Fractional flow reserve for guiding coronary intervention and functional SYNTAX score

Coronary angiography gives a visual impression about the severity of the stenosis. But it need not imply the actual functional significance of the stenosis in terms of flow physiology. It is often difficult to decide which are the flow limiting lesions when there are multiple stenoses in same or different territories. It is here that the fractional flow reserve estimation helps.

FFR is estimated using a guide wire with a pressure transducer. FFR wires have properties similar to the floppy guide wires so that they can passed across coronary lesions back and forth easily to assess the pressure drop across the lesions.

The flow reserve is calculated after inducing maximal hyperemia in the distal territory with intracoronary adenosine or papaverine or intravenous adenosine given in a central vein. FFR is obtained by dividing the pressure distal to the stenosis by the central aortic pressure, which is usually equal to the pressure proximal to the stenosis if there is no additional stenosis in between. Normal FFR is 1.0 and an FFR below 0.75 indicates inducible ischemia while an FFR above 0.80 excludes ischemia in 90% of cases. So, it is evident that the grey zone in FFR evaluation is very limited.

FFR measurement is successful in almost 99% of cases and the values are reproducible. If the FFR normalizes after stenting, the restenosis rates at six months is less than 5%. Since the FFR wire can be used for guiding balloon catheters and stents, it is easy to make post procedure measurements without any additional effort. When there are multiple stenoses, the wire will pick up the pressure drop at each lesion so that we can decide on which all lesions are significant and needs tackling.

FAME study showed that at one year follow up, rate of major adverse coronary events was reduced by approximately 30% by routinely measuring FFR. Routine FFR measurement probably lead to more judicious use of stents and improved outcomes. FAME study had randomly assigned 1005 patients with multivessel coronary artery disease to either percutaneous coronary intervention with drug eluted stent implantation guided by FFR or by angiography alone.

Cut off FFR was 0.8 in the study. Lesions with FFR more than 0.8 were left on medical treatment in the FFR guided PCI arm. Naturally the FFR guided group received lesser number of stents. They had lower rates of mortality or myocardial infarction. PCI or coronary artery bypass surgery rates were also lower, though not statistically significant. The lesions deferred on basis of FFR had only a 0.2% myocardial infarction rate and 3.2% revascularization rate at 2 year follow up.

A downside of the study was that it had included lesions of 50 to 79% stenosis also. But the authors justify their decision mentioning that 35% of these lesions were hemodynamically significant and leaving them untreated based on angiographic appearance alone would not have been ideal.

Another potential draw back of the data is that theoretically the lesions left alone based on FFR can also progress beyond the study period of two years and present later with significant stenosis.

Fractional flow reserve is the fraction of the maximal coronary flow that remains in the presence of an epicardial coronary lesion. Hence it is useful in assessing the severity of lesions, especially in case of lesions thought to be borderline on angiography.

The flow has contributions from the factors due to the epicardial coronary artery, myocardium and the collateral flow. Hence a good collateral flow can lead to underestimation of the severity of stenosis estimated by FFR.

Advantage of FFR over coronary flow reserve is that as it is calculated only at peak hyperemia, it is mostly independent of basal flow, aortic pressure, heart rate and the status of the microcirculation. There is a strong correlation between FFR and inducible myocardial ischemia. An FFR below 0.75 identified physiologically significant stenosis. In patients with coronary lesions, FFR can be used to identify patients who will benefit from percutaneous coronary interventions.
An FFR of less than 0.90 after coronary stenting would predict a higher event rate of 20% and an FFR below 0.80 an event rate of 30% compared with 5-6% event rates in those with FFR above 0.90. Guide catheters without side holes are preferred for FFR estimation. Contrast should be flushed out and the guide catheter filled with saline for good pressure measurements.

Excess adenosine will have to be given to get adequate hyperemia if there are side holes for the catheter, due to extra spillage of drug into the aorta. Matching of the wire tip pressure and the aortic pressure should be done before crossing the lesion.  The level of the external pressure transducer should be adjusted to get a match of the tracings if necessary. Conventionally the transducer position corresponds to a level 5 cm below the sternal level indicating the level of the right atrium.

A loose Y connector and a retained guidewire introducer can cause pressure leakage. Drift in signals can be identified by repeat matching of the pressures after the wire pull back. There is a limitation while assessing serial lesions as the true FFR across a lesion can be known only after complete relief of the other lesion.

There are formulae available for calculating the significance of individual lesions. But this will require measurement of wedge pressure which can be done only during interventions and not during diagnostic catheterizations. FFR estimation using the Doppler wire is useful in assessing the need for a side branch stent in bifurcation disease. Usually a stent is considered in bifurcation disease only if the side branch is large and almost equal in size to the distal vessel.

Using a side branch stent increases the risk of stent thrombosis in the main vessel and is especially to be avoided in a thrombotic situation as in acute myocardial infarction. If an FFR is available, it can measure the pressure difference across the lesion and if the distal pressure is more than 0.75 times the proximal pressure (FFR >0.75) a side branch stent is considered unnecessary.

SYNTAX score is calculated on a publicly available website using an online software. It can also be calculated on a downloadable software. It is used for coronary arteries with diameters >1.5 mm and having narrowing of >50%. It also considers the potential difficulty in performing a PCI.
Functional SYNTAX score is an FFR guided SYNTAX score. It recalculates SYNTAX score by incorporating ischemia producing lesions determined by FFR. This reduces the number of high risk patients and better discriminates risk for adverse events in patients with multivessel disease undergoing PCI.

About one third of the patients originally thought to have high or intermediate risk were re-classified as lower risk by the Functional SYNTAX score. The functional SYNTAX score was found to be better than SYNTAX score in predicting composite risk of death, myocardial infarction, and target vessel revascularization as well as the composite risk of death and myocardial infarction at one year.

FAME 2 study randomized 1220 patients with stable coronary artery disease and angiographically significant stenoses in whom at least one stenosis had FFR 0.8 or less. They were assigned to either FFR guided PCI plus medical therapy or medical therapy alone. FFR guided PCI was associated with significantly lower rate of primary composite end point of death, myocardial infarction or urgent revascularization at 5 years than medical therapy alone. Those without hemodynamically significant stenosis who were entered in a registry, had a favorable long term outcome with medical therapy alone.

References

1. Tonino PA et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009 Jan 15;360(3):213-24.
2. Pijls NH et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol. 2010 Jul 13;56(3):177-84.
3. Nam C-W et al. FAME Investigators. Functional SYNTAX score for risk assessment in multivessel coronary artery disease. J Am Coll Cardiol. 2011;58:1211-1218.
4. Xaplanteris P et al. Five-Year Outcomes with PCI Guided by Fractional Flow Reserve. N Engl J Med. 2018 Jul 19;379(3):250-259.