Bi smart bivalirudin in St-elevation M

BI SMART

Author: Per Albertsson MD, PhD

Div of Cardiology

Sahlgrenska University Hospital

413 45 Göteborg

Sweden
1. BACKGROUND

1. 
   PCI for Myocardial infarction
   

Percutaneous Coronary Intervention (PCI) for ST-elevation Myocardial Infarction (STEMI) is a Class I A indication according to both the European Society of Cardiology and the American College of Cardiology (1, 2).

PCI is clearly superior to fibrinolysis for patients admitted to hospitals with angioplasty facilities (3).

This benefit has also been demonstrated for patients who are transferred from community hospitals (4).

In the Western of Sweden it has been agreed that patients with STEMI who are identified by the ambulance organisation or in a hospital without angioplasty facilities, should be transferred for emergency PCI.

2. 
   Facilitated PCI
   

Facilitated PCI refers to a strategy of administration of pharmacological agents prior to the intervention in STEMI.

The rational is to provide an opportunity to start treating patients who have a time delay to intervention (due to geography or logistics), and hopefully restore coronary flow, to reduce the associated irreversible loss of myocardial muscle that occurs as onset of symptoms-to-balloon time increases.

Pharmacological strategies before PCI include; thrombolytic therapy, glycoprotein IIb/IIIa inhibitor alone, or a combination of thrombolytic therapy plus glycoprotein IIb/IIIa inhibitor. Ongoing trials are evaluating different combinations of thrombolytic and glycoprotein IIb/IIIa inhibitor therapy.

3. 
   Bivalirudin (Angiox®)
   

Bivalirudin is a peptide that directly inhibits all known actions of thrombin. This includes inhibition of conversion of fibrinogen to fibrin and inhibition of platelet activation.

Short and long-term clinical outcome with Bivalirudin and provisional gp IIb/IIIa blockade is comparable with that of Heparin and planned use of gp IIb/IIIa blockade (5, 6).

The on-going Acuity trial will address the question of efficacy of Bivalirudin in patients with unstable coronary syndromes (7).

Bivalirudin treatment in patients with STEMI has so far only been investigated in registry studies (8, 9), but a large multicenter randomized trial, “Horizon”, is pending.

Prehospital administration of Bivalirudin is yet to be investigated.

• 
  Rate of TIMI II or TIMI III flow at time of initial angiography
  

• 
  Rate of ST-segment resolution >50 %, 60 minutes post start of procedure.
  

• 
  Rate of Myocardial Blush grade III (immediately post procedure).
  

• 
  Corrected TIMI frame count.
  

• 
  MACE (Major Adverse Cardiac Events) at 30 days and 1 year
  

• 
  Coronary Flow immediately post-procedure using thermodilution curves (sub-study only)
  

• 
  Size of myocardial infarction measured with MRI at 30 days(sub-study only)
  

The treatments groups are 1) Bivalirudin administered before transfer or 2) Bivalirudin administered after the diagnostic catheterization.

2. 
   ST-segment elevation of >1 mm in two ore more contiguous
   

2. 
   ST-segment depression >2 mm in V1, V2, or V2, V3 with reciprocal ST-elevation in II (true posterior infarction)
   

4. Written informed consent before randomization

20. Expected angiography within 30 minutes from qualifying ECG

21. Enrolment in another study that has not completed the follow up phase.
22. Unwillingness to participate in the trial or expected problems with compliance

4. STUDY PLAN
4.1 Pre randomization procedures.
Written informed consent will be obtained for this study from all patients who meet all inclusion and no exclusion criteria.

Patients could be randomised by the ambulance organisation or in another hospital in the region before transfer for Direct PCI.

A 12 lead ECG will be taken and sent to Sahlgrenska University Hospital, electronically or by fax and the PCI-team will be alerted.
4.2 Randomization procedure.
Patients will be randomised with the use of closed envelopes that will be provided to all participating hospitals and ambulance organisations.
4.3. Continuous Vectorcardiography (cVCG)
cVCG will be performed with the use of the HP-MIDA system.

At arrival at the catheterization laboratory eight electrodes will be positioned on the patient, for continuous signal collecting. Mean vectorcardiograpic complexes are formed from the three orthogonal positions and the magnitude of ST-vector (ST-VM) is calculated

The rate of ST-VM resolution >50% from baseline (60 minutes post-procedure) will be calculated.
4.4 Catheterization
4.4.1 Coronary Angiography
Coronary angiography will be performed with the use of 6F catheters via the femoral or radial approach to the operator’s discretion.

The first injection before the procedure, and the last injection after the procedure, will be performed with a field size of 9 inch and at the following views:

• 
  Right Coronary Artery is the Infarct related artery: LAO 30º (0º cranio/caudal)
  
• 
  Left Coronary Artery is the Infarct related artery: RAO 30º (0º cranio/caudal)
  

All angiograms will be sent to an independent core-lab and quantitative coronary analyzes (QCA) will be performed.

• 
  Grade 0: Complete occlusion without any peripheral flow
  
• 
  Grade 1: Some penetration of contrast media, but no perfusion of the distal coronary bed
  
• 
  Grade 2: Perfusion of the entire vessel into the distal bed but with delayed flow compared with a normal artery
  
• 
  Grade 3: Normal flow with full perfusion
  

This will be performed after the coronary angioplasty, after injection of 250 ug Nitroglycerin i.c.

• 
  Grade 0: Failure of dye to enter the microvasculature.
  
• 
  Grade 1: Dye slowly enters but fails to exit the microvasculature.
  
• 
  Grade 2: Delayed entry and exit of dye from the microvasculature.
  
• 
  Grade 3: Normal entry and exit of dye from the microvasculature. There is the ground-glass appearance (“blush”) or opacification of the myocardium that clears normally (gone or mildly persistent after 3 cardiac cycles).
  

Care should be taken not to mistake filling of the venous system such as the great cardiac vein as blush. This appears as a linear vascular structure rather than as a diffuse or round collection of dye.

Blush should be assessed during the same phase of the cardiac cycle, as it may be less intense during diastole.


4.4.2 Angioplasty
Coronary angioplasty will be performed according to routine practice. Whenever possible, a coronary stent should be implanted in the culprit lesion.
4.4.3 Coronary Flow Measurement
In a sub-study coronary flow immediately after the angioplasty procedure will be performed.

A Pressure Wire® will be inserted to the culprit vessel at the end of the procedure. Distal coronary pressure is constantly recorded.

4 ml of Saline at room temperature is injected in to the vessel to obtain a thermodilution curve at rest. Adenosin 160 µg/kg/min is the switched on and a hyperaemic thermodilution curve is obtained.


4.5 Post procedure, Hospital face
Blood tests will be performed as mentioned in paragraph 6

Adverse events will be registered according to paragraph 4.7

An AE is any unfavourable sign or symptom associated with the study agents or the coronary intervention.

• 
  Death or
  
• 
  Life-threatening event or
  
• 
  Prolongation of existing hospitalisation or new unplanned hospitalisation or
  
• 
  Persistent or significant disability or
  
• 
  Intracranial haemorrhage
  

Patients will be contacted by telephone.

Patients will be contacted by telephone.

All patients will receive a loading dose of 600 mg Clopidogrel. (13)

Metoprolol, opioids, and nitroglycerin will be given according to local standard care.
5.1.2 Administration of Study Agent
Patients will receive a bolus dose of Bivalirudin (Angiox®) 0.75 mg/kg given as a rapid bolus dose before the ambulance transfer, followed by an infusion of 1,75 mg/kg/h or a bolus dose plus infusion of Placebo.
5.2. Medication in the Cath-lab
All patients will receive nitroglycerin 250µg intracoronary before the first angiogram.
The infusion of Bivalirudin (Angiox®) 1.75 mg/kg/h or Placebo will be continued throughout the PCI.
Provisional gpIIb/IIIa blockade could be administered for procedural or angiographic complications at any time during the PCI. Indications for use of gpIIb/IIIa use are abrupt target vessel closure, abrupt side-branch closure, obstructive dissection, impaired coronary flow post stenting, new or suspected thrombus or distal embolization.

Abciximab (Reopro®) or Eptifibatide (Integrillin®) are the recommended gpIIb/IIIa-blockers.

The drugs will be administrated according to local routine practise.

Clopidogrel will be prescribed 75 mg o.d. for three month.

We assume that the proportion of patients with TIMI II or III will increase to 40% with the study drug. With 80 % power and a p value of <0.05 this trial will need 82 individuals in each group. To ensure enough patients for evaluation 200 patients will be included in the trial.

No interim analysis is planned.

8. ETHICAL CONSIDERATION
An informed consent form will be prepared according to the institution of University of Göteborg requirements for informed consent.

The study will be conducted according to the World Medical Association Declaration of Helsinki: “Ethical Principals for Medical Research Involving Human Subjects”.

(Adopted in 1964 (Helsinki) and revised in 1975 (Tokyo), 1983 (Venice), 1989 (Hong Kong), 1996 (Somerset-West) and 2000 (Edinburgh)

References.
1. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions: the task force for percutaneous coronary interventions of the European society of cardiology.

Eur Heart J. 2005 Apr;26(8):804-47.

Lancet. 2003 Jan 4;361(9351):13-20.

intervention: REPLACE-2 randomized trial. JAMA. 2003 Feb 19;289(7):853-63. Erratum in: JAMA. 2003 Apr 2;289(13):1638.

percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA. 2004 Aug 11;292(6):696-703.

Circulation. 1996 Mar 1;93(5):879-88.