Clinical trial NCT03707314: Very Early Versus Delayed Angiography +/- Intervention on Outcomes in Patients With NSTEMI
Official title: A Randomised Controlled Trial of Very Early Angiography +/- Intervention Versus Standard of Care on Outcomes in Patients With Non ST-elevation Myocardial Infarction
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Cardiovascular; Attack
Keywords: NSTEMI
Lead sponsor: University Hospitals, Leicester
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
name: University of East Anglia
name: University of Leicester
First posted: 2018-10-16
Enrollment: 425
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-centre parallel design
Primary purpose: TREATMENT

Brief summary: Prospective, open, multicentre, randomised controlled trial in patients with higher risk non-ST elevation myocardial infarction acute coronary syndrome

Detailed description: Background: Clinical event rates in Non ST elevation myocardial infarction acute coronary syndrome (N-STEMI ACS) patients remain high, with one year MACE rates as high as 20%. While there may be early mortality differences between N-STEMI and STEMI, outcomes beyond one year become very similar. N-STEMI ACS patients therefore rightly remain the focus of a number of research directives. The objective of the RAPID-NSTEMI trial is to determine if clinical outcomes can be improved by very early intervention in a pre-determined higher risk N-STEMI ACS population. Published data has shown that inpatient Percutaneous Coronary Intervention (PCI) in N-STEMI ACS patients reduces subsequent clinical events. This had led to guidelines supporting its use in clinical practice. However, there is much less certainty regarding the timing of the PCI and, in particular, whether this should be a strategy used early to optimize outcomes. Thus, while evidence based guidelines (NICE and European) provide general time parameters for PCI, immediate angiography with a view to intervention in higher risk patients has never been robustly tested in any adequately powered, prospective randomised trial with clinical end points. The RAPID-NSTEMI trial sets out to test the benefits, or otherwise, of a strategy of immediate angiography with follow-on revascularisation in higher risk N-STEMI ACS patients.

Hypothesis: Very early angiography +/- PCI improves clinical outcomes in higher risk NSTEMI patients when compared to standard invasive management.

Methods: In order to identify higher risk patients as soon as possible after presentation, a high sensitivity troponin (Hs-Troponin-T or Hs-Troponin-I) will be taken, allowing calculation of a GRACE 2.0 score (GS 2.0) early after admission. The GS 2.0 will be determined in sufficient time to be able to test an early intervention strategy arm. Patients with GS 2.0 of ≥118 alone, or ≥90 with additional high risk features will be randomised in a 1:1 fashion to one of two groups:

Group A: immediate angiography with follow-on revascularisation if required Group B: standard care - pharmacological treatment until angiography with follow on revascularisation if required (preferably within 72 hours as per current guidelines).

The primary outcome for the main study will be a 12-month of all-cause mortality, new myocardial infraction and hospital admission with heart failure.

Power calculations indicate that 2314 patients are required to show MACE superiority for early intervention in such higher risk N-STEMI ACS patients.

Analyses will be primarily according to "intention to treat", with a secondary analysis according to trial treatment received (comparing those who actually received follow-on revascularisation at the two different trial time points). There will be a cost effectiveness analysis.

Mechanistic sub-studies in the two groups will be undertaken.

1. Cardiac magnetic resonance imaging substudy to assess differences in infarct size, oedema, microvascular obstruction and left ventricular ejection fraction between the two arms.
2. Novel biomarkers substudy that will be funded separately after appropriate funding applications

Expected value of results: The investigators have designed a superiority trial to anticipate that outcomes will be improved in higher risk patients revascularised very early after presentation with N-STEMI. Irrespective of outcome, this trial should determine whether there is a need for a change in current patient management of a common condition and, in particular, if all N-STEMI patients should be admitted to a PCI-capable hospital to allow for very early intervention. The results will inform national and international guidelines. The planned cost effectiveness analysis will become particularly important if clinical outcomes are no different between groups since length of stay should be different.

Eligibility criteria: Inclusion Criteria

* 18 years of age and over
* Patients presenting to hospitals with a clinical diagnosis of non-ST elevation myocardial infarction comprising:

  * Ischaemic symptoms (as defined in Appendix III of protocol)
  * Elevated high sensitivity Troponin T or I (above the normal range for individual hospitals)
* GRACE-2.0 score (www.gracescore.org) of either:

  * ≥118 (corresponding to 6-month death \>6%) OR
  * ≥90 but \<118 (corresponding to 6-month death \>3% but \<6%)
* If GRACE 2.0 score ≥90 or \<118 must have at least one additional high risk feature:

  * Anterior location of ECG changes (leads V2 - V5)
  * ST-segment depression in 2 contiguous leads (any territory) of 0.15mV/ 1.5mm.
  * Diabetes Mellitus on medication
  * High-sensitivity Troponin I or T 3 x ULN
* Onset of ischaemic symptoms at any time prior to admission but most recent episode within 12 hours to admission
* Intention to perform angiography and, if indicated, follow-on revascularisation
* Provision of assent or written consent
* Randomisation must be performed within 6 hours of admission

Exclusion Criteria

* ST elevation myocardial infarction
* Evident type 2 myocardial infarction (e.g. anaemia)
* Evidence of previous known cardiomyopathy
* Cardiogenic Shock
* Known severe valvular heart disease
* Need for urgent PCI according to ESC Guidelines (haemodynamic instability, VT, VF, recurrent or persistent pain)
* Any contraindication to PCI
* Current participation in another intervention trial

Primary outcomes:
measure: Major adverse cardiovascular events
timeFrame: 12 months
Secondary outcomes:
measure: All-cause mortality
timeFrame: 12 months
measure: New myocardial infarction
timeFrame: 12 months
measure: Heart failure
timeFrame: 12 months
measure: Cardiovascular mortality
timeFrame: 12 months
measure: Length of in-patient stay
timeFrame: Through study completion, 3 years
measure: All-cause mortality prior to planned coronary angiography
timeFrame: During index admission
measure: New myocardial infarction prior to planned coronary angiography
timeFrame: During index admission
measure: Major bleeding prior to planned coronary angiography
timeFrame: During index admission
measure: Admission for ischaemia-driven revascularisation
timeFrame: 12 months
measure: Admission for any cause
timeFrame: 12 months
measure: Quality of life measured using Seattle Angina Questionnaire
timeFrame: 12 months
measure: Quality of life measured using EuroQoL-5D-5L questionnaire
timeFrame: 12 months
measure: BARC 3-5 bleeding
timeFrame: 12 months
measure: Stroke
timeFrame: 12 months
measure: Cost effectiveness
timeFrame: 12 months
measure: Left ventricular ejection fraction on cardiac MRI
timeFrame: 7 days (+/-3 days)
measure: Infarct size on cardiac MRI
timeFrame: 7 days (+/-3 days)
measure: Proportion of patients needing emergency/urgent revascularisation
timeFrame: 3-4 days (standard of care timing angiography will vary between recruiting centres)
measure: Total access site complications
timeFrame: 12 months
measure: Major access site complications
timeFrame: 12 months
measure: Sensitivity and specificity of novel biomarkers for predicting need for revascularisation
timeFrame: 3-4 days (standard of care timing angiography will vary between recruiting centres)
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Glenfield Hospital, University Hospitals of Leicester NHS Trust
Study officials:
affiliation: Oxford University Hospitals NHS Trust
name: Adrian Banning
role: STUDY_CHAIR
References:
citation: Kite TA, Banning AS, Ladwiniec A, Gale CP, Greenwood JP, Dalby M, Hobson R, Barber S, Parker E, Berry C, Flather MD, Curzen N, Banning AP, McCann GP, Gershlick AH. Very early invasive angiography versus standard of care in higher-risk non-ST elevation myocardial infarction: study protocol for the prospective multicentre randomised controlled RAPID N-STEMI trial. BMJ Open. 2022 May 3;12(5):e055878. doi: 10.1136/bmjopen-2021-055878.