One Step Further

Adding physiologic assessment to angiography enhances clinical decision-making.

Angiography alone can likely determine whether revascularization is necessary in patients with severe coronary artery stenoses, but for those in whom the answer is less clear, interventionalists may need to move beyond angiography and use physiologic assessment.

“Previous studies have demonstrated a poor correlation between noninvasive ischemia tests and angiographic stenosis severity,” Matthias Gotberg, MD, PhD, director of the cardiac cath lab in the department of coronary heart diseases at Skåne University Hospital in Lund, Sweden, wrote in an email to Cardiology Today’s Intervention. “Thus, relying on visual assessment in daily cardiology practice carries a risk of not only treating lesions without ischemia that could have been safely deferred, but also not treating lesions that cause symptoms.”

During the past 2 decades, fractional flow reserve emerged as the preferred physiologically based assessment due to its technical simplicity. More recently, trials demonstrating the benefits of instantaneous wave-free ratio have given physicians another option for functional assessment.

“The starting point for use of these modalities is the appreciation that the angiogram does not accurately reflect the ischemic potential of a stenosis,” Morton J. Kern, MD, MSCAI, FACC, FAHA, professor of medicine at University of California, Irvine, chief of medicine at the VA Long Beach Healthcare System and a member of the Cardiology Today’s Intervention Editorial Board, said in an interview. “When there is uncertainty about the severity of a lesion, it’s time to measure.”

A Simple Procedure

FFR and iFR are both indices that use the concept of flow reserve to evaluate the severity of a coronary stenosis. However, whereas FFR is a ratio of the distal pressure to the aortic pressure during adenosine-induced hyperemia, iFR is a resting, or non-hyperemic, pressure ratio.

For interventional cardiologists, performing FFR or iFR is straightforward, according to Nils Johnson, MD, associate professor of medicine at McGovern Medical School at UTHealth (Houston).

“The vast majority of the procedure involves the same steps we would take to place any wire in a coronary artery,” he said in an interview.

Both FFR and iFR involve connecting a pressure wire to a console and calibrating it, administering heparin, engaging the coronary artery with a guiding catheter and giving intracoronary nitroglycerin to eliminate epicardial spasm, according to William F. Fearon, MD, professor of medicine and director of interventional cardiology at Stanford University School of Medicine.

“The pressure wire is advanced so that the pressure sensor (3 cm from the top of the wire) is positioned at the ostium of the guide catheter where the two pressure readings are equalized. The pressure wire is then advanced to the distal two-thirds of the vessel, beyond the lesion,” he told Cardiology Today’s Intervention.

Then, iFR or any other diastolic (eg, diastolic pressure ratio) or whole cycle (eg, distal coronary pressure to aortic pressure ratio or resting full cycle ratio) resting ratio can be measured. To measure FFR, intracoronary or IV adenosine can be administered to induce hyperemia, Fearon said.

After obtaining the measurement, the interventionalist can decide whether to perform PCI based on cutoff values. Lesions with an FFR value of less than 0.8 or an iFR value of less than 0.9 are considered abnormal and deemed appropriate for revascularization.

“If the resting ratio is already abnormal, there isn’t a need to induce hyperemia,” Kern said. “However, if you’re uncertain about the value obtained, then iFR can serve as the first screen and you can then administer IV or intracoronary adenosine.”

At the end of the measurement, Kern noted, the wire is pulled back to the guide catheter to ensure there is no drift.

“The hardest part for some operators is accepting the number you’ve just generated and taking action based on that number,” Kern said.

Available Data Support Use

Not only has FFR been in use for more than 2 decades, but a wealth of data supports its use in clinical practice, according to experts who spoke with Cardiology Today’s Intervention.

“We know from these studies that FFR-guided stenting is superior to traditional angiogram-driven therapy and that stenting lesions with reduced FFR improves long-term outcomes and is economically advantageous,” said Lloyd W. Klein, MD, professor of medicine at Rush Medical School and a member of the Cardiology Today’s Intervention Editorial Board.

Specifically, the FAME trial, published in 2009 in The New England Journal of Medicine, showed that routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents decreased adverse outcomes at 1 year (See Table).

“FAME ended up being a game-changer for physiology,” Johnson said. “Before the study, FFR was modestly recommended in the guidelines, but not many people were using it. As a result of FAME, though, physiology became mainstream.”

FAME 2, published in NEJM in 2014, also linked FFR-guided PCI plus medical therapy to better outcomes at 2 years compared with medical therapy alone in patients with stable CAD — results which were confirmed at 5 years and also published in NEJM in 2018 (See Table). Moreover, a cost-effectiveness analysis published in Circulation in 2018 indicated that FFR-guided PCI is “economically attractive” when compared with medical therapy alone.

Additionally, 15-year results from the DEFER study, published in the European Heart Journal in 2015, showed that deferring PCI based on FFR value resulted in favorable long-term outcomes with no signs of late “catchup” in patients with intermediate stenoses (See Table).

Other trials, including DANAMI-3-PRIMULTI, published in The Lancet in 2015, and COMPARE-ACUTE, published in NEJM in 2017, have also demonstrated the benefits of FFR-guided complete revascularization, including staged PCI, in patients with multivessel CAD (See Table).

In contrast, only two major trials — DEFINE-FLAIR and iFR-SWEDEHEART — have evaluated iFR-guided revascularization in CAD, according to Kern. Both studies, published in NEJM in 2017, demonstrated that iFR-guided revascularization was noninferior to FFR-guided revascularization with respect to a composite endpoint of all-cause death, nonfatal MI and unplanned revascularization in the moderately low-risk populations studied (See Table). Results also indicated that the correlation between iFR and FFR was 80%.

Although there are fewer data available for iFR, experts said the measurement is still valuable.

“The results indicate that iFR is a good tool, and is certainly better than using angiography alone to guide practice and will lead to more favorable outcomes based on the use of physiology- or ischemia-directed lesion selection,” he said.

Benefits and Drawbacks

Despite the similar nature of the procedures, FFR and iFR each harbor unique advantages and disadvantages.

“The major advantage of FFR includes the huge wealth of clinical outcomes data over a number of years and by multiple groups in a vast range of clinical conditions supporting its use,” Fearon said.

Additionally, unlike iFR, FFR has also been validated against ischemic stress testing, Kern noted.

However, the adenosine used to induce hyperemia during FFR can present problems, experts told Cardiology Today’s Intervention. For instance, some patients experience chest pain or dyspnea with IV, although not intracoronary, adenosine. Gotberg, who was an investigator for the iFR-SWEDEHEART trial, also noted that adenosine has been associated with transient bradycardia or high-degree atrioventricular block in some cases and its administration prolongs procedure time.

“This is an important finding because it means that iFR possibly streamlines cath lab workflow and also potentially lowers the threshold of performing coronary physiology,” Gotberg said.

A recent cost-effectiveness analysis of DEFINE-FLAIR presented at the 2018 American College of Cardiology Scientific Session has also associated iFR with significant cost-savings compared with FFR.

Nevertheless, iFR is a proprietary technology and only available through one manufacturer (Philips/Volcano), which is a limiting factor, Gotberg noted.

The lack of data on iFR is also problematic in specific patient subsets such as left main stenosis, according to Klein.

“We don’t have clinical studies of iFR in all circumstances, such as left main lesions,” he said. “Therefore, we’re less sure of its benefit in certain patient populations.”

One weakness of both FFR and iFR, however, is the uncertainty about how a physician should proceed when the measurement is close to the cutoff value, according to Klein.

Use in Clinical Practice

At this point, the evidence does not indicate whether FFR or iFR is better suited for a specific patient population, according to experts who spoke with Cardiology Today’s Intervention. They noted, however, that there are certain clinical scenarios in which they might choose one test over the other.

For example, Johnson said he sometimes avoids hyperemia in situations where there is a large gradient.

“In patients who don’t have large gradients, hyperemia has a real advantage by letting you understand which vessel causes the problem when the patient is doing something that increases demand, such as exercising,” he said.

“Right now, I would say iFR is suitable for most routine, non-high-risk, noncomplex anatomy, while FFR is suitable for left main disease, complex lesions, bifurcation and other populations in which FFR has been studied, in addition to less complex patients,” Kern said.

However, Keith G. Oldroyd, MBChB, MD(Hons), FESC, FRCP(Glasg), consultant interventional cardiologist at West of Scotland Regional Heart and Lung Centre in the Golden Jubilee National Hospital and NHS Research Scotland, said he always prefers FFR to iFR due to the large amount of data on FFR. He also said it is important to bear in mind the discordance between FFR and iFR in 20% of patients, and noted that the clinical outcomes of this discrepancy have not yet been properly investigated.

New Ways Forward

Further analyses of the current trials, such as a cost-effectiveness analysis and 2-year outcome data from iFR-SWEDEHEART, will be available in the near future, but there are a number of new studies about which interventional cardiologists are excited.

DEFINE-FLOW, for instance, is a study that is evaluating a way of assessing stenoses using FFR in addition to coronary flow reserve, according to Oldroyd.

FULL REVASC is also of interest, Johnson noted. The randomized trial will evaluate whether a strategy of systematic complete revascularization with FFR-guided PCI after STEMI or very high-risk non-STEMI leads to better outcomes compared with conservative management of nonculprit lesions.

Additionally, FAME 3 is a multicenter, randomized clinical trial comparing FFR-guided PCI to CABG in patients with multivessel CAD; enrollment should be completed in approximately 1 year.

New technologies are also in development, according to Oldroyd.

“There’s enormous interest in using either CT scans or angiography itself to calculate FFR,” he said. “None of these techniques are going to match FFR because there are many assumptions incorporated into the calculations, but their noninvasive nature will be attractive to some doctors and patients.”

Focus on iFR Pullback

Although not new, the concept of iFR pullback has also received attention lately.

“IFR pullback is performed by a slow manual pullback of the pressure wire across the lesions while sampling the pressure, which allows for an accurate measurement of where along the coronary vessel the pressure drop occurs. This may be coupled with a software that produces an overlay on an angiographic image. This method provides additional information on focal or diffuse coronary disease, which can be used to more accurately guide the revascularization procedure,” Gotberg, who said he considers the technology to be the most exciting evolution of coronary physiology in recent years, told Cardiology Today’s Intervention.

Improving Uptake

Despite the spotlight on FFR and iFR, physiologic assessment remains underutilized in clinical practice, experts told Cardiology Today’s Intervention.

In terms of clinical guidelines, the use of physiologic assessment in CAD is generally recommended to varying degrees, according to Kern. European guidelines have given FFR a class I recommendation, whereas the 2017 ACC/American Heart Association appropriate use criteria for coronary revascularization give FFR or iFR a class IIa recommendation.

In July, the Society for Cardiovascular Angiography and Interventions published a focused update of an expert consensus statement confirming the utility of FFR or iFR as a measure of PCI propriety when the significance of a lesion is uncertain in stable ischemic heart disease, according to Klein, who chaired the committee tasked with writing the statement, and Kern, who served on the committee. The update also states that FFR can safely guide revascularization in left main CAD and non-STEMI, and can guide staged complete revascularization during STEMI.

A number of factors, such as the type of technology stocked by one’s institution, can affect a physician’s preference for FFR or iFR. However, it is primarily part of a larger issue, according to Oldroyd, who noted that many interventional cardiologists are confident they can identify a significant lesion by looking at the angiogram (See Sidebar).

“The choice to use physiology often ends up being a philosophical one, which can be a real psychological hurdle to the use of physiology,” Johnson said.

Nevertheless, experts who spoke with Cardiology Today’s Intervention emphasized the need to perform and become comfortable performing these measurements.

“The complete interventionalist must use all available tools, including invasive physiology, noninvasive physiology and imaging, to make the best decisions,” Kern said. “There will be lesions in which the severity or ischemic potential is unknown, and in these lesions, the operator is obligated to measure the translesional physiology. Whether this is done through FFR or iFR doesn’t matter as long as the patient gets the benefit of this measurement and treatment decision.” - by Melissa Foster

• References:
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• For more information:
• William F. Fearon, MD, can be reached at wfearon@stanford.edu.
• Matthias Gotberg, MD, PhD, can be reached at matthias.gotberg@med.lu.se.
• Nils Johnson, MD, can be reached at nils.johnson@uth.tmc.edu.
• Morton J. Kern, MD, MSCAI, FACC, FAHA, can be reached at mkern@uci.edu.
• Lloyd Klein, MD, can be reached at lloyd_klein@rush.edu.
• Keith G. Oldroyd, MBChB, MD(Hons), FESC, FRCP(Glasg), can be reached at keith.oldroyd@nhs.net.

Disclosures: Fearon reports he has received research support from Abbott Vascular, CathWorks and Medtronic; he has received advisory board honoraria from Boston Scientific; and he has minor stock options with HeartFlow. Gotberg reports he has received minor consultant fees from Boston Scientific and Philips. Johnson reports his institution has received research support from Philips/Volcano for DEFINE-FLOW and St. Jude Medical for CONTRAST; his institution has a licensing and consulting agreement with Boston Scientific for the smart-minimum FFR algorithm that he developed; and he has received speakers’ fees, honoraria and travel expenses from academia and industry. Kern reports he has spoken for Abbott/St. Jude Medical, Acist, HeartFlow, Opsens and Philips/Volcano. Oldroyd reports he has received research support from Abbott Vascular and Boston Scientific. Klein reports no relevant financial disclosures.