Bi smart bivalirudin in St-elevation M



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Synopsis 2006-01-20


BI SMART




BIvalirudin in

St-elevation Myocardial infarction –

A Randomized Trial

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.


    1. 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.




    1. 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.



2. HYPOTHESIS.
The primary objective of this study is to demonstrate that administration of Bivalirudin prehospital to patients with STEMI will improve TIMI-flow in the infarct related coronary artery, and facilitate the following coronary intervention leading to a shorter time to ST-segment resolution compared to standard therapy administered in the Cath-lab.


2.1 Primary Endpoint


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


2.2 Secondary Endpoint


  • 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)



3. STUDY OVERVIEW
This study will be a multi centre pilot trial, with a randomized double-blind placebo-controlled design. The study population consists of 200 subjects with ST-elevation Myocardial Infarction, who are randomized in the ambulance or in another hospital within 12 hours from symptom onset, and then transferred to Sahlgrenska University Hospital for PCI.

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




4. PATIENT SELECTION
4.1 Inclusion Criteria
1. >18 years of age
2. On-going Acute Myocardial Infarction with onset of symptoms within 12 hours prior to randomisation
3. ECG changes given suspicion of myocardial infarction
a. ST-segment elevation of >2 mm in two ore more contiguous precordial leads (anterior infarction)


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

limb leads (inferior or lateral infarction)


  1. 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



4.2 Exclusion Criteria
1. Left Bundle Branch Block
2. Use of fibrinolytic agent within 14 days prior to randomization
3. Use of GPIIb/IIIa inhibitor within 14 days prior to randomization
4. Use of Low Molecular Weight Heparin within 24 hours prior to randomization
5. PCI within 30 days prior to randomization
6. Suspected ongoing active internal bleeding
7. Gastrointestinal bleeding of clinical significance within 4 weeks prior to randomization
8. Genitourinary bleeding of clinical significance within 4 weeks prior to randomization
9. Major surgery within 4 weeks prior to randomization
10. History of intracranial bleeding
11. Cerebrovascular accident within 12 month prior to randomization
12. Neurosurgery within 3 month
13. Severe hypertension not adequately controlled by antihypertensive therapy at time of study entry (BP> 180/100mmHg)
14. Ongoing treatment with Warfarin
15. Known allergy to Aspirin
16. Known allergy to Bivalirudin
17. Coexistent condition associated with limited life expectancy
18. Prolonged (>20 minutes) cardiopulmonary resuscitation within 4 weeks prior to randomization
19. Pregnancy

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)

The duration of filming should exceed 3 cardiac cycles in the washout phase to assess the washout of the myocardial blush.  This would require filming for approximately 5 to 6 cardiac cycles (5 to 6 seconds).

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


4.4.1.1 TIMI Grade Flow
Flow in the infarct related vessel would be graded using the TIMI grading system (10):

  • 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

The dye injection should be done at least 30 seconds after the test injections on fluoroscopy before filming. If the film is taken immediately after a test injection, there may be dye retention, and the incidence of TIMI flow 1 may be overestimated.
4.4.1.2 TIMI frame count
The number of frames required for dye to reach the distal part of the infarct related vessel will be counted (11).

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


4.4.1.3 Myocardial Blush
Myocardial Blush grade immediate post procedure will be examined according to the TIMI myocardial perfusion (TMP) grade (12).

  • 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).

Blush should be assessed distal to the culprit lesion.

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


4.6 Discharge
Adverse Events (AE) and Serious Adverse Events (SAE) will be reported.

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


4.6.1 Serious Adverse Event
A SAE is any AE occurring that results in

  • Death or

  • Life-threatening event or

  • Prolongation of existing hospitalisation or new unplanned hospitalisation or

  • Persistent or significant disability or

  • Intracranial haemorrhage


4.6.2 Bleeding
All major or minor bleedings will be reported.
4.6.2.1 Major bleeding
Major bleeding is defined as either intracranial bleeding or, a decrease in haemoglobin of more than 50g/L or intracranial bleeding or bleeding requiring surgery.
4.6.2.2 Minor bleeding
Minor bleeding is defined as, a decrease in haemoglobin of more than 30g/L (but less than 50 g/L) or spontaneous gross hematuria or haematemesis, or haematoma or pseudoaneurysm requiring treatment (other than surgery).
4.7 30 day follow up
Serious Adverse Events (SAE) will be reported.

Patients will be contacted by telephone.


4.8 12 month follow up
Serious Adverse Events (SAE) will be reported.

Patients will be contacted by telephone.


4.9 Report of adverse events
The investigator is responsible for reporting of safety information to local authorities according to Swedish legislation and forward a copy to Nycomed central pharmacovigilance.

5. TRIAL MEDICATION
5.1.1 Prehospital Medication
All patients will receive 300 mg of open labelled Aspirin.

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.



6. Blood chemistry
6.1 Haemoglobin
Blood samples for haemoglobin will be obtained at baseline, 24 (± 8) hours after the procedure, and at day of discharge.
6.2 Platelet count
Blood samples for platelet count will be obtained at baseline, 4 hours post bolus dose of abciximab, 24 (± 8) hours post bolus dose of abciximab and at day of discharge.

6.3 Potassium, Sodium and Kreatinin
Blood samples for Potassium, Sodium and Kreatinin will be obtained at baseline, 24 (± 8) hours after the procedure, and at day of discharge.

6.4 CK-MB and TnT
Blood samples for CK-MB and TnT will be obtained at baseline, 8 (± 2) hours post procedure, 16 (± 4) hours post procedure and at 24 (± 4) hours post procedure.
6.5 Glucose and HbA1c
Blood samples for fasting p-Glucose and HbA1c will be obtained at the day after the procedure.
.

7. STATISTICAL CONSIDERATION
This is a randomised double blind single centre, placebo controlled, pilot trial designed to evaluate the efficacy of Bivalirudin administered prehospital to patients with STEMI.
According to earlier trials 20% of the patients treated with placebo will have TIMI flow II or III at time of initial angiography.

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.


2. Antman EM, Anbe DT, Armstrong PW, Bates ER, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004 Aug 4;44(3):671-719.
3. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials.

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


4. Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003 Aug 21;349(8):733-42.
5. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary

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


6. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during

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


7. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J. 2004 Nov;148(5):764-75.
8. Stella JF, Stella RE, Iaffaldano RA, et al. Anticoagulation with bivalirudin during percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Invasive Cardiol. 2004 Sep;16(9):451-4.
9. Rossi PA, Matar F, Pilcher H, et al. Angiomax is as effective as heparin and gpIIb/IIIa platelet receptor blockers in patients with ST elevation myocardial infarction undergoing percutaneous coronary intervention: a multicenter registry study. Abstract Oral presentation TCT;TCTMD.com
10. The TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. N Engl J Med 1985;31:932-936
11. Gibson CM, Cannon CP, Daley WL,et al. TIMI frame count: a quantitative method of assessing coronary artery flow.

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


12. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000 Jan 18;101(2):125-30.
13. Patti G, Colonna G, Pasceri V, et al. Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention. Results From the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study. Circulation. 2005 Mar 6; [Epub ahead of print]



Prehospital


Cath. Lab.


Post procedure



Day after procedure

Discharge


30 days



1 year

History

X




















ECG (12-lead)

X





X





X







Call invasive cardiologist, Study Centre

X



















Informed consent

X




















Randomisation

X




















Study Drug/Placebo Bolus

X



















Aspirin


X





X

X

X

X

X

Clopidogrel

X




X

X

X

X




Bivalirudin Bolus + Infusion






















Continuous Vectorcardiography




X


X













Coronary Angiography (Including TIMI Flow, TIMI Frame Count, Blush,)




X
















Angioplasty




X
















Provisional gp IIbIIIa receptor blocker if Angioplasty is performed




X
















Coronary flow




Optional
















CK-MB, TNT

X







X










Echocardiography










X










MRI (Infarct size)
















X




MACE













X


X

X

Flow Chart


Bi Smart


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