Clinical trial NCT01747174: REperfusion Facilitated by LOcal Adjunctive Therapy in ST-elevation Myocardial Infarction
Official title: Randomized Controlled Trial Comparing Intracoronary Administration of Adenosine or Sodium Nitroprusside to Control for Attenuation of Microvascular Obstruction During Primary Percutaneous Coronary Intervention
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: ST-elevation Myocardial Infarction (STEMI)
Keywords: STEMI
Microvascular Obstruction
No-reflow
Adenosine
Sodium Nitroprusside
Lead sponsor: University Hospitals, Leicester
Sponsor class: OTHER
First posted: 2012-12-11
Enrollment: 247
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether intra-coronary adenosine or sodium nitroprusside (SNP) delivered selectively via a thrombus aspiration catheter (or if unsuccessful via a coronary microcatheter) following thrombus aspiration in Primary Percutaneous Coronary Intervention (P-PCI) reduces microvascular obstruction (MVO) parameters and infarct size as measured with cardiac MRI, compared with standard treatment following thrombus aspiration in patients presenting with ST-elevation myocardial infarction (STEMI).

Detailed description: \>100,000 patients suffering STEMI present in the UK each year. P-PCI in the UK is increasing exponentially. In 2004 there were \<1500 P-PCI and in 2007 and 2008 these figures had increased to 5902 and 9224 respectively (BCIS database).

Although P-PCI delivered quickly is more effective than thrombolysis, the efficacy of this, essentially mechanical, technique is limited by the unpredictable phenomenon of no-reflow and the under-stated lesser degrees of MVO. As more UK centres adopt P-PCI the dilemma of how to attenuate MVO will remain. Currently there is no consensus on the optimal management to prevent or attenuate MVO particularly when thrombus laden lesions are treated with P-PCI.

There is divergent clinical practice, even within institutions, in the UK and worldwide. This is because there is no solid evidence base to inform clinicians. The current options for interventional cardiologists are:

1. Routinely aspirate thrombus and give IC vasodilator during the intervention but only in high burden thrombus formation lesions.
2. Perform a standard P-PCI only and then give IV vasodilator if angiographic no-reflow develops.
3. Routinely consider that angiographically silent MVO (i.e a grade below true "no-reflow") may have important impact on infarct size and clinical outcome and treat prophylactically.

Few if any clinicians follow this thinking. Indeed, it appears impossible to predict the incidence of (no-reflow/MVO) from the presenting angiogram (pre- or post- wire or balloon) and it can be argued that irrespective of thrombus burden it would be better to undertake prophylactic treatment in all patients, following the use of aspiration catheter, with delivery of agents able, in theory at least, to reduce (angiographically undetectable) MVO. Several studies of IC adenosine or SNP have shown favourable effects in attenuating MVO. However, the size of effect with either drug and whether indeed there is a difference between them in reducing MVO and infarct size is undetermined.

The objectives of our proposed study are to determine:

1. Whether adjunctive pharmaco-therapy at time of P-PCI and following thrombus aspiration, reduces CMR-determined MVO and infarct size.
2. Whether there is a difference between adenosine and SNP in reducing CMR-detected MVO and infarct size, both given selectively and distally via a thrombus aspiration catheter or a coronary microcatheter.
3. The correlation of angiographic, including the recently designed computer-assisted myocardial blush quantification 'Quantitative Blush Evaluator'(QuBE), and other myocardial perfusion markers, with CMR detected MVO and infarct size, as well as with clinical outcome (MACE) at 30 days.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years age.
* Informed ASSENT (verbal consent) prior to angiography.
* STEMI ≤ 6 hrs of symptom onset, requiring primary reperfusion by PCI.
* Single-vessel coronary artery disease (non culprit disease ≤70% stenosis at angiography)
* TIMI flow 0/I at angiography.

Exclusion Criteria:

* Contraindications to: P-PCI \*, CMR\*\*, contrast agents, or study medications: Adenosine\*\*\*, SNP\*\*\*\*, Aspirin, Thienopyridine and Bivalirudin.
* SBP ≤ 90mmHg
* Cardiogenic Shock
* Previous Q wave myocardial infarction
* Culprit lesion not identified or located in a by-pass graft
* Stent thrombosis.
* Left main disease.
* Known severe asthma.
* Known stage 4 or 5 chronic kidney disease (eGFR\<30ml/min).
* Pregnancy.

Notes:

* \* Exclusion criteria for P-PCI (presentation timing, inadequate arterial access etc); patient unable to tolerate "prolonged" PCI procedure (in operators' opinion).
* \*\* Absolute contra-indication to CMR (Pacemaker, ICD, intra-cranial metal clips).
* \*\*\* Contraindications to Adenosine (known hypersensitivity to Adenosine, sick sinus syndrome, second or third degree atrio-ventricular block - except in patients with functioning artificial pacemaker, long QT syndrome has been defined as QTc \> 450 ms at baseline). ECG will be undertaken just after the first dose of the study drug and QT/QTc will be recorded and compared to the baseline. If the QTc recorded after the first dose of the study drug exceeds 450ms or there is an increase in the QT/QTc of \> 60 ms from baseline, the second dose will be abandoned and this will be recorded.
* \*\*\*\* Contraindications to SNP (known hypersensitivity to SNP, compensatory hypertension - as may be seen in arteriovenous shunts or coarctation of the aorta, high output failure, congenital optic atrophy or tobacco amblyopia).

Primary outcomes:
measure: CMR measured infarct size (% LV mass)
timeFrame: 48-72 hours post procedure
Secondary outcomes:
measure: CMR incidence and extent of MVO (% LV mass)
timeFrame: 48-72 hours post procedure
measure: CMR measured myocardial salvage index, haemorrhage, LV EF and volumes
timeFrame: 48-72 hours post procedure
measure: Myocardial Blush Grade assessed by validated computer software 'Quantitative Blush Evaluator' (QuBE
timeFrame: During P-PCI
measure: Incidence pre- and post- procedure angiographic true "no-reflow"
timeFrame: During P-PCI
measure: Any in-patient clinical events
timeFrame: Within 6 months from presentation with, and PCI for, STEMI
measure: Overall MACE
timeFrame: 1 month
measure: Degree of ST segment resolution on ECG
timeFrame: Assessed immediately following P-PCI (expected on average 1 hour)
measure: Echocardiographic assessment of LV
timeFrame: 6-8 weeks post-procedure/MI
measure: Corrected TIMI Frame Count
timeFrame: During procedure
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
state: Leicestershire
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne and Wear
city: Coventry
country: United Kingdom
facility: University Hospital
state: West Midlands
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
state: West Yorkshire
Study officials:
affiliation: University of Leicester
name: Anthony H Gershlick, MBBS, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nazir SA, McCann GP, Greenwood JP, Kunadian V, Khan JN, Mahmoud IZ, Blackman DJ, Been M, Abrams KR, Shipley L, Wilcox R, Adgey AA, Gershlick AH. Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial. Eur Heart J. 2016 Jun 21;37(24):1910-9. doi: 10.1093/eurheartj/ehw136. Epub 2016 May 4.
citation: Nazir SA, Khan JN, Mahmoud IZ, Greenwood JP, Blackman DJ, Kunadian V, Been M, Abrams KR, Wilcox R, Adgey AA, McCann GP, Gershlick AH. The REFLO-STEMI trial comparing intracoronary adenosine, sodium nitroprusside and standard therapy for the attenuation of infarct size and microvascular obstruction during primary percutaneous coronary intervention: study protocol for a randomised controlled trial. Trials. 2014 Sep 25;15:371. doi: 10.1186/1745-6215-15-371.