‘Functional’ SYNTAX Score May Hone PCI, CABG Choices in Multivessel Disease

Adding functional information to the SYNTAX score helps better identify patients with less complex three-vessel CAD who appear to benefit as much from PCI as they would from CABG surgery, according to a new analysis of the FAME 3 trial.

In this prespecified analysis, half of the patients randomized to PCI had a low functional SYNTAX score, reflecting low anatomic complexity and a negative fractional flow reserve (FFR), and these PCI-treated patients had 1-year outcomes on par with those who were treated with surgery.

“There were lots of patients reclassified when we analyzed the functional SYNTAX score and compared it with the SYNTAX score,” lead investigator Yuhei Kobayashi, MD (NewYork-Presbyterian Brooklyn Methodist Hospital, NY), told TCTMD. “With a low functional SYNTAX score—less than 22—those patients had similar outcomes when comparing PCI with CABG surgery.”

Similarly, where FFR identified nonfunctionally significant lesions (despite the presence of three-vessel disease on angiogram), patients fared as well with PCI as with surgery.

Importantly, said Kobayashi, the paper suggests that not all three-vessel CAD is the same and not all such patients need to be sent automatically for surgery. The findings support combining anatomic and functional assessments of three-vessel CAD when attempting to define the best revascularization option, he added.

FAME 3, published in 2021, was hailed as a big win for surgery over PCI in stable patients with three-vessel coronary artery disease. In the original study, PCI guided by FFR failed to match surgery for the reduction of major adverse cardiovascular and cerebrovascular events in 1,500 patients with angina and/or evidence of myocardial ischemia.

Cardiac surgeon Michael Reardon, MD (Houston Methodist Hospital, TX), a member of the FAME 3 steering committee, said the new analysis is attempt to really find out who has physiologically significant three-vessel disease, a group that does better with CABG surgery.

“If you do FFR and you find that one of those three vessels isn’t important, then you’re really dealing with two-vessel disease,” Reardon told TCTMD. “We know from SYNTAX that if you have a SYNTAX score of 22 or less, you tend to do OK with PCI. The problem is that if you’re looking at this and using a visual marker of 50% or more [stenosis on angiography], a fair number of those lesions aren’t going to be physiologically important.”

The ability to downgrade vessels using functional testing, and spare patients from undergoing CABG surgery if it isn’t necessary, is also a laudable goal, said Reardon. “I think, sometimes, we overtreat coronary artery disease from a surgical standpoint.” These data, he added, support PCI in appropriate patients with a functional SYNTAX score less than 22 as it doesn’t show that surgery offers a substantial benefit over the less invasive approach.

Benjamin Hibbert, MD (Mayo Clinic, Rochester, MN), who wasn’t involved in the study, said the new analysis should be considered hypothesis-generating given that FAME 3 didn’t meet its primary endpoint. Nonetheless, the new data may have practical applications in that they support how many operators are practicing.

“I don’t think a lot of operators routinely calculate SYNTAX scores,” Hibbert told TCTMD. “It’s cumbersome. It’s not really a facile scoring system to use. So, while the bulk of this analysis is around calculating the functional SYNTAX score, I think reclassifying patients into one- or two-vessel disease category—which they were able to do in a third of cases—is a really pragmatic application of their data. It reflects what people were doing, and it’s certainly how I’d been practicing where if a patient had multivessel disease with a lot of borderline lesions we’d do a functional assessment, or an imaging assessment. If some of those lesions came out nonsignificant, especially LAD disease, we were less likely to send them for CABG. I think the data supports that kind of practice.”

Hibbert highlighted an open question in light of the landmark ISCHEMIA trial that showed no benefit of coronary revascularization with either PCI or CABG in patients who have stable CAD. If FFR reclassifies patients into lower-risk categories, it’s possible that optimal medical therapy might do just as well as coronary revascularization.

“Maybe the patient doesn’t need CABG, the patient mightn’t even need PCI,” he said. “Maybe the medical approach might also be appropriate.”    

Arnold Seto, MD (VA Long Beach Health Care System, CA), who also commented on the results for TCTMD, noted that FAME 3 did show that PCI was associated with a lower risk of MACCE in patients with a low SYNTAX score (< 22), a subgroup that made up one-third of the overall population. The functional SYNTAX score shifts the percentage of patients expected to do as well with PCI as with surgery from 33% (low SYNTAX score) to 50% (low functional SYNTAX score) while the addition of functional testing with FFR reduced the number of patients with “true” three-vessel CAD from 100% to 67%.

While the functional SYNTAX score is not routinely used in clinical practice, Seto is a proponent of using FFR. “For those of us who are physiologists, we certainly think it adds some value,” he said. “This [FAME 3] analysis suggests that it does and that’s exciting.”

The study was published online September 11, 2023, in JACC: Cardiovascular Interventions.

Refining Complexity

The most recent US and European guidelines both recommend assessing anatomic complexity based on the SYNTAX score to help guide revascularization decisions in patients with multivessel disease. The functional SYNTAX score, in contrast, utilizes both anatomic data from the angiogram-based SYNTAX score and FFR data. It has previously been shown to reduce the number of high-risk patients identified using the SYNTAX score alone, and to better predict the risk of adverse events.

“The obvious challenge is its application clinically,” said Kobayashi. “In a population with three-vessel disease, it’s pretty challenging to do [FFR] in all three vessels.”  

With this prespecified analysis, researchers attempted to determine whether the functional SYNTAX score identified a proportion of patients with less complex three-vessel CAD who would have similar outcomes with PCI and CABG surgery.

Of the 1,476 patients who had angiograms analyzed by the core laboratory, mean SYNTAX scores were 26.0 in the PCI arm and 25.7 in the CABG arm. Among the PCI patients, the mean functional SYNTAX score was 22.7. When the FFR information was factored in, 27.0% of patients in the PCI arm were reclassified from a SYNTAX score > 22 to a functional SYNTAX score ≤ 22, with 368 of 733 PCI-treated patients having a low functional SYNTAX score. Additionally, while all patients had three-vessel CAD on the angiogram, only two-thirds had functionally significant CAD in all vessels.

For highly-complex CAD, CABG is better than PCI. For lower-risk, less-complex patients, PCI provides similar outcomes to CABG, often with less morbidity and stroke. Arnold Seto

Overall, patients with a low functional SYNTAX score (≤ 22) randomized to PCI had a lower rate of MACCE at 1 year than those with a higher functional SYNTAX score (6.3% vs 15.1%; P < 0.001). The composite of death, MI, or stroke was also lower in those with a low functional SYNTAX score (5.2% vs 9.6%; P = 0.02). The rate of MACCE and death/MI/stroke in those with a low functional SYNTAX score was similar to the rates seen in patients who underwent CABG surgery.

In the surgery arm, the rates of MACCE and death/MI/stroke were 6.9% and 5.2%, respectively, which are not significantly different when compared with PCI-treated patients with a functional SYNTAX score ≤ 22.

Similarly, PCI-treated patients without true functionally significant three-vessel disease had a significantly lower rate of MACCE, and there was a trend toward lower rates of death/MI/stroke, compared with PCI-treated patients with functionally significant three-vessel disease. When contrasted with those undergoing surgery, the MACCE and death/MI/stroke event rates at 1 year did not significantly differ among PCI-treated patients without functionally significant three-vessel disease.

In an editorial, Patrick Serruys, MD, PhD, Pruthvi Revaiah, MD, and Yoshinobu Onuma, MD, PhD (all University of Galway, Ireland), write that primary benefit of the functional SYNTAX score is reclassifying higher-risk groups into lower-risk categories, which was demonstrated in the original FAME study. Although outcomes between the PCI-treated patients with low functional SYNTAX scores and CABG-treated patients was similar, further studies will be needed to determine if these patterns persist beyond 1 year.

Moving Toward Angiography-Based FFR

The FAME 3 analysis, said Hibbert, is reassuring for operators using functional assessments to reclassify candidates in that it can be done safely. In the analysis, lesions not requiring revascularization based on the FFR had a low event rate, with MI and revascularization attributable to the deferred lesion occurring in 0.5% and 3.2% of cases.     

For Seto, the new analysis reinforces the message learned from the original 2009 SYNTAX trial, which was also observed in FAME 3, showing that surgery is superior to PCI for patients with highly complex disease, but that there is a role for PCI in select patients.

“For highly-complex CAD, CABG is better than PCI,” Seto told TCTMD. “For lower-risk, less-complex patients, PCI provides similar outcomes to CABG, often with less morbidity and stroke. This study shows that FFR is still better than angiography alone in defining who is high risk and how complex a patient’s CAD is.”

One of the limitations of the new analysis is that it isn’t an entirely an “apples-to-apples comparison,” said Seto, noting that the PCI-treated patients with a low functional SYNTAX score were compared against the entire surgical group. As such, this includes surgery patients with a range of anatomically complex lesions, such as those with intermediate and high SYNTAX scores.

“Inherently, when people have more-complex coronary disease, they are at higher risk for events,” said Seto.

Given that functional assessments can be time-consuming and challenging in patients with multivessel disease, Seto said FFR-derived from coronary angiography represents an exciting development. What would be interesting would be to calculate a functional SYNTAX score based on angiography alone to see how many patients shifted into the lower-complexity cohort and whether PCI performs as well as CABG in that setting.

“It would a simpler and safer way of performing FFR on all these patients and better advising them what their options are,” he said.

Kobayashi agreed, saying the introduction of angiographic-derived functional assessments would help physicians more feasibly calculate the functional SYNTAX score and use it more regularly in clinical practice. Other functional assessment tools are also in the works, including FFR derived from CT, optical computed tomography, and intravascular ultrasound.