Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX

Phase IIIb Study Minimizing Adverse Haemmhorragic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX)

This protocol describes a study to compare intended trans-radial versus trans-femoral intervention and bivalirudin monotherapy versus current European standard of care consisting of unfractionated heparin (UFH) plus provisional use of glycoprotein IIb/IIIa inhibition via the use of one of the three available agents on the market (e.g. abciximab, tirofiban or eptifibatide) in patients (≥18 years) with ACS, that are intended for an invasive management strategy. This study will be conducted in compliance with Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements.

The use of combined antithrombotic therapies over the last two decades has decreased the risk of a heart attack after percutaneous coronary intervention substantially but has also been associated with a significant increase in bleeding risk. Therapies or strategies that maintain the benefits seen with currently available antithrombotic therapies but which have lower bleeding risk are therefore of great clinical importance. Indeed, major bleeding is currently the most common non-cardiac complication of therapy for patients with coronary artery disease who have undergone percutaneous coronary intervention (PCI).

Bleeding in patients with acute coronary syndrome (ACS) is associated with an increased risk of long term mortality and morbidity, and this relationship is currently thought to be causal. Therefore' reducing the frequency of bleeding events while maintaining efficacy is an important goal in the management of patients with ACS. The most common site of bleeding in invasively managed patients with ACS is at the femoral artery puncture site used for heart catheterization

The MATRIX study is a multi-centre, prospective, randomised, open-label, 2 by 2 factorial comparison of trans-radial vs. trans-femoral intervention and bivalirudin vs. unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitor.

Objectives:

1. To demonstrate that trans-radial intervention as compared to femoral access site is associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.
2. To demonstrate that bivalirudin infusion as compared to standard of care therapy consisting of unfractionated heparin and provisional use of glycoprotein IIb/IIIa inhibitors are associated to lower rate of the composite endpoint of death, MI or stroke within the first 30 days after randomization in acute coronary syndrome patients undergoing early invasive management.

Patients randomly assigned to receive bivalirudin will be randomized to stop bivalirudin infusion at the end of PCI or to prolong bivalirudin at an infusion rate of 0.25 mg/kg/hour for at least 6 hours after completion of PCI. The primary hypothesis in this sub-randomization is that prolonged post-intervention bivalirudin infusion will be superior to no bivalirudin post-PCI infusion with respect to the net composite outcome consisting of any death, MI, stroke, urgent TVR, stent thrombosis and BARC-defined type 3 and 5 bleeding events within 30 days. Secondary objectives for the sub-randomization of prolonged bivalirudin versus no post-PCI infusion in the bivalirudin group will consist of each component of the primary composite endpoint through the entire follow-up duration

Inclusion Criteria:

NSTEACS definition: Patients with all of the following criteria will be eligible:

1. history consistent with new, or worsening ischemia, occurring at rest or with minimal activity;
2. enrollment within 7 days of the most recent symptoms;
3. planned coronary angiography with possible indication to PCI;
4. at least 2 of the following criteria: 1. Aged 60 years or older, 2. Troponin T or I or creatine kinase MB above the upper limit of normal; 3. Electrocardiograph changes compatible with ischemia, ie, ST depression of 1 mm or greater in 2 contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts;

STEMI definition: i) chest pain for >20 min with an electrocardiographic ST-segment elevation ≥1 mm in two or more contiguous electrocardiogram (ECG) leads, or with a new left bundle-branch block, or an infero-lateral myocardial infarction (MI) with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave and ii) admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia or previous lytic treatment.

Exclusion Criteria:

1. Patients who can not give informed consent or have a life expectancy of <30 days
2. Allergy/intolerance to Bivalirudin or unfractionated heparin.
3. Stable or silent CAD as indication to coronary angiography
4. Treatment with LWMH within the past 6 hours
5. Treatment with any GPI in the previous 3 days
6. Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast or to any of the study medications including aspirin or clopidogrel.
7. Contraindications to angiography, including but not limited to severe peripheral vascular disease.
8. If it is known pregnant or nursing mothers. Women of child-bearing age will be asked if they are pregnant or think that they may be pregnant.
9. If it is known a creatinine clearance <30 mL/min or dialysis dependent.
10. Previous enrollment in this study.
11. Treatment with other investigational drugs or devices within the 30 days preceding
12. Randomisation or planned use of other investigational drugs or devices in this trial.
13. Severe uncontrolled hypertension (defined as persistent systolic blood pressure higher than 220 mmHg despite medical treatment).
14. Subacute bacterial endocarditis
15. PCI in the previous 30 days