Clinical trial NCT01764334: Fractional Flow Reserve Versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes
Official title: A Developmental Clinical Study of Management Guided by Coronary Angiography Combined With Fractional Flow Reserve (FFR) Measurement Versus Management Guided by Coronary Angiography Alone(Standard Care) in Patients With Non-ST Elevation MI.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: NonST Elevation Myocardial Infarction
Myocardial Infarction
Keywords: NonST elevation myocardial infarction (NSTEMI)
Fractional flow reserve (FFR)
Coronary angiogram
Diagnosis
Coronary revascularization
Prognosis
Health economics
Lead sponsor: NHS National Waiting Times Centre Board
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
name: Abbott Medical Devices
name: University of Glasgow
First posted: 2013-01-09
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Diagnostic intervention using fractional flow reserve
Primary purpose: DIAGNOSTIC

Brief summary: Background: In patients with acute non-ST elevation myocardial infarction (NSTEMI) coronary arteriography is usually recommended however visual interpretation of the coronary angiogram is subjective. A complementary diagnostic approach involves measuring the pressure drop across a coronary stenosis (fractional flow reserve, FFR) with a pressure-sensitive guidewire.

Hypothesis: Routine FFR measurement is feasible in NSTEMI patients and has additive diagnostic, clinical and health economic utility, as compared to angiography-guided standard care.

Design: A prospective multi-center randomized controlled trial in 350 NSTEMI patients with ≥1 coronary stenosis ≥30% severity (threshold for FFR measurement). Patients will be randomized immediately after coronary angiography to the FFR-guided group or angiography-guided group (FFR measured, not disclosed). All patients will then undergo FFR measurement in all vessels with a coronary stenosis ≥30% severity. FFR will be measured in culprit and non-culprit lesions in all patients. FFR will be disclosed to guide treatment in the FFR guided-group but not disclosed in the 'angiography-guided' group. In the FFR-guided group, an FFR\>0.80 will be an indication for medical therapy whereas an FFR≤0.80 will be an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG), as appropriate. The primary endpoint is the between-group difference in the proportion of patients allocated to medical management compared to revascularization. A key secondary composite outcome is the occurrence of cardiac death or hospitalization for myocardial infarction or heart failure. Other secondary outcomes include quality of life, hospitalization for unstable angina, coronary revascularization or stroke, and healthcare costs. Exploratory analyses will also assess the relationships between FFR and angiographic lesion characteristics (severity, culprit status). The minimum and average follow-up periods for the primary analysis are 6 and 18 months respectively. A secondary analysis with longer term follow-up (minimum 3 years) is planned. Screen failures who gave informed consent will be entered into a registry.

Importance: Our developmental clinical trial will address the feasibility of FFR measurement in NSTEMI and the influence of FFR disclosure on treatment decisions and health and economic outcomes.

Detailed description: Background

Acute non-ST elevation myocardial infarction (NSTEMI) is the commonest form of acute coronary syndrome (ACS) and a leading global cause of premature morbidity and mortality. A coronary angiogram is recommended in intermediate-high risk NSTEMI patients to detect obstructive coronary artery disease (CAD) and so identify patients who may benefit from coronary revascularization. In ACS patients, stress testing before invasive management is not recommended and so functional information on ischemia is usually not available. Therefore, usual care is based on visual interpretation of coronary disease severity revealed by the angiogram and treatment decisions include medical therapy, percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Since visual assessment of the angiogram may be inaccurate, judgements made by cardiologists in every day practice are subjective, potentially leading to misdiagnosis and incorrect treatment decisions.

Recent studies (DEFER, FAME, FAME II) in patients with stable coronary artery disease (CAD) have presented a new approach to the diagnostic management of CAD. Fractional flow reserve (FFR) is an index of the physiological significance of a coronary stenosis and is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow. An FFR ≤0.80 is an evidence-based physiological threshold that correlates with the presence of inducible ischemia on non-invasive testing. Alternatively, an FFR \>0.80 indicates that patients can be managed safely with medical therapy. DEFER and FAME highlighted the benefits of FFR measurement in stable CAD to more accurately identify flow-limiting stenoses and guide PCI leading to improved outcomes and reduced costs compared to angiography alone. In FAME 2, compared to optimal medical therapy alone, PCI combined with optimal medical therapy reduced the likelihood of urgent revascularization in patients with stable symptoms and functionally significant coronary disease. Overall, FFR measurement can identify and exclude obstructive coronary artery disease with high diagnostic accuracy, including in patients with prior MI.

FFR measurement in unstable coronary artery disease

There is some uncertainty over the validity of FFR when measured in patients with recent MI. FFR measurement requires maximal coronary hyperemia which theoretically may be less readily achieved in patients with recent MI, potentially, because of microvascular injury.

The results of several recent studies support the notion that FFR measurements are valid in medically stabilized MI patients. First, Ntalianis et al measured FFR in 112 non-culprit coronary lesions repeatedly (average interval 35±4 days) in 101 patients with recent MI and found similar FFR values at each time-point. In one other study, FFR correctly identified inducible ischemia on SPECT in 57 patients \>6 days after MI and in one other study of 124 ACS patients, deferring revascularization in lesions with an FFR ≥ 0.75 was safe during longer term follow-up. In hospitalized patients with recent MI and angiographic intermediate coronary lesions, FFR-guided management reduced in-hospital costs compared to deferred management with revascularization guided by myocardial stress perfusion scintigraphy. Finally, nearly one third of the patients randomized in FAME had a history of medically stabilized unstable angina or NSTEMI five or more days from randomization. The FAME investigators performed a post-hoc analysis of these patients and found a similar risk reduction for major adverse cardiovascular events in the FFR group compared to the angiography-guided group leading them to conclude that the benefit of using FFR to guide PCI in multivessel disease may not differ between patients with unstable vs. stable coronary disease. The FAME investigators concluded that their post hoc analysis could not prove equivalence of effects between subgroups since FAME was neither designed nor powered to do so.

Therefore, the potential diagnostic, prognostic and health economic impact of FFR measurement to inform the management of unselected patients with recent (i.e. \< 5 days) medically stabilized NSTEMI has not been established.

Specific uncertainties with angiography-guided treatment decisions in NSTEMI.

First, treatment decisions for non-obstructive (FFR\>0.80) culprit CAD lack an evidence base to guide management. On the one hand, a stent which covers a ruptured coronary plaque might reduce the risks of recurrent thrombosis. On the other hand, optimal medical therapy with dual anti-platelet drugs and high dose statins might suffice and unnecessary stenting can be harmful (e.g. stent thrombosis). Second, in NSTEMI patients with multivessel coronary disease, evidence is lacking as to whether non-culprit obstructive lesions should undergo revascularization or not. A post-hoc analyses of the contemporary large scale Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial found that incomplete coronary revascularization was a multivariable predictor of major adverse cardiac events at 1 year and the risk was related to the number of non-revascularized lesions. A post hoc analysis of NSTEMI patients treated during usual care has found that FFR disclosure does influence cardiologists' treatment decisions leading to improved diagnostic efficiency compared angiography-guided decisions. Third, uncertainties remain about whether maximal coronary hyperemia can be achieved in patients with recent MI using the standard dose of adenosine (140 micrograms/kg/min) or whether higher doses of adenosine (170 - 210 micrograms/kg/min) might be needed. This question is relevant since sub-maximal coronary vasodilatation could be associated with a falsely elevated FFR value which in turn could result in an inappropriate decision in favor of medical therapy rather than revascularization.

Rationale for a trial of FFR-guided management vs. angiography alone in NSTEMI.

FFR measurement is not a current standard of care in NSTEMI patients. Therefore, in our study, FFR will be measured but not disclosed in the angiography-guided control group. Second, FFR values and their relationships with clinical outcomes may differ in patients with unstable coronary disease compared to patients with stable coronary disease. In our trial, FFR will be measured in all patients including in the angiography-guided control group (175 patients) in whom FFR will be measured but not disclosed to the clinical team responsible for the patient. Since patients will be followed-up for clinical events, the relationships (and ROC values) between FFR and health outcomes (composite cardiovascular events) will be prospectively evaluated.

Third, since stress testing is not appropriate in acute MI patients, FFR-guided management could obviate the need for 'deferred' management. Fourth, FFR has the potential to guide the decision for or against revascularization of culprit and non-culprit lesions. Since there are no data to support stenting in lesions which are not functionally significant, the investigators propose that the treatment decisions are consistently guided by the FFR values in both culprit and non-culprit arteries using the established FFR threshold of 0.80 for revascularization. Non-flow limiting lesions (FFR\>0.80) would be treated with optimal medical therapy and flow-limiting lesions (FFR≤0.80) should revascularized by PCI or CABG. Fifth, when stenting is performed, the post-stent FFR can be used to ensure that an optimal stent result is achieved i.e. an FFR \>0.9 in both the culprit and non-culprit lesions treated by PCI.

Study Hypothesis

Routine FFR measurement is feasible in NSTEMI patients and has additive diagnostic, clinical and health economic utility, as compared to current standards of care based on visual assessment of the angiogram.

Methodology

Overall aim: To generate evidence that will permit (or not) the development of new diagnostic and disease management strategies which will accurately and efficiently distinguish between flow limiting and non-flow limiting coronary stenoses, a major challenge in current revascularization strategies in patients with recent MI directed by angiography alone.

Primary Aims:

1) To determine if the treatment and outcomes of NSTEMI patients whose management is guided by FFR disclosure differ compared to patients whose treatment is guided by visual interpretation of the angiogram alone (FFR measured, not disclosed).

Secondary Aims:

1. To determine the feasibility and safety of routine coronary guidewire-based FFR measurement in NSTEMI,
2. To determine the level of agreement between functional (FFR) and visual assessments of coronary disease severity in NSTEMI patients,
3. To assess the proportion of patients with a clinical response to adenosine (initial dose of 140 µg/kg/min, maximum dose 210 µg/kg/min), as revealed by typical changes in heart rate and blood pressure and the occurrence of patient symptoms,
4. To determine the relationships between FFR values during the baseline procedure (and receiver operating characteristic) and cardiac events during follow-up in all patients,
5. To provide preliminary data on whether FFR-guided management is associated with improved health outcomes and quality of life in the longer term compared to angiography-guided treatment decisions,
6. To perform a health-economic analysis.

Standard care of NSTEMI patients in the UK National Health Service

The participating hospitals adhere to current guidelines for optimal medical therapy and optimal revascularization. A left main stenosis of \>50% and an epicardial coronary stenosis \>70% are usually taken to be obstructive lesions for which revascularization should be considered. In usual care, FFR is normally measured in a minority of patients (\<10% of patients overall) and is not standard care. Patients who may be candidates for CABG will be discussed at the Multidisciplinary Heart Team meeting in each center. If staged PCI is clinically indicated then all procedures should take place during the index hospitalization.

Setting and Design

A prospective randomized controlled trial will be conducted in up to 6 UK centers including 3 academic cardiothoracic centers and 3 non-academic regional hospitals.

Study population

The investigators estimate 1400 consecutive NSTEMI patients with known or suspected Type 1 MI will be screened before coronary angiography. The inclusion and exclusion criteria are listed below. Patients who have given informed consent but were not randomized will be included in a follow-up registry.

Catheter laboratory study protocol

Once the coronary angiogram has been obtained, the cardiologist will assess whether or not the patient is eligible based on angiographic criteria to continue in the study and be randomized. If this is the case, randomization should take place immediately in the catheter laboratory. All eligible patients will be included wherever possible to minimize selection bias.

The main angiographic inclusion criterion is the presence of one or more non-critical coronary stenoses ≥30% severity which are (1) amenable to revascularization, (2) associated with normal coronary blood flow (TIMI grade III) and (3) in the opinion of the attending cardiologist FFR measurement is feasible and may have diagnostic value. Although an epicardial coronary stenosis of 70% is usually accepted as a threshold for revascularization, a minimum stenosis severity of 30% is adopted for FFR measurement in our study because stenosis severity may be visually underestimated. Inclusion of a stenosis \>90% severity is permissible provided the cardiologist believes FFR has the potential to influence the treatment decision based on coronary and patient characteristics. Left main stem disease is included and the upper limit for stenosis severity is 80%. The pressure wire (Certus, St Jude Medical, Uppsala) will be used to provide an FFR value across all coronary narrowings ≥30% severity as appropriate.

Randomization

Once the coronary angiogram has been acquired, the cardiologist will then confirm whether or not the patient is eligible for randomization. In this case, before randomization the cardiologist will initially state the treatment plan based on the available clinical information including the angiogram. The treatment plan will then be recorded by the research team. Next, randomization will then follow-on immediately using a web-based computer randomization tool provided by the independent Clinical Trials Unit. Ineligible patients will be entered into a registry.

FFR informed group: FFR will be measured by the cardiologist immediately after randomization and the FFR result will used to guide treatment decisions based on a threshold of 0.80. An FFR ≤ 0.80 should result in a treatment decision for revascularization by PCI or CABG combined with optimal medical therapy and an FFR\>0.80 should result in treatment with optimal medical therapy alone. Changes in treatment compared to the treatment plan prior to FFR disclosure will be recorded at the time.

Angiography-guided group and blinding: The patient and the clinical team responsible for the patient, including the interventional cardiologists and nurses, will be blinded to FFR. The RadiAnalyzer Xpress (St Jude Medical, Uppsala) will be turned away such that it is impossible for the clinical team to see the data which will be collected by the research team. The pressure wire recording will not be displayed on any other monitor in the catheter laboratory. Quality control checks, such as assessments of equalized pressure recordings and verification of hemodynamic changes with intravenous adenosine, will be conducted in the usual way, with the guidance of the unblinded clinical research team. These steps will be followed for all FFR measurements. Adherence to the blinding protocol, including any non-protocol disclosure of FFR at any time, will be prospectively recorded and blinding procedures will be monitored with site visits.

Eligibility criteria: Inclusion Criteria:

1. NSTEMI with an elevated troponin (\> upper limit of normal for local reference range) with at least one CAD risk factor (e.g. diabetes, age \> 65 years, prior CAD, prior peripheral vascular disease, hypertension, hyperlipidaemia, family history of CAD).
2. At least one coronary lesion ≥ 30% stenosis severity.
3. Invasive management scheduled within 10 days of admission and ideally performed within 72 h of admission or a history of recurrent ischemic symptoms within 5 days.

Exclusion Criteria:

1. On-going ischemic symptoms (i.e. chest pain) not controlled by medical therapy.
2. Cardiogenic shock or hemodynamic instability.
3. Angiographic exclusion: highly tortuous or calcified arteries, left main stenosis \>80% angiographically (i.e. consistent with severe left main disease).
4. Life expectancy of \< 1 year.
5. MI with persistent ST elevation.
6. Intolerance to anti-platelet drugs.
7. Unsuitable for either PCI or CABG on clinical or angiographic grounds.
8. Coronary artery disease \< 30% reference vessel diameter.
9. Absence of a non-flow limiting coronary stenosis ≥30%.
10. Non-coronary cardiac surgery (e.g. concomitant valve repair or replacement).
11. Inability to give informed consent.
12. Age \< 18 years (no upper age limit).

Primary outcomes:
measure: The between-group difference in the proportion of patients allocated to medical management compared to revascularization.
timeFrame: Baseline: the treatment decision will be made by the clinical team in the cardiac catheter laboratory during the index procedure or shortly afterwards during the index hospitalization when a multidisciplinary heart team review is indicated.
Secondary outcomes:
measure: The safety and feasibility of routine FFR measurement in patients with recent NSTEMI.
timeFrame: Post randomization index procedure at baseline.
measure: The % rate of discordance between an FFR <= or >0.80 and coronary stenosis severity (stenosis > or <70% of reference vessel diameter (50% for left main) assessed visually).
timeFrame: Baseline: Visual assessment of the angiogram before randomization, index procedure
measure: Major adverse cardiac events are defined as cardiac death or hospitalization for myocardial infarction (MI) or heart failure.
timeFrame: Post-randomization (any time including the index procedure through follow-up), expected average follow-up of 18 months (minimum follow-up 6 months).
measure: Health economics
timeFrame: Post-randomization (including the index procedure through longer term mean follow-up of 18 months (minimum follow-up 6 months).
measure: Quality of life
timeFrame: Baseline through longer term follow-up (average follow-up 18 months, minimum follow-up 6 months)
Other outcomes:
Locations:
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
state: Dunbartonshire
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
state: East Lancashire
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
state: Hampshire
city: East Kilbride
country: United Kingdom
facility: Hairmyres Hospital
state: Lanarkshire
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne and Wear
city: Sunderland
country: United Kingdom
facility: City Hospitals Sunderland NHS Foundation
state: Tyne and Wear
Study officials:
affiliation: University of Glasgow
name: Colin Berry, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nottingham University Hospitals, Nottingham, UK
name: Robert Henderson, MD FRCP
role: STUDY_CHAIR
affiliation: Robertson Centre for Biostatistics - University of Glasgow
name: Ian Ford, PhD
role: STUDY_DIRECTOR
affiliation: Health Economics and Health Technology Assessment, University of Glasgow
name: Andrew Briggs, PhD
role: STUDY_DIRECTOR
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