Key Points:

1. The prognosis for deferred and performed revascularization in coronary stenosis with FFR values in the grey zone (0.75–0.80) was evaluated in 1334 native coronary stenosis in as many number of patients.

2.  The primary outcome, a composite of death, target-vessel myocardial infarction (MI), and target vessel revascularization (TVR) as well as overall  mortality and spontaneous MI did not differ between the groups, whereas myocardial infarction (mainly periprocedural) was significantly higher in the performed group and target vessel revascularization was significantly higher in the deferred group.

Study Protocol:

Out of all patients in The Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve (IRIS-FFR) registry, which is a prospective, multicenter registry designed for investigating the prognosis of coronary stenosis assessed using FFR in routine clinical practice, patients with a de novo native coronary artery stenosis with an FFR value in the grey zone (0.75–0.80) were enrolled for this study. The decision regarding revascularization for such patients was at the operator’s discretion. 

Follow-ups were conducted during hospitalization, at 30 days, 6 months, and 12 months after the index procedure and subsequently at 6 month intervals. The patients’ clinical status, interventions, and adverse events were recorded at each follow up.

Outcomes:

During a median follow-up of 2.9 years, overall mortality did not differ between the groups (2.5% in deferred group vs. 2.0% in performed group; aHR 0.82, 95% CI 0.34–2.00; P = 0.66). The performed group showed a significantly higher risk of target vessel MI (0.7% vs. 3.2%; aHR 0.27, 95% CI 0.09–0.80; P = 0.02), mainly because of a higher risk of periprocedural MI but the incidence of spontaneous MI did not differ between the groups (0.7% vs. 0.5%; aHR 1.85, 95% CI 0.35–9.75; P = 0.47). Definite stent thrombosis did not occur. The risk of TVR was higher in the deferred group (5.9% vs. 3.7%; aHR 2.17, 95% CI 1.17–4.02; P = 0.01).

The clinical outcomes on subgroup analysis and propensity score matching showed a similar trend.

The indications for TVR were angina with CCS III or IV, ischemia documented by non-invasive test or angiographic progression to more than 90% diameter stenosis.

ACS and multivessel disease were the dominant predictors for major adverse cardiac events in both the groups.

Conclusion:

For coronary stenosis with grey-zone FFR values, revascularization was associated with a high risk of periprocedural MI which was offset by a high risk of TVR in the deferred group, without any significant difference in overall clinical outcomes including mortality.

Comment:

Although an observational study, it is based on the largest cohort of prospectively enrolled patients with the longest follow-up duration that could give clinically relevant information for the issue of FFR in the grey zone.

The other strengths were: adjudication by an independent committee, adjustment for potential confounders, and vessel-level outcomes.

Questions that beg for answers are the reasons for revascularizing some lesions as compared to others, information about baseline symptoms, and upstream stress tests.

Like prior several non-randomized, observational studies, the same message appears from this study, namely that death and myocardial infarction remain uncommon in the FFR grey zone. Subsequent TVR takes place in more number of deferred stenoses with a higher incidence of periprocedural MI in the revascularization group.

Suggested Readings:

1. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van't Veer M, et al. FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–224.

2. De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med  2014;371:1208–1217.

3. Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J  2015;36:3182–3188.

4. Courtis J, Rodés-Cabau J, Larose E, Déry J-P, Nguyen CM, Proulx G, et al. Comparison of medical treatment and coronary revascularization in patients with moderate coronary lesions and borderline fractional flow reserve measurements. Catheter Cardiovasc Interv  2008;71:541–548.

5. Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mügge A, et al. Clinical outcome following conservative vs revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements. Clin Cardiol  2010;33:77–83

6. Adjedj J, De Bruyne B, Flore V, Di Gioia G, Ferrara A, Pellicano M, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 2016;133:502–508.

7. Agarwal SK, Kasula S, Edupuganti MM, Raina S, Shailesh F, Almomani A, et al. Clinical decision-making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol  2017;29:371–376.

8. Yamashita J, Tanaka N, Shindo N, Ogawa M, Kimura Y, Sakoda K, et al. Seven-year clinical outcomes of patients with moderate coronary artery stenosis after deferral of revascularization based on gray-zone fractional flow reserve. Cardiovasc Interv Ther 2015;30:209–215.

9. Shiono Y, Kubo T, Tanaka A, Ino Y, Yamaguchi T, Tanimoto T, et al. Long-term outcome after deferral of revascularization in patients with intermediate coronary stenosis and gray-zone fractional flow reserve. Circ J 2014;79:91–95.

10. Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, et al. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv 2013;6:222–225.

11. Johnson NP and  Zimmermann FM. Yellow traffic lights and grey zone fractional flow reserve values: stop or go? European Heart Journal, 2018:39(18):1620–1622.