A Pilot Randomized Controlled Trial of Intravenous N-acetyl Cysteine in STEMI

Phase 2

Completed

Brief Summary: The PANACEA trial is an investigator-initiated prospective, single-center, two-arm, non-blinded pilot randomized controlled trial of high-dose IV N-Acetylcysteine therapy used as an adjunct to pharmaco-invasive reperfusion in patients presenting early after a large STEMI.

Detailed Description: Patients presenting with ST-segment elevation myocardial infarction within 3 hours of symptom onset and satisfying all of the inclusion criteria after informed consent would be randomly allocated to either intravenous N-Acetylcysteine or standard treatment using a 1:1 allocation ratio. Those randomized to IV N-Acetylcysteine would be administered a bolus of 1200 mg over 0.5 hours (in 5% Dextrose) followed by 600mg/hour for the remaining 47.5 hours (in 5% dextrose). A total N-acetylcysteine dose of 29.7 grams is administered over 48 hours. The infusion is continued during the primary percutaneous coronary intervention. Patients would be followed up for a minimum of 90 days. The primary clinical endpoint will be myocardial infarct size measured by late gadolinium enhancement CMR imaging at 3-5 days from first medical contact. Primary feasibility outcome will be the rate of recruitment, the number of patients undergoing cardiac MRI within the stipulated time frame, and completeness of the study data collection.

Recruitment & Eligibility

Inclusion Criteria

Patients presenting with STEMI within 3 hours of symptom onset and satisfying all of the following criteria:

Patient age ≥ 18 years
Have received thrombolysis, with intend to pursue a pharmaco-invasive reperfusion strategy. Onset of chest pain to reperfusion time of < 3hrs.
STEMI involving anterior and/or inferior wall
An absence of baseline Q-waves on the initial ECG: The presence of Q waves defined at baseline using the Selvester QRS screening criteria
Have a high-risk STEMI ECG defined as:
- ≥2mm ST-segment elevation in 2 anterior or lateral leads; or
- ≥2 mm ST-segment elevation in 2 inferior leads coupled with ST-segment depression in 2 contiguous anterior leads for a total ST-segment deviation of ≥4 mm

Exclusion Criteria

Previous myocardial infarction
Known to have moderate to severe LV systolic dysfunction (LV EF< 45%)
Known allergy to thrombolytic therapy or NAC
Presence of left bundle branch block
Cardiogenic shock (defined as systolic blood pressure of < 90mm Hg, for at least 30 minutes, not responsive to fluid resuscitation)
Permanent pacemaker or cardioverter defibrillator implanted previously
Patients with contra-indications to thrombolytic therapy
Patients with loss of consciousness or confusion
Patients with known chronic kidney disease (GFR < 30ml/min/m2) or on dialysis
Current pregnancy
Planned therapy with primary PCI

Arm && Interventions

Group	Intervention	Description
Intravenous N-Acetylcysteine arm	Intravenous N-Acetylcysteine	On arrival at the recruiting hospital, eligible and consenting STEMI patients randomly allocated to the experimental arm would be administered an intravenous N-Acetylcysteine bolus of 1200 mg over 0.5 hours (in 5% Dextrose) followed by 600mg/hour for the remaining 47.5 hours (in 5% dextrose). A total N-acetylcysteine dose of 29.7 grams is administered over 48 hours.

Primary Outcome Measures

Name	Time	Method
Myocardial infarct size	3-5 days after first medical contact	The primary clinical endpoint will be myocardial infarct size measured by late gadolinium enhancement CMR imaging at 3-5 days from first medical contact.
Feasibility outcomes	Assessed at the end of the study	Primary feasibility outcomes would include the rate of recruitment, the number of patients undergoing cardiac MRI within the stipulated time frame, and completeness of the study data collection.

Secondary Outcome Measures

Name	Time	Method
Myocardial salvage	3-5 days after infarction	Myocardial salvage as measured by T2-weighted short tau inversion recovery on CMR assessed at 3-5 days after infarction
Creatine kinase MB area under the curve	24 hours after admission	Creatine kinase MB area under the curve through 24 hours
Von Willebrand factor fragmentation	At the time of angiography, assessed up to 7 days from admission	The proportion of Von Willebrand factor multimers in the low, intermediate and high molecular weight form at the time of angiography
Allergic reactions	From time of randomization, upto 48 hours	Allergic reactions including hypotension (SBP\< 90 mm Hg or a fall in BP \>30 mm Hg below baseline), urticaria, flushing, wheezing and/or angioedema
Left ventricular ejection fraction	3-5 days after infarction	Left ventricular ejection fraction on CMR at 3-5 days
ST-segment elevation resolution	90-minutes after thrombolysis	ST-segment elevation resolution at 90 minutes after thrombolysis as assessed by the worst lead on electrocardiogram (ECG core lab).
TIMI frame count in infarct related artery	During index coronary angiogram which will be performed within 24 hours of admission	TIMI frame count on baseline coronary angiogram in the infarct-related artery
Bleeding	From time of randomization until the date of discharge or date of death from any cause, whichever came first, assessed up to 90 days	Bleeding research consortium type II, III and V bleeding; safety outcome