TAVR (transcatheter aortic valve replacement) wasn’t the whole story for interventional cardiology at ACC.17. Much discussion will be had in the next weeks and months about fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) spurred by the results of the DEFINE-FLAIR and iFR-SWEDEHEART studies, as well as FFR in the acute setting spurred by the Compare-Acute study. Other topics of discussion will be intervention for chronic total occlusion (CTO), thanks to the DECISION-CTO trial, and the fate of the Absorb bioresorbable vascular scaffold (BVS) led by the ABSORB III results, which also garnered a letter to physicians from the U. S. Food and Drug Administration (FDA).

Fractional Flow Reserve: What’s Next?

The DEFINE-FLAIR and iFR-SWEDEHEART trials demonstrated that iFR was non-inferior to FFR in terms of incidence of major adverse cardiac events (MACE) at one year in patients experiencing angina or a myocardial infarction (MI). MACE was defined as death, non-fatal MI, or unplanned revascularization. The studies also showed iFR resulted in markedly less patient discomfort and reduced procedure-related adverse events compared with FFR. Although iFR has been validated in several smaller studies, these two new trials are the largest to date and the first to assess how using the new alternative method affects patient outcomes.

Both DEFINE-FLAIR and iFR-SWEDEHEART – designed to reflect real-world practice, with the latter study using the registry-based randomized clinical trial design – enrolled patients who had stable angina or acute coronary syndrome (ACS) and randomized them 1:1 to FFR-guided or iFR-guided revascularization. The treatment cut-points were ≤0.80 for FFR and ≤0.89 for iFR.

For DEFINE-FLAIR there were 2,492 patients from 49 centers in 17 countries. In iFR-SWEDEHEART, of the 2,037 patients at 15 centers in Sweden, Denmark and Iceland, 2,019 patients were treated per protocol, with 1,012 patients receiving iFR and 1,007 receiving FFR.

With both strategies, there was a similar rate of the MACE primary endpoint at one year: 7.0 percent with FFR and 6.8 percent with iFR (p < 0.001 for non-inferiority) in DEFINE-FLAIR and 6.1 percent and 6.7 percent, respectively (p = 0.007 for non-inferiority) in iFR-SWEDEHEART. All-cause mortality was somewhat higher in DEFINE-FLAIR with iFR (1.77 percent vs. 1.04 percent with FFR; hazard ratio 1.74; p = 0.11), but otherwise there was no difference for the individual components of the composite endpoint in either study.

“Our study shows that it is safe to use either the iFR or FFR technique,” said Justin E. Davies, MBBS, PhD, lead author of DEFINE-FLAIR. “I think iFR lowers the barriers to physiological measurement, which I believe is key to getting more people to use coronary physiology to guide coronary revascularization decision-making.”

iFR-SWEDEHEART revealed a substantial reduction in patient discomfort, with just 3 percent of iFR patients reporting discomfort in a post-procedure questionnaire compared with 68 percent of FFR patients. DEFINE-FLAIR showed a substantial 10-fold reduction in symptoms of both patient-reported and physician-reported procedure-related adverse events, which occurred in 3.1 percent of iFR patients and 30.8 percent of FFR patients overall.

“If patients could choose between two methods, given that there is no difference in outcomes, patients would probably appreciate not having to experience the side effects of the vasodilator,” said Matthias Götberg, MD, PhD, lead author of iFR-SWEDEHEART. “For cardiologists who are hesitant to use FFR, iFR might provide an opportunity to increase adoption rates of coronary physiology and benefit more patients.”

“The results of the DEFINE-FLAIR study should prove reassuring to interventional cardiologists who are accustomed to performing physiologic assessments of stenosis of intermediate severity using the FFR technique,” said Claire Duvernoy, MD, FACC. “I would expect that many would choose to add iFR to their diagnostic armamentarium, if not switch to it as their favored technique given its ease and speed of use.”

However, one question that remains is the cost of the procedure. If it’s significantly more expensive than FFR, Duvernoy noted, this might prove a barrier to widespread adoption of the technique.

Compare-Acute is the first randomized clinical trial in which physicians used FFR to precisely assess secondary blockages. Compared with STEMI patients in whom only the infarct-related blockage was treated, patients who received FFR-guided evaluation and treatment of all significantly narrowed arteries were 65 percent less likely to experience the trial’s primary endpoint – a composite of all-cause mortality, non-fatal MI, stroke and subsequent revascularization at 12 months.

“The Compare-Acute study adds to our growing body of data that seems to be indicating that a strategy of multivessel PCI outperforms culprit-only PCI in STEMI patients,” said Dipti Itchhaporia, MD, FACC.

A total of 885 STEMI patients were enrolled at 24 sites in 12 countries in Europe and Asia. Immediately after PCI for the infarct-related artery, stable patients were randomly assigned to receive FFR-guided infarct-only revascularization (590 patients) or FFR-guided assessment and PCI to treat additional lesions when indicated by an FFR of 0.80 or lower (complete revascularization; 295 patients).

The primary endpoint occurred in 20.5 percent of patients receiving infarct-only revascularization and 7.8 percent of patients receiving FFR-guided complete revascularization (p < 0.001). The major driver of this reduction in the primary endpoint was a lower rate of repeat revascularization in the complete revascularization arm (6.1 percent vs. 17.5 percent for infarct-only revascularization; p < 0.001). No significant difference in the rates of all-cause mortality, non-fatal MI or stroke was observed.

All non-urgent revascularization procedures performed within the first 45 days after the initial PCI based on symptoms or stress tests were excluded from this analysis to avoid biasing the results in favor of complete revascularization.

When assessing the lesions other than the infarct-related artery, the researchers found that about half of these lesions were sufficiently constricted to require treatment. Together, these results suggest that treating non-infarct related lesions is beneficial and that FFR can help clinicians to precisely identify these lesions.

“The results show that using FFR in the acute phase of STEMI is feasible and safe,” said lead author Pieter Smits, MD. “Furthermore, FFR-guided complete revascularization allows you to fine-tune the treatment and get better outcome results.”

It’s important to note, however, “that whether the FFR-guided complete revascularization strategy will reduce the rate of hard end points, such as recurrent MI and cardiovascular mortality, is uncertain,” said Itchhaporia. Larger studies powered for these hard endpoints are needed. She also raised the need to be cautious about the interpretation of a negative FFR near the infarct zone; the farther away from the infarct zone, the more confidence one can have about the FFR value.

Disappointment For PCI for Chronic Total Occlusions

DECISION-CTO – the first randomized study to compare revascularization with PCI plus optimal medical therapy against OMT alone – found no difference in the primary or secondary endpoints. The study was terminated early because of slower than expected enrollment. A total of 834 patients with silent ischemia, stable angina or ACS and a de novo CTO were enrolled (398 allocated to OMT and 417 to PCI) at nineteen cardiac centers in Asia. Loss to follow-up increased over time, at about 8 percent at 3 years and about 12-17 percent at 5 years.

In the trial, led by Seung-Jung Park, MD, PHD, FACC, et al., patients who received OMT (aspirin, beta-blocker, calcium channel blocker, statin) had a similar rate of the primary composite outcome of death, MI, stroke or repeat revascularization at three years, occurring in 19.6 percent of patients compared with 20.6 percent of the PCI patients in the intention-to-treat (ITT) analysis. At 5 years, the secondary endpoint, the rates were 25.1 percent and 26.3 percent, respectively, for OMT and PCI. No differences were seen for the individual endpoints. Likewise, no difference was seen across subgroups.

Although OMT was shown to be non-inferior to PCI as an initial strategy for the primary endpoint in the ITT analysis, OMT did not meet the statistical criteria for non-inferiority set for the per-protocol or the as-treated population-based analyses, even though the event rates were not statistically significantly different at 3 years, according to Park.

“PCI is not the only solution to treat CTO, and in terms of patient outcomes, cost versus benefit, and other considerations, it is not beneficial to use PCI for all CTO lesions,” said Park. “The size of the ischemia, patient symptoms and cardiac function must be taken into account prior to the decision to perform PCI.”

ABSORB III: Evaporating Clinical Promise?

The risk of target lesion failure (TLF), the primary endpoint of the ABSORB III trial, was higher at two years with the Absorb GT1 BVS than with the conventional Xience drug-eluting stent, according to results presented at ACC.17 by Stephen Ellis, MD, FACC.

The trial protocol was revised, because it was deemed unlikely for superiority to emerge before the completion of the bioresorption process at about three years, based on reports of very late events between one and three years with the Absorb BVS in small studies. The trial sought to demonstrate non-inferiority at one year, and superiority over three to seven years by combining the ABSORB III and ABSORB IV data.

TLF was a composite defined as cardiac death, target vessel MI (TV-MI) and ischemia-driven target lesion revascularization. A total of 2,008 patients with stable ischemic heart disease and stabilized ACS were randomized 2:1 to the Absorb or XIence device.

At one year, the Absorb BVS was non-inferior to Xience with respect to TLF, but rates of device thrombosis were higher with the Absorb versus the Xience device when implanted in small vessels (reference vessel diameter [RVD] <2.25 mm), leading to a change in the FDA-approved instructions for use.

At 25 months, TLF occurred in 10.9 percent of the Absorb patients and 7.8 percent of the Xience patients (hazard ratio 1.42; p = 0.03). TV-MI was the driver of this difference (7.3 vs. 4.9 percent, respectively). And, the difference in TLF remained numerically but not statistically significant when patients with vessel diameters of <2.25 mm were excluded from the analysis. In vessels >2.5 mm, TLF was 9.4 percent and 7.0 percent in the Absorb and Xience arms. Stent thrombosis was 1.9 percent with Absorb and 0.8 percent with Xience.

“The jury is still out on the Absorb BVS for now,” said Herbert D. Aronow, MD, MPH, FACC. Long-term data, in particular for vessels 2.5 cm and larger, are needed to determine its relative safety and efficacy. Additional data will be needed in patients with more complex coronary artery disease and in the setting of ACS.

“Before widespread practice change can occur, we would need to establish the long-term superiority of BVS (when deployed with appropriate vessel preparation, sizing and post-dilation) versus conventional drug-eluting stents. Furthermore, we would need to see this in appropriately sized coronary arteries, in the setting of stable ischemic heart disease and ACS, and with varying levels of anatomic complexity,” Aronow added. Importantly, the cost-effectiveness of the BVS must also be determined.

The FDA issued a letter to physicians informing them of the increased risk of MACE with the Absorb device compared with Xience, along with a reminder that Absorb is not approved for use in small (<2.25 mm) vessels.

Keywords: Cardiology Interventions, ACC Publications, Absorbable Implants, Coronary Stenosis, Fractional Flow Reserve, Myocardial, Transcatheter Aortic Valve Replacement, United States, United States Food and Drug Administration, Vascular Diseases