Impact of Post-Percutaneous Coronary Intervention Fractional Flow Reserve Measurement on Procedural Management and Clinical Outcomes: The REPEAT-FFR Study

Abstract: Objective. We evaluated the impact of post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) in a prospective study. Methods. This was a single-center, prospective registry of patients undergoing PCI following a baseline FFR ≤0.80. Patients were divided according to the post-PCI FFR value (<0.90 vs ≥0.90). The primary endpoint was the proportion of cases in which further action was undertaken in light of a post-PCI FFR value <0.90. Results. Of 65 PCIs, a total of 43 (66%) had a post-PCI FFR <0.90 and 22 (34%) had a post-PCI FFR ≥0.90. Baseline characteristics were similar between groups. Baseline FFR was similar between patients with post-PCI FFR <0.90 and ≥0.90 (0.72 ± 0.08 vs 0.69 ± 0.14; P=.40). Post-PCI FFR values were 0.82 ± 0.05 in post-PCI FFR <0.90 patients and 0.94 ± 0.02 in post-PCI FFR ≥0.90 patients (P<.001). The most common reason for a post-PCI <0.90 was residual small-vessel disease (42%). In 15 patients (35%) with a post-PCI FFR <0.90, an action was undertaken. An increase of 0.05 ± 0.07 in FFR value (P=.01) was noted after these maneuvers. However, a final FFR value ≥0.90 was achieved in only 3 patients (20%). The major adverse cardiac event (MACE) rate at 1-year follow-up was higher in patients with final FFR <0.90 (31.6% vs 9.1%; P=.047). Conclusions. A suboptimal physiologic outcome is observed in two-thirds of patients undergoing PCI. Despite further interventions, a satisfactory outcome is achieved in only a minority of cases. A post-PCI suboptimal physiologic outcome appears to be associated with a higher incidence of MACE at follow-up.

J INVASIVE CARDIOL 2019;31(8):229-234. Epub 2019 June 15.

Key words: fractional flow reserve, coronary physiology, percutaneous coronary intervention

Visual estimation of coronary stenoses to evaluate the indication for percutaneous coronary intervention (PCI) carries several limitations. Specifically, assessment of lesion severity is subjective and can be inconclusive in cases of eccentric plaques, particularly if adequate projections are not obtained. Moreover, the functional significance of a stenosis depends on several variables beyond the degree of luminal narrowing, most importantly on the extent of viable myocardium in the subtended territory.¹ Fractional flow reserve (FFR) is a widely validated method that allows these limitations of coronary angiography to be overcome, especially in the case of moderate (30%-70%) lesions. Accordingly, several studies have confirmed the positive impact of FFR on prognosis when incorporated in the preprocedural evaluation of coronary artery disease.^2-4

Initial data suggest that the FFR value post stenting as a means to assess the physiologic outcome of PCI could also have an impact on long-term prognosis, since patients with a post-PCI FFR <0.90 are at an increased risk of a major adverse cardiac event (MACE).^5,6 There are several reasons why FFR values may not be optimal after the procedure, including presence of diffuse disease, geographic miss, suboptimal stent expansion, or residual edge dissection. These situations may at times not be apparent at angiography. However, such findings are derived from retrospective studies, where post-PCI FFR values were only recorded and not used to influence decision-making in the catheterization laboratory. The aim of the present study was to assess the impact of routine post-stenting FFR measurements on clinical practice and outcomes. In particular, a post-PCI FFR value <0.90 was considered indicative of suboptimal physiological outcomes, and the operators were asked to consider undertaking further action to improve the result.

Methods

Patient population. This was a single-center, prospective, observational study including consecutive patients undergoing FFR-guided coronary PCI for either stable or unstable coronary artery disease. Inclusion criteria were: age >18 years; angina and/or documentation of inducible myocardial ischemia; presence of ≥1 coronary stenosis evaluated at 30%-70% by visual estimation; baseline FFR value ≤0.80; successful PCI (final Thrombolysis in Myocardial Infarction flow grade 3 and <30% residual stenosis); and written informed consent. Exclusion criteria were: ST-elevation myocardial infarction on index procedure; prior coronary artery bypass graft surgery; left main lesion >50%; severe asthma; baseline FFR >0.80; pregnancy; and inability to provide written informed consent. Patient inclusion took place between October 2016 and April 2017. Baseline, procedural, and hospitalization data were recorded. All patients signed an informed consent for inclusion in the study and the procedure, which was approved by the local ethics committees.

Study workflow. Baseline and post-PCI FFR measurements were performed with the Acist Navvus Rapid Exchange FFR rapid-exchange microcatheter (Acist Medical Systems) following intravenous infusion of adenosine at 140 µg/kg/min.

Following measurement of a baseline FFR value ≤0.80, PCI was performed according to standard practice and the technique was left at the operator’s discretion. High-pressure postdilation with non-compliant balloons after stent implantation was recommended, as per standard practice.

At the end of the procedure, the FFR value was reassessed and the operator decided if further interventions (eg, postdilation) or diagnostic tests (eg, intravascular imaging) were necessary. This measurement was deemed post-PCI FFR. Because there is no established threshold for this variable, and that a functionally suboptimal revascularization may be appropriate in some situations (eg, diffuse small vessel disease), the decision to accept the post-PCI result or not was based on the operator’s judgment. Therefore, the study protocol did not mandate a threshold for final FFR. However, the physician was asked to provide an explanation for an FFR value <0.90. Final FFR was defined as the FFR value measured at the end of the procedure, and was meant to reflect possible further interventions undertaken in light of a post-PCI FFR <0.90; this value equaled the post-PCI FFR if no further maneuver was performed.

Study endpoints. The primary endpoint was to evaluate the proportion of cases where any action was taken after post-PCI FFR. This included the following: performance of additional tests (intravascular ultrasound or optical coherence tomography); further stenting (with drug-eluting stents, bare-metal stents, or bioresorbable vascular scaffolds); further postdilation; and/or treatment of the distal vessel with a drug-eluting balloon. The secondary endpoint was the MACE rate at 1-year follow-up. MACE was defined as a composite of cardiac death, myocardial infarction, ischemia-driven target-vessel revascularization, and readmission for angina.

Statistical analysis. Continuous variables are presented as mean ± standard deviation and compared with Student’s t-test. Categorical variables are presented as frequency (percentages) and compared with Chi-square test. For the evaluation of the primary endpoint, patients were divided according to the post-PCI FFR value (<0.90 vs ≥0.90). Subsequently, the secondary endpoint was assessed according to the final FFR value (<0.90 vs ≥0.90). Kaplan-Meier curves of 1-year MACE-free survival were plotted and compared with the log-rank test. A P-value <.05 was considered statistically significant. Analyses were performed using SPSS 24 (IBM Corporation).

Results

Clinical characteristics. Sixty-five PCIs were included during the study period; of these, a total of 43 patients (66%) had a post-PCI FFR <0.90 and 22 patients (34%) had a post-PCI FFR ≥0.90. Baseline clinical characteristics were similar between groups (Table 1). In the entire study population, mean age was 68.9 ± 9.3 years and 91% of patients were male. The prevalence of cardiovascular risk factors and comorbidities was high, with one-third of patients having diabetes and prior myocardial infarction, and  two-thirds having prior PCI. Mean left ventricular ejection fraction was 51.8 ± 10.0%. Two-thirds of patients presented with stable coronary artery disease, and one-fourth presented with acute coronary syndrome.

Angiographic and procedural characteristics. Angiographic and procedural data are shown in Table 2. Overall the average SYNTAX score was 13.9 ± 7.9, with no difference between the two groups. While the left anterior descending (LAD) was the most frequently treated vessel in both groups, the prevalence of LAD as the target vessel was significantly higher in patients with post-PCI FFR <0.90 vs post-PCI FFR ≥0.90 (84% vs 59%, respectively; P=.03). Baseline FFR was similar between patients with post-PCI FFR <0.90 and ≥0.90 (0.72 ± 0.08 vs 0.69 ± 0.14,  respectively; P=.40) (Figure 1). Predilation technique was similar between groups; however, patients with post-PCI FFR <0.90 tended to receive fewer stents (1.3 ± 0.7 vs 1.8 ± 1.4 in patients with post-PCI FFR ≥0.90; P=.08) and had shorter total stent length (33.0 ± 19.1 mm vs 47.0 ± 32.9 mm in patients with post-PCI FFR ≥0.90;  P=.08). Postdilation balloon diameter tended to be smaller in patients with post-PCI FFR <0.90 (3.3 ± 0.4 mm vs 3.5 ± 0.4 mm in patients with post-PCI FFR ≥0.90; P=.09).

Post-PCI FFR. Post-PCI FFR values were 0.82 ± 0.05 in patients with post-PCI FFR <0.90 vs 0.94 ± 0.02 in patients with post-PCI FFR ≥0.90 (P<.001) (Figure 1). Figure 2 outlines the presumptive reasons for a post-PCI <0.90, as reported by the operators. Residual disease not amenable to treatment was identified in 42%. Less common reasons included residual uncovered plaques, stent under-expansion, and edge dissections. No plausible factor could be identified in 37%. In 15 patients (35%) with a post-PCI FFR value <0.90, an action was undertaken to further improve the physiological PCI result (Figure 3). Six patients underwent intravascular imaging, 11 had further stenting, 12 had further postdilation, and 1 had treatment of the distal vessel with a drug-eluting balloon. An increase of 0.05 ± 0.07 in FFR value (P=.01) was noted after such maneuvers in these 15 patients. However, a final FFR value ≥0.90 was achieved in only 3 of these patients (20%); further stenting on a previously untreated proximal plaque was performed in all 3 patients. Final FFR was 0.87 ± 0.07 overall, and 0.83 ± 0.05 and 0.94 ± 0.02 in patients with post-PCI FFR <0.90 vs ≥0.90, respectively (P<.001).

Outcomes on follow-up. Table 3 shows 1-year outcomes according to the final FFR value. Five patients (8%) were lost to follow-up. The incidence of MACE was higher in patients with final FFR <0.90 (31.6% vs 9.1% in patients with final FFR ≥0.90; P=.047), with a numerically higher incidence of all endpoint components, particularly ischemia-driven target-vessel revascularization (13.2% vs 4.5% in patients with final FFR ≥0.90; P=.28) and readmission for angina (21.1% vs 4.5% in patients with final FFR ≥0.90; P=.08). Kaplan-Meier analysis confirmed the aforementioned difference in MACE-free survival (Figure 4).

Discussion

The main findings of this study are as follows: (1) a suboptimal post-PCI FFR value (<0.90) is observed in up to two-thirds of patients undergoing FFR-based PCI; (2) the most frequent reason for this finding is residual diffuse distal disease, but in over one-third of cases, no factor can be identified; (3) a final FFR ≥0.90 is achieved in only 20% of patients in whom additional maneuvers are performed to correct such a suboptimal FFR value; and (4) a final FFR <0.90 appears to be associated with a higher incidence of MACE at 1-year follow-up.

Several studies have provided compelling data for the implementation of FFR in the diagnostic evaluation of intermediate stenosis,^2-4 indicating that patients with lesions with FFR ≤0.80 treated with PCI have a better MACE-free survival compared with medical therapy, similar to patients with functionally non-significant stenosis.⁴ However, scarce evidence exists regarding the role of post-PCI FFR in the decision-making and outcomes of patients undergoing PCI. Ito et al⁵ studied 97 patients treated with optimal drug-eluting stent implantation under FFR and intravascular ultrasound guidance. The MACE rate was 10.3% at a median follow-up of 17.8 months, and FFR after stenting was lower in this group (0.86 ± 0.04 vs 0.91 ± 0.04). The optimal FFR threshold to predict MACE was 0.90. Similarly, Reith et al⁶ analyzed 66 patients treated by stent implantation, in whom post-stenting FFR data were compared and related to MACE at follow-up. Similar to our report, the 20-month cumulative incidence of MACE was greater in patients with FFR ≤0.905 vs those with FFR>0.905 (35.9% vs 5.3%, respectively). A Li et al⁷ substudy on 1476 patients in the DKCRUSH VII registry indicated that a post-PCI FFR ≤0.88 strongly correlated with target-vessel failure. Disease in the LAD, stent length, and stent diameter were independent predictors of impaired post-PCI FFR. A postprocedure FFR ≤0.88 was the only predictor of target-vessel failure, which was observed in 4.0% of patients with FFR >0.88 vs 8.0% of patients with FFR ≤0.88 at 1-year follow-up, mainly driven by target-vessel revascularization and cardiac death. Baranauskas et al⁸ studied a cohort of 74 patients undergoing PCI on long diffuse disease with a stent length ≥30 mm. They found that a post-PCI FFR value of >0.95 was achieved in only 12%, and was not achieved in any patient with a total stent length ≥50 mm, suggesting that diffuse coronary artery disease cannot be effectively treated using long and ultra-long stenting in the majority of cases.

Prior to the present report, only Agarwal et al⁹ have performed a randomized or prospective study to investigate the role of post-PCI FFR; in their cohort of 574 subjects undergoing FFR-guided PCI, 21% of patients demonstrated a post-PCI FFR in the ischemic range (FFR ≤0.81). After subsequent interventions, FFR in this subgroup increased from 0.78 ± 0.08 to 0.87 ± 0.06, with only 9% of patients still in the ischemic range. Patients who achieved a final FFR >0.86 had a significantly lower MACE rate vs those with a final FFR ≤0.86 (17% vs 23%, respectively) at a mean follow-up of 31 ± 16 months. A final FFR ≤0.86 had incremental prognostic value over clinical and angiographic variables for MACE prediction.

We have observed that a suboptimal post-PCI FFR value (<0.90) is found in two-thirds of patients undergoing FFR-based PCI, which is higher than reported by Reith et al⁶ (39%) and Ito et al⁵ (55%) and comparable to the figure reported by Baranauskas et al⁸ (72%). This finding can be related to different proportions of LAD as the target vessel across studies, which has been identified as a predictor of suboptimal post-PCI FFR.⁷

We have used an FFR cutoff of <0.90 to identify patients with a suboptimal physiologic PCI result following the publication of the early studies by Ito et al⁵ and Reith et al.⁶ The subsequent Li et al⁷ and Agarwal et al⁹ studies utilized similar cutoffs (0.88 and 0.86, respectively). There are several possible explanations for a suboptimal post-PCI FFR, some of which are easily identifiable with FFR interrogation (residual proximal/distal plaques) or intravascular imaging (stent under-expansion, edge dissections), and treatable with additional balloon dilation or stenting. However, an important proportion is due to distal small-vessel disease or to factors that cannot be easily identified with tools that are commonly available in the catheterization laboratory. We speculate that additional physiology testing (eg, coronary flow reserve and index of microcirculatory resistance) could help provide an exact diagnosis in some cases.

There is compelling evidence that a suboptimal physiological PCI result (final FFR <0.90 to 0.86, depending on the definition used^5-7,9) is linked to worse clinical outcomes on follow-up, and our findings confirm this observation. However, it is much less clear whether and to what extent further maneuvers performed in light of a suboptimal post-PCI FFR can improve the physiologic result of PCI. In fact, we have observed that a final FFR ≥0.90 could be achieved in only 20% of cases, which was also reported by Agarwal et al⁹ (although an exact comparison is hampered by the utilization of a different cut-off in their study). This might reflect the presence of incorrigible factors (eg, diffuse small-vessel disease) and/or an incomplete understanding of coronary physiology in the setting of PCI.

Study limitations. First, although this is a prospective study, no randomization was performed depending on the post-PCI FFR value. Therefore, although our findings do not suggest that a suboptimal physiological PCI result can be significantly improved in the majority of patients, we cannot rule out that such a modest improvement could still be associated with better clinical outcomes on follow-up. Second, we could not identify a plausible reason for a post-PCI FFR <0.90 in 37% of patients. We cannot rule out that further insight into this aspect could have been provided by additional physiology testing (eg, coronary flow reserve and/or index of microcirculatory resistance). Third, the exact mechanisms linking a final FFR <0.90 with adverse events on follow-up are not entirely understood, and could involve chronic progression of functionally moderate stenoses, acute rupture of such plaques, impaired vasomotion due to extensive stenting, and microvascular dysfunction, among others. Fourth, our small sample size precluded performing multivariable adjustment to identify independent predictors of a suboptimal post-PCI FFR value and MACE. Finally, the single-center nature and small sample size of our study preclude drawing definitive conclusions on the role of post-PCI FFR, and our findings need to be confirmed by larger, multicenter cohorts.

Conclusions

A suboptimal physiological outcome is observed in up to two-thirds of patients undergoing PCI. Often, the reasons for this finding are unknown. Despite further interventions, a satisfactory physiological outcome is achieved in only a minority of cases in which additional maneuvers are performed to correct such findings. Patients with a suboptimal physiological outcome of PCI suffer a higher incidence of adverse events at 1-year follow-up.

References

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8. Baranauskas A, Peace A, Kibarskis A, et al. FFR result post PCI is suboptimal in long diffuse coronary artery disease. EuroIntervention. 2016;12:1473-1480.

9. Agarwal SK, Kasula S, Hacioglu Y, Ahmed Z, Uretsky BF, Hakeem A. Utilizing post-intervention fractional flow reserve to optimize acute results and the relationship to long-term outcomes. JACC Cardiovasc Interv. 2016;9:1022-1031.

From the ¹Interventional Cardiology Division, Cardio-Thoracic-Vascular Department, San Raffaele Scientific Institute, Milan, Italy; ²Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom; ³Interventional Cardiology Unit, GVM Care & Research Maria Cecilia Hospital, Cotignola, Italy; and ⁴Department of Cardiology, Montefiore Medical Center, The Bronx, New York.

Funding: This study was funded with an unrestricted research grant from ACIST Medical Systems.

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Azzalini reports honoraria from Abbott Vascular, Guerbet, Terumo, and Sahajanand Medical Technologies; research support from ACIST Medical Systems, Guerbet, and Terumo. Dr Chieffo reports consulting/speaker honoraria from Abbott Vascular, Abiomed, Amaranth, Biosensor, Cardinal Health, and GADA. Dr Latib serves on the advisory board of Medtronic, Abbott, and Philips and reports research support from ACIST Medical Systems. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted February 20, 2019, accepted March 4, 2019.

Address for correspondence: Lorenzo Azzalini, MD, PhD, MSc, Interventional Cardiology Division, Cardio-Thoracic-Vascular Department, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Email: azzalini.lorenzo@hsr.it