Fractional Flow Reserve-Guided Percutaneous Coronary Intervention plus Optimal Medical Treatment versus Optimal Medical Treatment Alone in Patients with Stable Coronary Artery Disease

In patients with unstable angina and acute myocardial infarction, randomized
trials have demonstrated substantial benefits of percutaneous coronary
angioplasty (PCI), including prevention of myocardial infarction and reduced
mortality rate.In patients with stable coronary artery disease, PCI has been
shown to improve anginal symptoms and quality of life. However, in these
patients, PCI has not significantly affected clinical outcomes such as death
and non-fatal myocardial infarction.
The COURAGE trial, a randomized trial comparing PCI plus optimal medical
treatment with optimal medical treatment alone, demonstrated no difference in
the primary end-point of death and myocardial infraction. This study has
introduced a sense of uncertainty as regard to the optimal management of
patients with stable angina and has had a significant impact on the referral
pattern to PCI in the United States and - albeit to a lesser degree - in
Europe. The study has been heavily criticized for a number of reasons of which
the most important is the very small number of patients finally included in the
study as compared to the number of patients screened. In addition, in the
COURAGE trial most patients had a non-invasive stress test performed prior to
entering the catheterization laboratory while a recent review showed that, in
the *real world* only 45% of patients ever had a stress test prior to PCI. This
has raised concerns about the applicability of the results to all comers as the
potential exist of a selection bias toward low risk patients.

An exploratory analysis of clinical outcomes in patients who underwent serial
myocardial perfusion imaging in the COURAGE-trial revealed that, regardless of
treatment assignment, (1) the risk of death or MI was proportional to the
magnitude of residual ischemia, and (2) that a 5% reduction in ischemia (by
whatever treatment) was associated with a significant reduction in this risk.
Like many others these data support the idea that revascularization is
effective in lesions which are responsible for myocardial ischemia but that
lesions that are not associated with ischemia should not be revascularized
mechanically.

The assessment of the hemodynamic significance of coronary atherosclerosis is
classically performed non-invasively by exercise ECG, stress echocardiography,
and myocardial perfusion imaging. Yet, these tests are not always available at
the time of the catheterization.In addition, it is generally acknowledged that
non-invasive stress testing is very reliable in patients with one vessel
disease and normal left ventricular function but that their usefulness in
guiding the need for revascularization is limited in patients with multiple
lesions as well as in many other clinical and anatomical subsets.

Pressure-derived fractional flow reserve has been developed and validated as a
surrogate for non-invasive testing.This information is more accurate in
moderate stenoses, its spatial resolution is unsurpassed and the information is
immediately available in the catheterization laboratory thus allowing the
operator to decide about the appropriateness of revascularization *on the
spot*. Robust clinical outcome data demonstrate the reliability of FFR and can
be summarized by saying that when FFR of a given stenosis is larger than 0.80,
no revascularization is mandated, while when FFR is lower than this threshold,
revascularization should at least be considered.The FAME study conducted in
patients with multivessel disease showed that a strategy of stenting only
ischemic stenoses but leaving alone non-ischemic stenoses (as assessed by
fractional flow reserve [FFR] measurements) was associated with significantly
less deaths and/or myocardial infarctions than a strategy of stenting all
angiographically visible stenoses. This data reinforce the concept of
*functionally (rather than anatomically) complete revascularization*.

In the COURAGE trial as well as in the recent BARI-2D trial it is very likely
that lesions have been stented which might actually have been left alone. This
hypothesis could - by itself - explain the absence of difference between the
PCI plus OMT arm and the OMT alone arm. Nevertheless, the conclusions of these
studies have been generalized to all patients with stable CAD and have led to
the general believe that in these patients medical treatment without invasive
approach is the preferred treatment.

The hypothesis of the FAME II trial is that FFR-guided PCI (with DES) plus
optimal medical treatment is superior to optimal medical treatment alone.
The overall purpose of the FAME II study is to compare the clinical outcomes,
safety and cost-effectiveness of PCI plus optimal medical treatment (OMT)
versus OMT alone in patients with stable coronary artery disease and in whom
both PCI and medical treatment can be considered on the basis of the presently
existing scientific evidence.

The FAME II study is a prospective, multicenter, multinational,
multi-continental, randomized clinical trial with an *all comers* design.

All consecutive patients with stable clinical condition and angiographically
defined one-, two, or three-vessel coronary artery disease and amenable for PCI
should be screened and considered for participation in the trial. However,
patients will be randomized only if at least one of the indicated stenoses is
hemodynamically significant as defined by an FFR value of less than 0.80. It is
expected that in 20% of patients no stenoses will be hemodynamically
significant. These patients will be treated according to local practice
(optimal medical treatment is advised) and will be followed-up in a registry.

Sixteen hundred patients with at least one hemodynamically significant lesion
will be randomized into PCI plus optimal medical treatment or optimal medical
treatment alone. Each center will be expected to enroll a minimum of 50
patients. The number of participating centers is projected to be approximately
40, with approximately 20-25 sites in Europe and 15-20 sites in the US.

At the time of the informed consent procedure, patients may refuse to be
randomized because of their personal preference for one treatment modality or
the other. According to the literature, this group is expected to represent
2-10 % of the patients eligible for randomization.18-20 These patients will not
be included in the trial, and data will not be collected.

For prospectively collected data in the randomized trial as well as in the
follow-up subset of the registries, an independent Clinical Events Committee
(CEC) will adjudicate all clinical endpoints (12-month MACE and at 2 and 5
years). An independent Data Monitoring Committee (DMC) will assess the results
with respect to patient safety at frequent pre-specified intervals.
Per amendment the patients from Group B randomised to "no follow-up" will be
asked for follow-up after 1, 2 and 5 years

Whatever the allocated intervention, all the indicated lesions will be assessed
using FFR. When the patient is randomized to optimal medical therapy (OMT)
alone, all lesions will be measured but none will be stented (regardless of the
FFR value). When the patient is randomized to the PCI+OMT arm, all lesions will
be measured and stented if, and only if the FFR is < 0.80.

No additional risk applicable because both treatment strategies are accepted
therapies for this kind of patients.
The burden for the patient consists of outpatient clinic visits.