Fractional flow reserve versus angiography in guiding management to optimize outcomes in non-ST-elevation myocardial infarction (FAMOUS-NSTEMI): rationale and design of a randomized controlled clinical trial.

BACKGROUND: In patients with acute non-ST-elevation myocardial infarction (NSTEMI), coronary arteriography is usually recommended; but visual interpretation of the angiogram is subjective. We hypothesized that functional assessment of coronary stenosis severity with a pressure-sensitive guide wire (fractional flow reserve [FFR]) would have additive diagnostic, clinical, and health economic utility as compared with angiography-guided standard care. METHODS AND
DESIGN: A prospective multicenter parallel-group 1:1 randomized controlled superiority trial in 350 NSTEMI patients with ≥1 coronary stenosis ≥30% severity (threshold for FFR measurement) will be conducted. Patients will be randomized immediately after coronary angiography to the FFR-guided group or angiography-guided group. All patients will then undergo FFR measurement in all vessels with a coronary stenosis ≥30% severity including culprit and nonculprit lesions. Fractional flow reserve 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 revascularization by percutaneous coronary intervention or coronary artery bypass surgery, as appropriate. The primary outcome is the between-group difference in the proportion of patients allocated to medical management only compared with revascularization. Secondary outcomes include the occurrence of cardiac death or hospitalization for myocardial infarction or heart failure, quality of life, and health care costs. The minimum and average follow-up periods for the primary analysis are 6 and 18 months, respectively.
CONCLUSIONS: 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.

RCT Entities:   Population Interventions Outcomes

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- to 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. 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). Because visual assessment of the angiogram may be inaccurate, judgments made by cardiologists in everyday practice are subjective, potentially leading to misdiagnosis and incorrect treatment decisions.

Recent studies (DEFER, FAME, FAME II) in patients with stable CAD have presented a new approach to the 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 noninvasive 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 with angiography alone. Overall, FFR measurement can identify and exclude obstructive CAD with high diagnostic accuracy, including in patients with prior MI.

FFR measurement in unstable CAD

Fractional flow reserve measurement requires maximal coronary hyperemia that theoretically may be less readily achieved in patients with recent MI because of microvascular injury. However, some recent studies support the notion that FFR measurements are valid in medically stabilized MI patients. Ntalianis et al measured FFR in 112 nonculprit coronary lesions repeatedly (average interval 35 ± 4 days) in 101 patients with recent acute MI and found similar FFR values at each time point. In one other study, FFR correctly identified inducible ischemia on single photon emission computed tomography in 57 patients >6 days after MI; and in a follow-up study of 124 ACS patients, deferring revascularization in lesions with an FFR ≥0.75 was safe. In hospitalized patients with recent MI, FFR-guided management is associated with lower in-hospital costs compared with deferred management guided by myocardial stress perfusion scintigraphy. Based on invasive measurement of coronary vasodilator capacity, we have recently shown that vasodilator reserve is similar in patients with stable angina and NSTEMI, consistent with preserved coronary vasodilator capacity in medically stabilized NSTEMI patients. Finally, nearly one-third of the patients randomized in FAME had a history of medically stabilized unstable angina or NSTEMI 5 or more days from randomization (or <5 days if the peak creatine kinase was <1,000 IU); and the benefit of FFR-guided PCI was similar in patients with unstable versus stable coronary disease. The FAME investigators concluded that their post hoc analysis could not prove equivalence of effects between subgroups because 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 medically stabilized NSTEMI has not been established.

Specific uncertainties with angiography-guided treatment decisions in NSTEMI

First, treatment decisions for nonobstructive (FFR >0.80) culprit coronary lesions lack an evidence base to guide management. On the one hand, a stent for coronary plaque rupture might reduce the risk of recurrent thrombosis. On the other hand, optimal medical therapy with dual antiplatelet drugs and high-dose statins might suffice; and unnecessary stenting can be harmful (eg, stent thrombosis, restenosis). Second, in NSTEMI patients with multivessel coronary disease, evidence is lacking as to whether nonculprit obstructive lesions should undergo revascularization or not. A post hoc analyses of the contemporary large-scale ACUITY trial found that incomplete coronary revascularization was a multivariable predictor of major adverse cardiac events at 1 year and that the risk was related to the number of nonrevascularized lesions. In a recent analysis of NSTEMI patients in whom FFR was measured during usual care in our hospital, we found that FFR disclosure influenced cardiologists' treatment decisions.

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

First, FFR measurement is not a current standard of care in NSTEMI patients.

Second, the prognostic relationship between FFR values and clinical outcomes in NSTEMI patients is uncertain and may not be the same as in patients with stable coronary disease. Therefore, to study the prognostic importance of FFR, it will be measured in all patients and disclosed in the FFR-guided group but not disclosed in the angiography-guided control group. Because all patients will be followed up for clinical events, the relationships between FFR and health outcomes (composite cardiovascular events) will be evaluated.

Third, because stress testing is not generally appropriate in patients with recent MI, FFR-guided management could obviate the need for “deferred” management.

Fourth, FFR has the potential to guide revascularization of culprit and nonculprit lesions. Because there are no data to support stenting in nonobstructive culprit lesions, we propose that the treatment decisions are consistently guided by the FFR values in both culprit and nonculprit lesions 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 be revascularized by PCI or CABG.

Fifth, when stenting is performed, the poststent FFR can be used to ensure that an optimal stent result is achieved, that is, FFR >0.9 in both the culprit and nonculprit lesions treated by PCI.

Study hypothesis

Our first hypothesis is that routine FFR measurement increases the proportion of NSTEMI patients that will be managed medically. Our second hypothesis is that routine FFR measurement in NSTEMI patients is feasible and has additive diagnostic, clinical, and health economic utility compared with standard care based on visual assessment of the angiogram.

Methodology

Primary aim

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

Secondary aims

The secondary aims are (1) to determine the feasibility and safety of routine 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 determine the relationships between FFR values during the baseline procedure (and receiver operating characteristic) and cardiac events during follow-up in all patients, (4) to provide preliminary data on whether FFR-guided management is associated with improved health outcomes and quality of life in the longer term compared with angiography-guided treatment decisions, and (5) to perform a health-economic analysis.

Standard care of NSTEMI patients in the 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 contemporary practice, FFR is only 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 planned, then all procedures should take place during the index hospitalization.

Setting and design

A prospective multicenter parallel-group 1:1 randomized controlled superiority trial will be conducted in 6 UK centers including 3 academic cardiothoracic centers and 3 nonacademic regional hospitals (Figure 1). The first patient was randomized on October 25, 2011; and the trial is expected to complete follow-up in November 2013 (Figure 2).

Figure 1

Flow diagram of the trial.

Figure 2

Gantt chart.

Study population

We estimate that approximately 1,400 consecutive NSTEMI patients with a clinical diagnosis of confirmed or suspected type 1 MI will be screened before coronary angiography. An NSTEMI is defined according to the occurrence of acute ischemic symptoms (eg, chest discomfort) and elevated cardiac biomarkers but without ST-segment elevation on the electrocardiogram. Type 1 represents spontaneous MI due to a reduction in myocardial blood flow secondary to atherosclerotic plaque rupture and/or coronary thrombosis in one or more arteries. Although underlying coronary disease is usually present, there may be mild or no coronary disease. The inclusion and exclusion criteria are described in Table. Patients who give informed consent but who are not randomized will be included in a registry. The reasons for exclusion from the trial after consent but before randomization (eg, coronary angiogram findings) and inclusion in the registry will be prospectively recorded. Similar information will be collected in the registry and randomized patients, including during follow-up. We aim to maximize participant retention and follow-up through telephone contact and use of national electronic databases for long-term follow-up.

Table

FAMOUS NSTEMI study design

Inclusion criteria

Medically stabilized NSTEMI with an elevated troponin (>upper limit of normal for local reference range) with ≥1 risk factor for CAD (eg, diabetes, age >65 y, prior CAD, prior peripheral vascular disease, hypertension, hyperlipidemia, family history of CAD)

≥1 noncritical coronary stenosis ≥30% severity with normal coronary blood flow (Thrombolysis in Myocardial Infarction grade III) in which FFR measurement might have diagnostic value

Invasive management within 72 h of hospital admission or a history of recurrent ischemic symptoms within 5 d

Exclusion criteria

Ongoing ischemic symptoms not controlled by medical therapy

Cardiogenic shock or hemodynamic instability

Angiographic exclusion: highly tortuous or calcified arteries, left main stenosis >80% (ie, consistent with severe left main disease)

Life expectancy of <1 y

MI with persistent ST elevation

Intolerance to antiplatelet drugs

Unsuitable for either PCI or CABG on clinical or angiographic grounds

CAD <30% reference vessel diameter

Noncoronary cardiac surgery (eg, an indication for concomitant valve repair or replacement)

Inability to give informed consent

Age <18 y (no upper age limit)

Catheter laboratory study protocol

Once the coronary angiogram has been obtained, the cardiologist will assess whether the patient is eligible to be randomized based on angiographic criteria (Table).

The main angiographic inclusion criterion is the presence of one or more noncritical coronary stenoses ≥30% severity that are associated with (1) normal coronary blood flow (ie, Thrombolysis in Myocardial Infarction grade III), (2) amenable to revascularization by PCI or CABG, and (3) FFR measurement is feasible and may have diagnostic value (Table). A minimum stenosis severity of 30% is adopted for FFR measurement in our study because visual assessment of the angiogram may underestimate stenosis severity. Inclusion of a more severe stenosis (eg, >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. The pressure wire (Certus, St Jude Medical, Uppsala, Sweden) will be used in all patients to provide an FFR value across all coronary narrowings ≥30% severity as appropriate. Our aim is to maximize inclusion of eligible patients to minimize selection bias.

Assessment of the coronary angiogram and recording of the initial treatment decision

Once the coronary angiogram has been obtained, the cardiologist will report the severity of all coronary lesions as > or <70% of the reference vessel diameter (50% for left main) based on visual interpretation of the angiogram and in line with usual care. The cardiologist will then establish an intended treatment plan based on all of the available clinical information and the angiogram findings. The cardiologist's interpretation of the diagnostic angiogram and the treatment plan will then be recorded at that time in the catheter laboratory. Therefore, the initial treatment decision will be established before randomization or treatment group assignment is known and before the pressure wire is passed into the coronary arteries. Therefore, no FFR measurements will be acquired before randomization.

Randomization

Once the coronary angiographic findings and treatment plan have been recorded and if, in the opinion of the treating cardiologist, the patient remains eligible to continue in the study, randomization will then be performed. Randomization will take place immediately in the catheter laboratory using a Web-based computer randomization tool provided by the independent Clinical Trials Unit. The randomization sequence was created using the method of randomized permuted blocks.

Patients who had consented but were ineligible on angiographic criteria will be entered into a registry.

FFR measurement

Myocardial FFR measurement is described in the online Appendix Supplementary material.

FFR-guided group

Fractional flow reserve 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 ≤.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, in line with contemporary guidelines for optimal secondary prevention drug therapies, cardiac rehabilitation, and risk factor modification. Any changes in treatment following FFR disclosure compared with the initial treatment plan prior to FFR disclosure will be recorded.

Angiography-guided group and blinding

In patients randomized to the angiography-guided group, the RadiAnalyzer Xpress (St Jude Medical) will be turned out of view by the research team such that it is impossible for the clinical team to see the pressure wire recording. The pressure wire recording will not be displayed on any other monitor in the catheter laboratory, and the clinicians and patients will not know the results. When the coronary pressure display is out of view of the clinical team, the cardiologist will then measure FFR as described above, guided by the research staff who will monitor and record the pressure wire data. Therefore, the patient and the clinical team responsible for the patient, including the interventional cardiologists and nurses, will be blinded to the pressure wire recording. Quality control checks, including assessments of equalized pressure recordings and verification of symptoms and hemodynamic changes with intravenous adenosine, will be conducted in the usual way, with the guidance of the unblinded research team. These steps will be followed for all FFR measurements.

Quality assurance procedures are described in the online Appendix Supplementary material.

End points

Primary outcome

The between-group difference is the proportion of patients allocated to medical therapy only instead of revascularization at baseline. The treatment decision will be made by the clinical team in the cardiac catheter laboratory during the index procedure or shortly afterward during the index hospitalization including when a multidisciplinary heart team review is indicated.

Secondary outcomes

The safety and feasibility of routine FFR measurement at baseline.

The percentage 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 in all patients in the catheter laboratory before randomization);

Major adverse cardiac events are defined as cardiac death or hospitalization for MI or heart failure after randomization. Therefore, emphasis has been placed on “spontaneous” “hard” outcomes. Because the decision for revascularization may be susceptible to bias, this event is not included in the primary outcome. Information on hospitalizations for other adverse events (ie, unstable angina, renal failure, stroke, PCI, CABG) will be prospectively recorded.

The prognostic value of FFR in all patients for subsequent adverse events will be assessed. The outcomes will be assessed during the study until the final randomized patient has completed a minimum of 6 months of follow-up. The 3-year event rates will also be assessed.

Health care costs (including revascularization procedures, stents, bed days) will be prospectively recorded for the index and any subsequent hospitalizations.

Quality of life (EuroQoL, EQ-5D).

Statistical methods

The sample size calculation and pilot data statistical and health economic analyses plans are described in the online Appendix Supplementary material.

Follow-up and timetable

A quality-of-life assessment will be completed at 6-month intervals (EuroQoL, EQ-5D). Clinical follow-up will continue for an average of 1.5 years (range 6-30 months). Follow-up assessments for adverse events will be performed by the clinical research staff by telephone or in person (eg, outpatient clinic review), as appropriate. Medical records will also be checked. Follow-up contact will occur at 6 monthly intervals until the last patient has achieved a minimum of 6 months of follow-up. Follow-up in the longer term will be supported by electronic record linkage with central government health records. The active phase of the project is intended to last about 30 months.

Ethics

FAMOUS-NSTEMI has full UK National Research Ethics Service approval (Reference 11/S0703/6).

Registration

The trial registration numbers are: NCT01764334; ISRCTN97489534.

Trial management

The trial will be conducted in line with Guidelines for Good Clinical Practice in Clinical Trials. Trial management will include a Trial Management Group, Trial Steering Committee, Clinical Event Committee, and Data and Safety Monitoring Board (online Appendix Supplementary material).

Definition of adverse events

Major adverse cardiovascular event is the composite of “cardiovascular death, nonfatal MI, unplanned hospitalization for transient ischemic attack or stroke.”

Major adverse cardiac events are defined as “cardiac death, or unplanned hospitalization for MI or heart failure.”

Percutaneous coronary intervention and CABG are nonmajor adverse events.

Myocardial infarction is defined according to the criteria specified in the Third Universal Definition of Myocardial Infarction (including type 4 MI for PCI and type 5 for CABG).

Contrast agent–induced nephropathy is defined as either a > 25% increase of serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL after a radiographic examination using a contrast agent.

Bleeding is defined according to the ACUITY criteria: major bleed = intracranial or intraocular bleeding, bleeding at the site of angiography requiring intervention, a hematoma of 5 cm in diameter, a reduction in hemoglobin level of at least 4 g/dL in the absence of overt bleeding or 3 g/dL with a source of bleeding, or transfusion.

Sources of funding

The trial is supported by a Project Grant from the British Heart Foundation (PG/11/55/28999) and the Chief Scientist Office of the Scottish Government. St Jude Medical UK Ltd has provided a restricted research grant for the pressure wires.

The trial sponsor is the National Waiting Times Centre, NHS Scotland. The authors are solely responsible for the design and conduct of the study, all analyses, the drafting and editing of the paper, and its final contents.

Discussion

Should our hypotheses prove correct, then favorable outcomes from our developmental clinical trial will inform the design and justification for undertaking a large multicenter outcome trial to further validate these initial findings.

Randomization is performed after coronary anatomy is known because coronary lesion severity defines the patients who are eligible to be randomized. However, this design renders the trial susceptible to selection bias, as may have occurred in other trials (eg, COURAGE, BARI2D, FAME, and FAME-2), potentially favoring inclusion of patients with less complex coronary disease. To facilitate inclusion of patients with complex disease (eg, chronic total occlusion, critically narrowed lesions), an FFR of 0.5 can be assigned without requirement to pass the pressure wire. This approach is intended to facilitate the inclusion of all eligible patients. Because FFR group assignment is “open,” by design, we have attempted to minimize treatment bias at the time of the procedure and during follow-up by not disclosing the FFR values in the angiography-guided group. Nondisclosure of FFR in the control group differentiates our study from FAME-2 where FFR values were known in all of the randomized patients.

Disclosures

Professor Berry and Professor Oldroyd have acted as consultants for St Jude Medical and received an unrestricted research grant, with these funds paid to their employers.