Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (F.A.M.E.)

In this multicenter, international study we are evaluating two approaches to determine which coronary artery narrowings require stent placement in patients with multivessel coronary artery disease. Patients will be randomized to an angiographic strategy, where only coronary angiography is used to determine which lesions to stent or to a pressure wire strategy where fractional flow reserve, an index measured with the pressure wire, will be used to determine which lesions to stent. The primary outcome will be major adverse cardiac events at 1 year. A secondary outcome will be cost-effectiveness.

Detailed protocol

• If a patient is eligible for the study (see inclusion and exclusion criteria) and has given informed consent, the operator has to define all lesions with a stenosis severity of at least 50% by visual estimate in which he would consider stent implantation. These stenoses are noted on a scheme of the coronary arteries before randomization.
• Thereafter, randomization is performed to the FFR-guided strategy or the angiography-guided strategy. If the patient is randomized to the angiography-guided strategy, all the lesions indicated beforehand, will be stented with drug-eluting stents. If the patient is assigned to the FFR-guided group, fractional flow reserve is measured in all lesions and only those lesions are stented with a fractional flow reserve </=0.80. Treatment after PCI is according to local routine and should include at least aspirin 80 mg daily and clopidogrel (Plavix) 75 mg per day for at least 12months.
• FFR should be determined by using i.v. adenosine 140 µg/kg/min, in order to make pull-back recordings and analyze different abnormalities along the coronary arteries. Adenosine i.v. by the femoral venous route, is mandatory for participation in the study.
• In case of serial stenosis, FFR 'of the complete vessel' should be </= 0.80 to warrant PCI of one of more of these lesions in case the patient belongs to the FFR-guided group. In case of the angio-guided group, every lesion >50% by visual estimation that the operator indicated a prior as requiring stenting, should be stented (this is mandatory). Long stents to cover a segment or multiple shorter stents, can be placed at the discretion of the operator.

Follow-up

All patients will be followed up after 1 month (±1 week), 6 months (±1 month), and 1 year (±1 month). All adverse cardiac events (death, acute MI, CABG or [re]-PCI will be noted, as well as functional class and number of anti-anginal drugs. If a patient is admitted to a hospital because of an acute coronary syndrome, repeat angiography is strongly advocated to define if the event is related to one of the deferred lesions or to one of the non-deferred lesions. If the patient belongs to the FFR-guided arm, repeat measurement of FFR is advocated for all lesions. If, during follow-up, patients in the FFR-guided group have to undergo coronary angiography because of recurrent angina or any other reason without an event, pressure measurement should be repeated as well.

On the contrary, once a patient has been assigned to the angiographic guided group, this strategy should be followed consistently during follow-up investigations. For example, if a patient in the angiographic guided arm has recurrent chest pain, undergoes angiography, and is found to have in-stent restenosis, re-PCI should be performed based on the angiogram and pressure wire use is prohibited.

In other words, the strategy to which the patient has been assigned initially, should be followed during the entire study period.

Endpoints

Primary endpoints

1. The primary clinical endpoint is the 12-month binary major adverse cardiac event (MACE) rate. MACE is defined as:

• All cause death,
• Documented myocardial infarction,
• Repeat revascularization (PCI and/or CABG) as adjudicated by the Clinical Event Committee

Secondary endpoints

1. Global cost effectiveness after one year
2. Cardiac death and myocardial infarction rate at 1 year
3. Functional class at 1 year.
4. Number of anti-anginal drugs after 1 year
5. Overall MACE rate at 1 month post-procedure and at 6 months, 2, 3 and 5 years.
6. A comparison of outcomes based on type of drug-eluting stent.
7. Prognostic value of FFR after stenting.
8. Correlation between FFR and nuclear perfusion imaging.

Inclusion Criteria:- at least 2 coronary lesions of 50% stenosis or greater in at least 2 major epicardial arteries

• age>/=18

Exclusion Criteria:-- STEMI < 5 days ago or non-STEMI with CK > 1000 U/l < 5 days ago

• Pregnancy
• Extremely tortuous or calcified coronary arteries, or other technical conditions interfering with reliable coronary pressure measurement
• Serious concomitant disease, decreasing life expectancy to <2 years
• Previous coronary bypass surgery (CABG)
• Contraindication for drug-eluting stent
• Cardiogenic shock
• Inability to give informed consent
• Suspicion of significant left main (LM) stenosis