A Study of Low-dose Intracoronary Thrombolytic Therapy in STEMI (Heart Attack) Patients.

Phase 3

Recruiting

• Conditions: Elevated IMR (>32); STEMI
• Interventions: Drug: Tenecteplase (1/3 systemic weight based dose); Other: Sterile water for injection (WFI)

• Registration Number: NCT03998319
• Lead Sponsor: University of Sydney

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.

Study Timeline

• Study First Submitted: 2019-05-06
• Study First Submitted QC: 2019-06-23
• Study First Posted: 2019-06-26
• Study Start: 2021-10-14
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-26
• Last Update Posted: 2023-10-30
• Primary Completion: 2024-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 445

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 5 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 <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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tenecteplase (1/3 systemic weight based dose)	Tenecteplase (1/3 systemic weight based dose)	Tenecteplase will be reconstituted in 20mL sterile water for injection at 1/3 of the weight based dose, and administered by intracoronary infusion over 3 minutes.
Sterile Water for injection (WFI)	Sterile water for injection (WFI)	Water for injection will be prepared to 20mL over an equivalent time period to the reconstitution time of the experimental arm, in order to maintain the blind, and administered by intracoronary infusion over 3 minutes.

Primary Outcome Measures

Name	Time	Method
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)	24 months	Cardiovascular mortality and rehospitalisation for heart failure assessed by medical record review.
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.	6 months after primary PCI procedure.	MI size and intramyocardial bleeding rates will be assessed upon cardiac MRI at discharge (3-7 days post procedure) as a baseline measure, and at 6 months post-PCI.

Secondary Outcome Measures

Name	Time	Method
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;	24 months after primary PCI procedure	Cardiovascular mortality and rehospitalisation for heart failure assessed by medical record review, respectively.
All-cause mortality	24 months after primary PCI procedure	All-cause mortality assessed by physical assessment and medical record review.
Fractional Flow Reserve (FFR)	0-2 hours	Fractional Flow Reserve measurement assessed by coronary pressure wire data output review prior to randomisation and immediately after primary PCI
Myocardial Blush Grade	0-2 hours	Myocardial Blush Grade measurement from angiogram will be used to assess cardiac function. The score goes from 0 to 3, with 3 being normal and 0 being absence of myocardial blush
Cardiac enzyme measurements	0-32 hours	Cardiac enzyme levels including troponin T, creatine kinase, creatine kinase-MB and high sensitivity troponin T, from blood samples collected during the hospitalisation period (prior to primary PCI and at 8, 16, 24 and 32 hours post primary PCI).
TIMI Myocardial Perfusion Grade	0-2 hours	Thrombolysis in myocardial infarction score from angiogram will be used to assess myocardial perfusion. This score goes from 0 to 3, 3 indicates normal flow within the artery and 0 indicates a complete coronary occlusion.
Number of stroke events	24 months after primary PCI procedure	Stroke events will be assessed by medical record review. Assessment will cover all aspects of the stroke event (including type, severity, frequency).
Number of incidences of bailout treatment use for no-reflow syndrome	24 months after primary PCI procedure	Use of Bailout treatment for no-reflow syndrome assessed by medical record review
Index of Microcirculatory Resistance (IMR)	0-2 hours	Index of microcirculatory resistance (IMR) measurement assessed by coronary pressure wire data output review.; This is a simple unit scale, with a higher number indicating a worse outcome with a score of more than 25 indicating abnormal microcirculatory function in the heart.
Coronary Flow Reserve (CFR)	0-2 hours	Coronary Flow Reserve measurement assessed by coronary pressure wire data output review, prior to randomisation and immediately after primary PCI.
Number of Major Adverse Cardiac Events (MACE)	24 months after primary PCI procedure	Major Adverse Coronary Events (these are combination events involving cardiovascular death, non-fatal MI, non-fatal stroke and unstable angina) assessed from physical assessment and medical record review
Occurrence of major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium	24 months after primary PCI procedure	Major (Type 3 or greater) and minor (Type 2) bleeding as defined by the Bleeding Academic Research Consortium. Assessed by medical record review.
Wall Motion Score	0-6 months	The score is measured by simple unit scale (1 = normal, 2 = hypokinetic (muscle impaired), 3= akinetic (muscle dead)). Each of the 16 segments of the hearts is scored, with the total being divided by 16 to derive the score.
Left ventricular ejection fraction (LVEF)	0-6 months	Left ventricular ejection fraction measurement from echocardiogram will be used to assess cardiac function prior to randomisation, 48 hours and 6 months post primary PCI
TIMI corrected frame count	0-2 hours	Thrombolysis in myocardial infarction score with corrected frame count from angiogram to assess myocardial perfusion

Trial Locations

Locations (22)

Victorian Heart Hospital; 🇦🇺 Clayton, Victoria, Australia

Bankstown-Lidcombe Hospital; 🇦🇺 Bankstown, New South Wales, Australia

Royal Prince Alfred Hospital; 🇦🇺 Camperdown, New South Wales, Australia

Northern Beaches Hospital; 🇦🇺 Frenchs Forest, New South Wales, Australia

Liverpool Hospital; 🇦🇺 Liverpool, New South Wales, Australia

Concord Repatriation General Hospital; 🇦🇺 Concord, New South Wales, Australia

John Hunter Hospital; 🇦🇺 New Lambton Heights, New South Wales, Australia

Prince of Wales Hospital; 🇦🇺 Randwick, New South Wales, Australia

Wollongong Hospital; 🇦🇺 Wollongong, New South Wales, Australia

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

Lyell McEwin Hospital; 🇦🇺 Elizabeth Vale, South Australia, Australia

Box Hill Hospital; 🇦🇺 Box Hill, Victoria, Australia

Jessie McPherson Private Hospital; 🇦🇺 Clayton, Victoria, Australia

The Northern Hospital; 🇦🇺 Epping, Victoria, Australia

Frankston Hospital; 🇦🇺 Frankston, Victoria, Australia

Sunshine Hospital; 🇦🇺 Saint Albans, Victoria, Australia

Royal Perth Hospital; 🇦🇺 Perth, Western Australia, Australia

Fiona Stanley Hospital; 🇦🇺 Murdoch, Western Australia, Australia

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

Christchurch Hospital; 🇳🇿 Christchurch, New Zealand

Wellington Hospital; 🇳🇿 Wellington, New Zealand

Waikato Hospital; 🇳🇿 Hamilton, New Zealand