stroke events
timeFrame: 24 months after primary PCI procedure
measure: Number of incidences of bailout treatment use for no-reflow syndrome
timeFrame: 24 months after primary PCI procedure
measure: Occurrence of major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium
timeFrame: 24 months after primary PCI procedure
measure: Index of Microcirculatory Resistance (IMR)
timeFrame: 0-2 hours
measure: Fractional Flow Reserve (FFR)
timeFrame: 0-2 hours
measure: Coronary Flow Reserve (CFR)
timeFrame: 0-2 hours
measure: Wall Motion Score
timeFrame: 0-6 months
measure: Left ventricular ejection fraction (LVEF)
timeFrame: 0-6 months
measure: Myocardial Blush Grade
timeFrame: 0-2 hours
measure: TIMI Myocardial Perfusion Grade
timeFrame: 0-2 hours
measure: TIMI corrected frame count
timeFrame: 0-2 hours
measure: Cardiac enzyme measurements
timeFrame: 0-32 hours
Other outcomes:
measure: DNA analyses (Subject to funding)
timeFrame: 0-6 months
measure: MicroRNA analyses (Subject to funding)
timeFrame: 0-6 months
measure: Vasoactive markers (Subject to funding)
timeFrame: 0-6 months
measure: Inflammatory markers (Subject to funding)
timeFrame: 0-6 months
measure: Angiogenic markers (Subject to funding)
timeFrame: 0-6 months
measure: Liver function (Subject to funding)
timeFrame: 0-6 months
measure: Thyroid Function (Subject to funding)
timeFrame: 0-6 months
measure: Lipid profile (Subject to funding)
timeFrame: 0-6 months
measure: Lipoprotein profile (Subject to funding)
timeFrame: 0-6 months
Locations:
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Frenchs Forest
country: Australia
facility: Northern Beaches Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Jessie McPherson Private Hospital
state: Victoria
city: Clayton
country: Australia
facility: Victorian Heart Hospital
state: Victoria
city: Epping
country: Australia
facility: The Northern Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Saint Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
Study officials:
affiliation: Royal Prince Alfred Hospital, Sydney, Australia
name: Martin Ng, MBBS (Hons)
role: STUDY_CHAIR
affiliation: Concord Repatriation General Hospital
name: Andy Yong, MBBS
role: STUDY_CHAIR
affiliation: National Health and Medical Research Council, Australia
name: Anthony Keech, MBBS
role: STUDY_CHAIR
affiliation: Stanford University
name: William Fearon, MD
role: STUDY_CHAIR
affiliation: Peninsula Health
name: Jamie Layland, MBBS
role: STUDY_CHAIR
affiliation: Green Lane Cardiovascular Service
name: Harvey White, FRCS
role: STUDY_CHAIR
References: