FFR Deferral of Nonculprit Lesions Riskier in ACS vs Stable Angina

The safety of fractional flow reserve (FFR)-based deferral of nonculprit lesions in patients varies by presentation, a pooled analysis of more than 8,000 patients confirms. Among those whose treatment is put off, researchers found an increase in major adverse cardiovascular events by 1 year for those with ACS compared with stable angina.

This difference is driven by unplanned, early revascularization, Enrico Cerrato, MD (Hospital Clínico San Carlos), and colleagues report. But they say the exact mechanism isn’t certain.

Data from DANAMI3-PRIMULTI, FAME, and Compare-Acute have previously shown the benefits of FFR guidance for multivessel PCI in ACS. Less is known, though, about how these patients fare when FFR informs the choice to defer.

An earlier analysis that combined data from 4,529 participants in the DEFINE-FLAIR and iFR-SWEDEHEART randomized trials, presented at EuroPCR 2017, also showed ACS patients to be more vulnerable after deferral than those with angina. This time, researchers expanded their data set by including three observational studies.

“The main intention of this study was to really bring together a massive amount of data coming from sound scientific efforts, so to speak: studies that have been peer reviewed, that have been published, that we know have a standard of quality,” Javier Escaned, MD, PhD (Hospital Clínico San Carlos, Madrid, Spain), senior investigator of the new paper published online last week in JACC: Cardiovascular Interventions, told TCTMD.

Although FFR appears less safe at informing deferral for ACS, there’s strong support for FFR-based deferral in stable CAD, he noted. “We know that the physiological framework is entirely different” between these two groups.

Exactly why ACS patients have excess events in this scenario is uncertain. For Escaned, the strongest possibility relates to the hyperemia induced during FFR measurement, a possibility that carries implications for clinicians interpreting FFR values.

Commenting on the study for TCTMD, Bina Ahmed, MD (Santa Barbara Cottage Hospital, Santa Barbara, CA), said that the study “raised more questions than it answered.”

 “There’s been a question mark regarding the efficacy of inducing hyperemia in the setting of patients presenting with acute myocardial infarction. You need an accurate test to make reliable conclusions. It may be accurate. We just don’t know if it is or not,” she said.

You need an accurate test to make reliable conclusions. Bina Ahmed

The study is valuable despite not being conclusive, Ahmed emphasized. “All of it is additive—I think all of the data we collect and all the questions that we ask steer us into the right direction.”

Three Registries Plus Two Studies

For the analysis, the researchers pooled patient-level data on 8,579 individuals from the R3F, POST-IT, and IRIS-FFR registries plus DEFINE-FLAIR and iFR-SWEDEHEART. Three-quarters presented with stable angina and the rest with ACS.

Based on FFR guidance, revascularization was deferred in 59.8% of patients. To be put into this category, each of the patients’ interrogated stenoses must have been left untreated.

Deferred patients had an increased risk of MACE if they presented with ACS rather than stable angina (4.46% vs 2.83%; adjusted HR 1.72; 95% CI 1.17-2.53). Among the endpoint’s components, unplanned early revascularization was increased (3.34% vs 2.04%; adjusted HR 1.81; 95% CI 1.09-3.00). Neither death (adjusted HR 1.60; 95% CI 0.68-3.79) nor MI (adjusted HR 1.80; 95% CI 0.76-4.27) significantly differed between acute versus stable patients.

On the other hand, there were no disparities in MACE among patients whose lesions were treated (6.51% vs 6.20%; adjusted HR 1.21; 95% CI 0.88-1.26).

Bimmer E. Claessen, MD, PhD, and Diederik F. van Wijk, MD, PhD (both Noordwest Ziekenhuisgroep Alkmaar, the Netherlands), point out in an editorial that much is unknown about these individuals and their trajectories.

For instance, thanks to the “different definitions of clinical presentation in the participating studies,” it was impossible to perform subgroup analyses for unstable angina, NSTEMI, and STEMI. Also, “no data were collected on how often both FFR-based lesion deferral and revascularization occurred within the same patient,” the editorialists note. “Additionally, if a patient needed unplanned revascularization during follow-up, it was not possible to ascertain whether this event was related to 1) a previously FFR-interrogated lesion; 2) the original culprit lesion; or 3) a lesion in neither category.”

Yet, they caution, “these considerations do not undermine the value of this well-designed and to date largest individual patient database demonstrating that FFR-guided deferral results in higher rates of MACE in patients presenting with ACS compared with those presenting with stable angina pectoris.” What’s needed now, they say, is additional research to tease out the mechanism.

Hyperemic Response Cited

Raising a possibility, Escaned pointed to an earlier study that took sequential FFR measurements at the time of STEMI, then 1 month thereafter. “What you can see clearly from these repeated measurements is that . . . FFR tends to perform more false negatives” during the index event, he explained. “In the acute setting, you have some decreased hyperemic response to adenosine and therefore a hyperemic index like FFR tends to underrate the true severity of stenosis [compared to] how things will look 2 weeks down the line.”

That same study found instantaneous wave-free ratio (iFR) values held steady between STEMI and follow-up assessment.

As to iFR’s performance when it comes to deferral of nonculprit lesions in the acute setting, the only evidence thus far has originated from the aforementioned DEFINE-FLAIR and iFR-SWEDEHEART analysis. And notably, in numbers that Escaned said haven’t yet been published, the MACE difference seen between iFR- and FFR-based deferral for ACS at 1 year was gone at 2 years.

“At this point, personally I would not claim that resting indices are superior to FFR in terms of assessing acute coronary syndromes. We don’t have evidence,” he said, stressing that FFR has been around for longer and is considered the gold standard. The choice between physiologic tests, added Escaned, shouldn’t distract from the larger discussions of how best to treat nonculprit lesions.

Keep using physiology. Javier Escaned

Ahmed, too, expressed curiosity over whether non-adenosine-based tests might have an advantage in ACS, but said “we’re pretty far away, I think, from knowing the answer to that particular question.”

What’s also clear is that the MACE difference observed in the current study is due to repeat revascularization. Given how soon these procedures occurred, it may be that the severity of stenosis in nonculprit lesions was underestimated, Escaned noted. “It does not sound like it is a problem of having more-vulnerable plaques in nonculprit coronary arteries.”

For Ahmed, “the practical question is: what should providers do if they have an NSTEMI or a STEMI patient that has residual intermediate stenoses? Should they proceed with an FFR-guided assessment or not? I feel that there’s not enough data to support its use as a routine for [these] lesions.” Angiography may be suitable “until we know more,” she said. “To date, that’s how it has been done and several large trials have used an angiographic cutoff for treating or not treating the residual disease.”

Clinicians should be more attuned to borderline FFR values and “more vigilant about the return of symptoms if there was a deferral of revascularization in a patient with an acute coronary syndrome in a nonculprit coronary artery,” Escaned said, which raises the possibility that the original FFR was underscored.

“Keep using physiology. If you are using FFR, keep using FFR. Just understand that [in ACS] the predictive value of FFR is not as high as in stable coronary artery disease,” he concluded.