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    Clinical Trial Results:
    Randomized Controlled Trial Comparing Intracoronary Administration of Adenosine or Sodium Nitroprusside to Control for Attenuation of Microvascular Obstruction During Primary Percutaneous Coronary Intervention

    Summary
    EudraCT number
    		 2010-023211-34
    Trial protocol
    		 GB  
    Global end of trial date
    10 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2019
    First version publication date
    03 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EDGE ID 11488 / CLRN 53469
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01747174
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals of Leicester NHS Trust
    Sponsor organisation address
    Trust HQ. Level 3. Balmoral Building. Leicester Royal Infirmary, Leicester, United Kingdom, LE1 5WW
    Public contact
    Professor Anthony Gershlick, University Hospitals of Leicester NHS Trust, agershlick@aol.com
    Scientific contact
    Professor Anthony Gershlick, University of Leicester, agershlick@aol.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal objective of our proposed study is to determine:- 1) Whether adjunctive medical treatment given via a very small tube (microcatheter) placed beyond the blockage downstream in the affected heart attack artery at the time of angioplasty for heart attack and following blood clot removal from the heart vessel, reduces downstream small blood vessel/microvascular obstruction (MVO) and heart muscle damage size (infarct size, IS) as determined by using cardiac magnetic resonance (CMR) scanners. The principal study question is: 1) How might we attenuate small blood vessel obstruction and thus reduce heart attack size in patients undergoing angioplasty for heart attack?
    Protection of trial subjects
    All patients received intravenous (IV) analgesia as required throughout the course of the treatment for their heart attack as part of standard therapy, pre-, peri- and post-procedure during which the blocked heart artery was re-opened using standard coronary angioplasty techniques.
    Background therapy
    		 In all cases, PPCI was performed in line with accepted practice with trans-radial or femoral arterial access using 6-7 French size sheaths. Patients were pre-treated with dual antiplatelet therapy with aspirin (300mg loading dose and 75mg/day maintenance) and Prasugrel (60mg loading dose and 10mg/day maintenance) or Ticagrelor (loading dose 180mg and maintenance dose of 90mg twice daily) and given for up to 12 months. Bivalirudin, an anticoagulant agent, was administered to all patients (0.75 mg/Kg bolus plus infusion of 1.75 mg/Kg/hr) (as was regarded as standard practice then, in the absence of specific contraindication
    Evidence for comparator
    		 Adenosine is a potent vasodilator of arterioles and has been shown to reduce adverse outcome and death in the setting of MVO. In experimental animal models, adenosine reduces ischaemia-reperfusion injury, limits IS, and improves ventricular function. Studies have reported lower MVO rates following IC adenosine boluses and reduced IS expressed as a percentage of the area at risk (AAR) following 3h IV adenosine infusion compared with placebo. Sodium nitroprusside (SNP) is a direct nitric oxide (NO) donor demonstrated to have multiple vascular functions, including vasodilatation of arterioles, inhibition of platelet adhesion and anti-inflammatory activity. Local delivery of SNP is effective in reducing MVO in animal reperfusion-injury models. Furthermore, IC SNP appears to produce an equivalent but more prolonged coronary hyperaemia than adenosine. Studies have reported improved myocardial reperfusion with IC SNP.
    Actual start date of recruitment
    01 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 247
    Worldwide total number of subjects
    247
    EEA total number of subjects
    247
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    167
    From 65 to 84 years
    76
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 STEMI patients were enrolled between October 2011 and April 2014 in four regional cardiac centres in the UK.

    Pre-assignment
    Screening details
    		 All patients >18 years age, presenting within 6 hours of symptom onset of STEMI, with ST-segment elevation ≥2mm in ≥2 contiguous leads and with a baseline corrected QT interval (QTc) <450ms on admission ECG were eligible and assented.

    Period 1
    Period 1 title
    Final enrolment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Following consent, patients were randomised 1:1:1 to: adjunctive IC adenosine, SNP or control (standard angioplasty alone), by a member of the research team, using a dedicated 24/7 computerised telephone service. All analyses were conducted blinded to patient details A clinical events committee, blinded to patient details and treatment allocation, reviewed and adjudicated key trial adverse events using original source documents.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard PCI + Intra-coronary (IC) Adenosine
    Arm description
    		 Drug: IC Adenosine IC Adenosine 1mg injected distally via micro-catheter in to infarct-related artery (IRA) following thrombus aspiration with further dose (1mg if IRA is right coronary artery otherwise 2mg) via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI (angioplasty) procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adenosine
    Investigational medicinal product code
    Other name
    Adenocor
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intracoronary use
    Dosage and administration details
    Following manual thrombectomy and thorough flushing of the catheter, the first drug dose (adenosine 1 mg) was injected as distally as possible via the thrombus aspiration catheter. Immediately following stent deployment, and providing a repeat measure of QTc was <450ms and remained <60ms increased over the baseline value, the second drug dose (adenosine 1mg if IRA was the right coronary artery (RCA) otherwise 2mg) was given by slow injection (over 1 minute) via the guide catheter.

    Arm title
    		 Standard PCI + IC Sodium Nitroprusside (SNP)
    Arm description
    		 Drug: IC Sodium nitroprusside (SNP) IC SNP 250mcg injected distally via micro-catheter distally in to IRA following thrombus aspiration with further 250 mcg dose delivered via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium nitroprusside
    Investigational medicinal product code
    Other name
    Sodium pentacyanonitrosylferrate(II), Sodium nitroferricyanide, Sodium pentacyanonitrosylferrate, SNP
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intracoronary use
    Dosage and administration details
    Following manual thrombectomy and thorough flushing of the catheter, the first drug dose (SNP 250 mcg) was injected as distally as possible via the thrombus aspiration catheter. Immediately following stent deployment, and providing a repeat measure of QTc was <450ms and remained <60ms increased over the baseline value, the second drug dose (SNP 250 mcg) was given by slow injection (over 1 minute) via the guide catheter.

    Arm title
    		 Standard PCI
    Arm description
    		 Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Standard PCI + Intra-coronary (IC) Adenosine Standard PCI + IC Sodium Nitroprusside (SNP) Standard PCI
    Started
    82
    79
    86
    Completed
    77
    75
    81
    Not completed
    5
    4
    5
         Consent withdrawn by subject
    4
    3
    5
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard PCI + Intra-coronary (IC) Adenosine
    Reporting group description
    		 Drug: IC Adenosine IC Adenosine 1mg injected distally via micro-catheter in to infarct-related artery (IRA) following thrombus aspiration with further dose (1mg if IRA is right coronary artery otherwise 2mg) via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI (angioplasty) procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Reporting group title
    Standard PCI + IC Sodium Nitroprusside (SNP)
    Reporting group description
    		 Drug: IC Sodium nitroprusside (SNP) IC SNP 250mcg injected distally via micro-catheter distally in to IRA following thrombus aspiration with further 250 mcg dose delivered via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Reporting group title
    Standard PCI
    Reporting group description
    		 Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Reporting group values
    		 Standard PCI + Intra-coronary (IC) Adenosine Standard PCI + IC Sodium Nitroprusside (SNP) Standard PCI Total
    Number of subjects
    		 82 79 86 247
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ± 12.8 60.5 ± 13.0 59.5 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    		 17 13 22 52
        Male
    		 65 66 64 195

    End points

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    End points reporting groups
    Reporting group title
    Standard PCI + Intra-coronary (IC) Adenosine
    Reporting group description
    		 Drug: IC Adenosine IC Adenosine 1mg injected distally via micro-catheter in to infarct-related artery (IRA) following thrombus aspiration with further dose (1mg if IRA is right coronary artery otherwise 2mg) via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI (angioplasty) procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Reporting group title
    Standard PCI + IC Sodium Nitroprusside (SNP)
    Reporting group description
    		 Drug: IC Sodium nitroprusside (SNP) IC SNP 250mcg injected distally via micro-catheter distally in to IRA following thrombus aspiration with further 250 mcg dose delivered via guide catheter following coronary stent deployment. Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Reporting group title
    Standard PCI
    Reporting group description
    		 Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard.

    Primary: CMR-infarct size

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    End point title
    		 CMR-infarct size
    End point description
    CMR measured infarct size (determined from late-gadolinium enhanced CMR images) expressed as % of total left ventricular mass (determined by functional analysis of CMR cine images)
    End point type
    Primary
    End point timeframe
    48-72 hours post-infarct
    End point values
    		 Standard PCI + Intra-coronary (IC) Adenosine Standard PCI + IC Sodium Nitroprusside (SNP) Standard PCI
    Number of subjects analysed
    63
    69
    65
    Units: % Left ventricular Mass
        median (inter-quartile range (Q1-Q3))
    10.1 (4.7 to 16.2)
    10 (4.2 to 15.8)
    8.3 (1.9 to 14)
    Statistical analysis title
    		 Adenosine vs Control
    Statistical analysis description
    Comparison of infarct size between patients receiving intra-coronary adenosine during angioplasty and control group (those who did not receive a study drug i.e. conventional primary angioplasty alone).
    Comparison groups
    Standard PCI + Intra-coronary (IC) Adenosine v Standard PCI
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.062
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Comparison of infarct size between groups via independent t-test on log-transformed scale. Potential significant confounders of infarct size (age, sex, diabetes, anterior MI, ischaemia time and collateral blood flow to the infarct territory determined by the Rentrop score were adjusted for.
    Statistical analysis title
    		 SNP vs Control
    Statistical analysis description
    Comparison of infarct size between patients receiving intra-coronary SNP during angioplasty and control group (those who did not receive a study drug i.e. conventional primary angioplasty alone).
    Comparison groups
    Standard PCI v Standard PCI + IC Sodium Nitroprusside (SNP)
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.16
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - Comparison of infarct size between groups via independent t-test on log-transformed scale. Potential significant confounders of infarct size (age, sex, diabetes, anterior MI, ischaemia time and collateral blood flow to the infarct territory determined by the Rentrop score were adjusted for.

    Secondary: MACE

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    End point title
    		 MACE
    End point description
    Composite of death, stroke, re-infarction, heart failure and target lesion revascularisation
    End point type
    Secondary
    End point timeframe
    Up to 6 months (180 days) follow-up from enrolment date (date of myocardial infarction)
    End point values
    		 Standard PCI + Intra-coronary (IC) Adenosine Standard PCI + IC Sodium Nitroprusside (SNP) Standard PCI
    Number of subjects analysed
    82
    79
    86
    Units: Integers
    12
    5
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All patients were followed up for at least one month following randomisation and throughout the course of the study until the last patient recruited to the trial had completed one-month follow-up.
    Adverse event reporting additional description
    Patients were contacted by telephone for follow-up at 6 months according to the study protocol. Unscheduled hospital admissions were also screened. Patients were additionally flagged with the Office for National Statistics to ensure mortality data was captured.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: all significant adverse events (serious and non-serious) are described in the publication of the main trial results, which has been attached to the record".

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2012
    1) Addition of Ticagrelor as 2nd antiplatelet following publication of PLATO trial in line with ESC guidance. 2) Change of bleeding criteria from that used in HORIZONS-AMI to the TIMI criteria, due to the latter being most commonly used in interventional cardiology trials

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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