Continuous, Independent Relationship With FFR and Outcomes, Modulated by Treatment

October 15, 2014

HOUSTON, TX — With measurements of fractional flow reserve (FFR), there is a "continuous and independent relationship" with clinical outcomes such that lesions with low FFR values benefit the most from coronary revascularization and lesions with higher FFR values receive less absolute benefit from either PCI or CABG surgery[1].

Investigators report that the optimal FFR cut point for determining whether or not to revascularize remains in the 0.75-to-0.80 range, which is the cut point used in major FFR studies like FAME, FAME 2, and DEFER, but their study moves the concept of FFR beyond looking at it as a simple "yes-or-no" issue. Within the range of FFR values, there is a further continuous benefit of treatment for those with lower measurements.

"We looked at FFR as spectrum," lead investigator Dr Nils Johnson (University of Texas Medical School, Houston) told heartwire . "I think the analogy we'd draw on is with other diseases such as hypertension or dyslipidemia with LDL cholesterol, realizing that these too are spectra. Hypertension is a fairly black-and-white line in the sand—it's in the guidelines, 140/80 mm Hg—but if you move beyond that and look at blood-pressure response, we know that patients with higher blood pressures have worse events and have a larger treatment benefit. We tried to take that same concept and apply it to FFR."

As a result, say investigators, FFR should be viewed not only as a physiologic biomarker because of the continuous relationship with clinical outcomes but as a "target for treatment, because revascularization alters the outcome curve." Ultimately, said Johnson, the results can help individualize treatment decisions, given that patients with lower FFR values have the most to gain from coronary revascularization.

In an editorial[2], Dr John Hodgson (Case Western Reserve School of Medicine, Cleveland, OH) writes that FFR guidance has been shown to be valuable in intermediate lesions, side branches, and left main lesions, among others. FFR has also been shown to improve outcomes, he adds, and the pressure wires are easy to use and the procedure is simple, reproducible, and, in the end, cost-effective.

Moreover, FFR is a class IIa indication and part of the appropriate-use criteria for diagnostic catheterization and revascularization for patients with intermediate lesions not already having corresponding evidence of stress-induced ischemia. "So, one is left wondering what part of the FFR link don't interventional cardiologists understand?" asks Hodgson. "The data are clear; the cardiology community should not tolerate continuing to ignore it."

FFR as a Continuous Marker of Risk

Published in the October 21, 2014 issue of the Journal of the American College of Cardiology, the new findings are derived from a meta-analysis of FFR studies, including 9173 lesions from the FFR trials and 6961 lesions from patient-level data. Overall, the vast majority of lesions with an FFR <0.75 underwent coronary revascularization, and approximately 90% of lesions with an FFR >0.80 received medical therapy. In total, 15% of lesions fell within the 0.75-to-0.80 range.

In a meta-regression analysis of the FFR studies, the optimal FFR cut point for the composite end point of death, MI, and coronary revascularization occurred at 0.75. It rose to 0.90 after adjustment for the variable length of follow-up in the trials. In the patient-level meta-analysis, the optimal FFR cut point for death, MI, and revascularization occurred at 0.67 but increased to 0.76 after adjustment for confounding variables. Investigators concluded that the optimal cut point for FFR remains in the 0.75-to-0.80 range.

"We took the FFR outcomes literature and we looked at it in two ways," said Johnson. "We did the typical study-level meta-analysis, and we also got a large number of collaborators to pool all the patient-level data. Both of the analyses support the original hypothesis, that FFR is a continuous marker of risk and that the benefit of revascularization is also continuous.

"When making decisions close to the cutoff value, either way the treatment effect will be modest, whereas an individual with an FFR of 0.65 is going to have a significant benefit from revascularization," explained Johnson. "It helps shape the discussion with revascularization in the same way it does when we treat blood pressure or lipids, where we take into account not only the presence of disease but also the severity."

Prognosis Using FFR After PCI

The researchers also looked at the prognosis of patients when FFR was measured after PCI. Normally FFR is measured prior to revascularization to help inform treatment, but data have suggested a measurement after PCI, with the pressure wire still in place, can predict future events. Johnson said they noted that FFR after stenting also has prognostic value. "The higher that number is, the lower the event rate," he told heartwire . "There's an inverse relationship between the two."

The reason for the relationship between FFR post-PCI and clinical outcomes is likely explained by diffuse disease. While stenting treats the focal lesion, a lower FFR value reflects the burden of atherosclerosis throughout the vessel and is not something that can be treated with a single stent, said Johnson. "The FFR measured after PCI acts like a physiologic coronary calcium score, if you will, such that it's a marker of diffuse disease, which carries a worse prognosis," he noted.

And finally, the researchers also performed a meta-analysis of 10 studies involving more than 15 000 patients and compared clinical outcomes among those treated with an FFR-based revascularization strategy against one that used anatomy only.

Overall, the frequency of PCI or CABG was just 42% with an FFR-based approach (vs 95% with anatomy) but the composite end point of death, MI, or revascularization was reduced 17% to 29% (fixed-effects vs random-effects modeling, respectively). The FFR-assisted strategy also provided superior relief from angina. The results were consistent in diabetic patients, those with left main disease, and acute coronary syndrome patients.

"We saw that we were able to reduce the number of revascularizations by about half, but in doing so we didn't put patients at any greater risk," said Johnson. "We didn't incompletely revascularize them in a way that's going to adversely affect prognosis. If anything, it's improved. We're not compromising on angina relief. We do less, but we do the right lesions, the lesions that are angina producing and that ones that go on to cause events."

Johnson has received funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis and has received significant institutional research support from St Jude Medical and Volcano. Disclosures for the coauthors are listed in the paper. Hodgson has received educational grants (>$10 000) and consulting fees (<$10 000) from Volcano, Boston Scientific, and St Jude Medical and serves on the speaker's bureau for Volcano, St Jude Medical, and InfraRedX.

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