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
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EudraCT number |
2010-023211-34 |
Trial protocol |
GB |
Global end of trial date |
10 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Apr 2019
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First version publication date |
03 Apr 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EDGE ID 11488 / CLRN 53469
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01747174 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University Hospitals of Leicester NHS Trust
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Sponsor organisation address |
Trust HQ. Level 3. Balmoral Building. Leicester Royal Infirmary, Leicester, United Kingdom, LE1 5WW
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Public contact |
Professor Anthony Gershlick, University Hospitals of Leicester NHS Trust, agershlick@aol.com
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Scientific contact |
Professor Anthony Gershlick, University of Leicester, agershlick@aol.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Dec 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Sep 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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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?
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 247
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Worldwide total number of subjects |
247
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EEA total number of subjects |
247
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
167
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From 65 to 84 years |
76
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85 years and over |
4
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Recruitment
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Recruitment details |
STEMI patients were enrolled between October 2011 and April 2014 in four regional cardiac centres in the UK. | ||||||||||||||||||||||||
Pre-assignment
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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
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Period 1 title |
Final enrolment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Adenocor
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intracoronary use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Sodium pentacyanonitrosylferrate(II), Sodium nitroferricyanide, Sodium pentacyanonitrosylferrate, SNP
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intracoronary use
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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.
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Arm title
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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
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Baseline characteristics reporting groups
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Reporting group title |
Standard PCI + Intra-coronary (IC) Adenosine
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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)
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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
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Reporting group description |
Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Standard PCI + Intra-coronary (IC) Adenosine
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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)
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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
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Reporting group description |
Procedure: Standard PCI PCI procedure with thrombectomy (via aspiration catheter) and bivalirudin given as standard. |
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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)
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End point type |
Primary
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End point timeframe |
48-72 hours post-infarct
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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).
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Comparison groups |
Standard PCI + Intra-coronary (IC) Adenosine v Standard PCI
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Number of subjects included in analysis |
128
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||||||
P-value |
= 0.062 | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Confidence interval |
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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. |
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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).
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Comparison groups |
Standard PCI v Standard PCI + IC Sodium Nitroprusside (SNP)
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||||||
P-value |
= 0.16 | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Confidence interval |
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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. |
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End point title |
MACE | ||||||||||||
End point description |
Composite of death, stroke, re-infarction, heart failure and target lesion revascularisation
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End point type |
Secondary
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End point timeframe |
Up to 6 months (180 days) follow-up from enrolment date (date of myocardial infarction)
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No statistical analyses for this end point |
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Adverse events information [1]
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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.
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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.
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Assessment type |
Systematic | ||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
14.1
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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". |
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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 |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |