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Background Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long-term clinical outcome of patients with stable coronary artery disease but no ischemia-inducing stenosis. Methods and Results We studied major adverse cardiovascular events (MACEs: all-cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post-percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80-2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5-year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log-rank P =0.040). The higher 5-year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log-rank P =0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977-0.998; P =0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966-0.998; P =0.032), and revascularization (HR, 0.985; 95% CI, 0.972-0.999; P =0.040). Conclusions Even in the absence of ischemia-producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5-year follow-up.

Background: During fractional flow reserve (FFR) measurement, the simple presence of the guiding catheter (GC) within the coronary ostium might create artificial ostial stenosis, affecting the hyperemic flow. We aimed to investigate whether selective GC engagement of the coronary ostium might impede hyperemic flow, and therefore impact FFR measurements and related clinical decision-making., Methods: In the DISENGAGE (Determination of Fractional Flow Reserve in Intermediate Coronary Stenosis With Guiding Catheter Disengagement) registry, FFR was prospectively measured twice (with GC engaged [FFR eng ] and disengaged [FFR dis ]) in 202 intermediate stenoses of 173 patients. We assessed (1) whether ΔFFR eng -FFR dis was significantly different from the intrinsic variability of repeated FFR measurements (test-retest repeatability); (2) whether the extent of ΔFFR eng -FFR dis could be clinically significant and therefore able to impact clinical decision-making; and (3) whether ΔFFR eng -FFR dis related to the stenosis location, that is, proximal and middle versus distal coronary segments., Results: Overall, FFR significantly changed after GC disengagement: FFR eng 0.84±0.08 versus FFR dis 0.80±0.09, P <0.001. Particularly, in 38 stenoses (19%) with FFR values in the 0.81 to 0.85 range, GC disengagement was associated with a shift from above to below the 0.80 clinical cutoff, resulting into a change of the treatment strategy from medical therapy to percutaneous coronary intervention. The impact of GC disengagement was significantly more pronounced with stenoses located in proximal and middle as compared with distal coronary segments (ΔFFR eng -FFR dis , proximal and middle 0.04±0.03 versus distal segments 0.03±0.03; P =0.042)., Conclusions: GC disengagement results in a shift of FFR values from above to below the clinical cutoff FFR value of 0.80 in 1 out of 5 measurements. This occurs mostly when the stenosis is located in proximal and middle coronary segments and the FFR value is close to the cutoff value.

Aims: Fractional flow reserve (FFR) has never been investigated in patients with reduced ejection fraction and associated coronary artery disease (CAD). We evaluated the impact of FFR on the management strategies of these patients and related outcomes., Methods and Results: From 2002 to 2010, all consecutive patients with left ventricular ejection fraction (LVEF) ≤50% undergoing coronary angiography with ≥1 intermediate coronary stenosis [diameter stenosis (DS)% 50-70%] treated based on angiography (Angiography-guided group) or according to FFR (FFR-guided group) were screened for inclusion. In the FFR-guided group, 433 patients were matched with 866 contemporary patients of the Angiography-guided group. For outcome comparison, 617 control patients with LVEF >50% were included. After FFR, stenotic vessels per patient were significantly downgraded compared with the Angiography-guided group (1.43 ± 0.98 vs. 1.97 ± 0.84; P < 0.001). This was associated with lower revascularization rate (52% vs. 62%; P < 0.001) in the FFR-guided vs. the Angiography-guided group. All-cause death at 5 years of follow-up was significantly lower in the FFR-guided as compared with Angiography-guided group [22% vs. 31%. HR (95% CI) 0.64 (0.51-0.81); P < 0.001]. Similarly, rate of major adverse cardiovascular and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, revascularization, and stroke) was significantly lower in the FFR-guided group [40% vs. 46% in the Angiography-guided group. HR (95% CI) 0.81 (0.67-0.97); P = 0.019]. Higher rates of death and MACCE were observed in patients with reduced LVEF compared with the control cohort., Conclusions: In patients with reduced LVEF and CAD, FFR-guided revascularization was associated with lower rates of death and MACCE at 5 years as compared with the Angiography-guided strategy. This beneficial impact was observed in parallel with less coronary artery bypass grafting and more patients deferred to percutaneous coronary intervention or medical therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Importance: Whether the improvement in myocardial perfusion provided by percutaneous coronary intervention (PCI) is associated with symptomatic relief or improved outcomes has not been well investigated., Objective: To investigate the prognostic value of the improvement in fractional flow reserve (FFR) after PCI (ΔFFR) on patients' symptoms and 2-year outcomes., Design, Setting, and Participants: This study is a post hoc analysis of data from patients undergoing FFR-guided PCI in the randomized clinical trials Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) 1 (NCT00267774; 2009) and FAME 2 (NCT01132495; 2012), with inclusion of 2 years of follow-up data. The FAME 1 trial included patients with multivessel coronary artery disease from 20 medical centers in Europe and the United States. The FAME 2 trial included patients with stable coronary artery disease involving up to 3 vessels from 28 sites in Europe and North America. Lesions from the group in the FAME 1 trial from whom FFR was measured and the group in the FAME 2 trial who received FFR-guided PCI plus medical therapy were analyzed. Data analysis occurred from May 2017 to May 2018., Interventions: Measure of post-PCI FFR., Main Outcomes and Measures: Vessel-oriented clinical events at 2 years, a composite of cardiac death, target vessel-associated myocardial infarction, and target vessel revascularization., Results: This analysis included 639 patients from whom pre-PCI and post-PCI FFR values were available. Of their 837 lesions, 277 were classified into the lowest tertile (ΔFFR≤0.18), 282 into the middle tertile (0.19≤ΔFFR≤0.31), and 278 into the highest tertile (ΔFFR>0.31). Vessel-oriented clinical events were significantly more frequent in the lowest tertile (n = 25 of 277 [9.1%]) compared with the highest tertile (n = 13 of 278 [4.7%]; hazard ratio, 2.01 [95% CI, 1.03-3.92]; P = .04). In addition, a significant association was observed between ΔFFR and symptomatic relief (odds ratio, 1.33 [95% CI, 1.02-1.74]; P = .02)., Conclusions and Relevance: In this analysis of 2 randomized clinical trials, the larger the improvement in FFR, the larger the symptomatic relief and the lower the event rate. This suggests that measuring FFR before and after PCI provides clinically useful information.

Aims: To assess the effect of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) with contemporary drug-eluting stents on the composite of cardiac death or myocardial infarction (MI) vs. medical therapy in patients with stable coronary lesions., Methods and Results: We performed a systematic review and meta-analysis of individual patient data (IPD) of the three available randomized trials of contemporary FFR-guided PCI vs. medical therapy for patients with stable coronary lesions: FAME 2 (NCT01132495), DANAMI-3-PRIMULTI (NCT01960933), and Compare-Acute (NCT01399736). FAME 2 enrolled patients with stable coronary artery disease (CAD), while the other two focused on non-culprit lesions in stabilized patients after acute coronary syndrome. A total of 2400 subjects were recruited from 54 sites world-wide with 1056 randomly assigned to FFR-guided PCI and 1344 to medical therapy. The pre-specified primary outcome was a composite of cardiac death or MI. We included data from extended follow-ups for FAME 2 (up to 5.5 years follow-up) and DANAMI-3-PRIMULTI (up to 4.7 years follow-up). After a median follow-up of 35 months (interquartile range 12-60 months), a reduction in the composite of cardiac death or MI was observed with FFR-guided PCI as compared with medical therapy (hazard ratio 0.72, 95% confidence interval 0.54-0.96; P = 0.02). The difference between groups was driven by MI., Conclusion: In this IPD meta-analysis of the three available randomized controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or MI compared with medical therapy, which was driven by a decreased risk of MI.

Aims: The aim of this study was to explore the evolution of coronary lesions which had repeated physiologic evaluation by FFR as an endpoint, describe the clinical significance of longitudinal FFR change (ΔFFR=FFRfollow-up-FFRbaseline) and its correlation with angiographic indices, and identify predictors of FFRfollow-up., Methods and Results: A retrospective, single-centre analysis of 414 stenoses (331 patients) with consecutive FFR measurements at least six months apart was performed (median time interval: 24 [17, 37] months). The change in percent diameter stenosis was 2% (-5%, 11%). FFR values at baseline and follow-up were 0.86 (0.82, 0.90) and 0.83 (0.79, 0.90), respectively (<0.0001). The median ΔFFR was -0.007 (-0.028, 0.010) per year. Worsening FFR (ΔFFR <-0.05) was observed in 105 (25%) stenoses, stable FFR (-0.05 ≤ΔFFR ≤0.05) in 276 (67%) and improving FFR (ΔFFR >0.05) in 33 (8%) stenoses. The number of haemodynamically significant stenoses (FFR ≤0.80) was higher at follow-up compared to baseline (33% versus 17%, p<0.0001); ΔFFR correlated weakly with delta diameter stenosis (Δ%DS, ρ=-0.111, p=0.024). In mixed effects repeated measures analysis, only lesion location had an independent correlation with FFR values after adjusting for multiple confounders. In ROC analysis, FFRbaseline values predicted future clinically significant values (c-statistic: 0.736 [95% CI: 0.682-0.783])., Conclusions: FFR values decrease slowly over a two-year follow-up. FFRbaseline, but not angiographic indices, is a predictor of significant functional atherosclerosis progression, predicting which stenoses will require revascularisation.

Background: We hypothesized that fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) would be superior to medical therapy as initial treatment in patients with stable coronary artery disease., Methods: Among 1220 patients with angiographically significant stenoses, those in whom at least one stenosis was hemodynamically significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus medical therapy or to medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy and were entered into a registry. The primary end point was a composite of death, myocardial infarction, or urgent revascularization., Results: A total of 888 patients underwent randomization (447 patients in the PCI group and 441 in the medical-therapy group). At 5 years, the rate of the primary end point was lower in the PCI group than in the medical-therapy group (13.9% vs. 27.0%; hazard ratio, 0.46; 95% confidence interval [CI], 0.34 to 0.63; P<0.001). The difference was driven by urgent revascularizations, which occurred in 6.3% of the patients in the PCI group as compared with 21.1% of those in the medical-therapy group (hazard ratio, 0.27; 95% CI, 0.18 to 0.41). There were no significant differences between the PCI group and the medical-therapy group in the rates of death (5.1% and 5.2%, respectively; hazard ratio, 0.98; 95% CI, 0.55 to 1.75) or myocardial infarction (8.1% and 12.0%; hazard ratio, 0.66; 95% CI, 0.43 to 1.00). There was no significant difference in the rate of the primary end point between the PCI group and the registry cohort (13.9% and 15.7%, respectively; hazard ratio, 0.88; 95% CI, 0.55 to 1.39). Relief from angina was more pronounced after PCI than after medical therapy., Conclusions: In patients with stable coronary artery disease, an initial FFR-guided PCI strategy was associated with a significantly lower rate of the primary composite end point of death, myocardial infarction, or urgent revascularization at 5 years than medical therapy alone. Patients without hemodynamically significant stenoses had a favorable long-term outcome with medical therapy alone. (Funded by St. Jude Medical and others; FAME 2 ClinicalTrials.gov number, NCT01132495 .).

Background: Fractional flow reserve (FFR)-guided coronary artery bypass graft (CABG) surgery has been associated with lower number of graft anastomoses, lower rate of on-pump surgery, and higher graft patency rate as compared with angiography-guided CABG surgery. However, no clinical benefit has been reported to date., Methods and Results: Consecutive patients (n=627) treated by CABG between 2006 and 2010 were retrospectively included. In 198 patients, at least 1 stenosis was grafted according to FFR (FFR-guided group), whereas in 429 patients all stenoses were grafted based on angiography (angiography-guided group). The 2 coprimary end points were overall death or myocardial infarction and major adverse cardiovascular events (composite of overall death, myocardial infarction, and target vessel revascularization) up to 6-year follow-up. In the FFR-guided group, patients were significantly younger (66 [57-73] versus 70 [63-76]; P <0.001), more often male (82% versus 72%; P =0.008), and less often diabetic (21% versus 30%; P =0.023). Clinical follow-up (median, 85 [66-104] months) was analyzed in 396 patients after 1:1 propensity-score matching for these 3 variables. The rate of overall death or myocardial infarction was significantly lower in the FFR-guided (n=31 [16%] versus n=49 [25%]; hazard ratio, 0.59 [95% confidence interval, 0.38-0.93]; P =0.020) as compared with the angiography-guided group. Major adverse cardiovascular events rate was also numerically lower in the FFR-guided than in the angiography-guided group (n=42 [21%] versus n=52 [26%]; hazard ratio, 0.77 [95% confidence interval, 0.51-1.16]; P =0.21)., Conclusions: FFR-guided CABG is associated with a significant reduction in the rate of overall death or myocardial infarction at 6-year follow-up as compared with angiography-guided CABG., (© 2018 American Heart Association, Inc.)

Background: Among patients with documented stable coronary artery disease and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and fractional flow reserve (FFR) in predicting natural history., Methods: The present analysis included the 607 patients from the FAME 2 trial (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2) in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74±0.16), and DS (by quantitative coronary analysis) varied from 8% to 98% (average 53±15). The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent, and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR≤0.80; DS≥50%), negative concordance (FFR>0.80; DS<50%), positive mismatch (FFR≤0.80; DS<50%), and negative mismatch (FFR>0.80; DS≥50%)., Results: The rate of VOCE was highest in the positive concordance group (log rank: X 2 =80.96; P =0.001) and lowest in the negative concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21-0.67; P =0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR≤0.80; hazard ratio, 0.77; 95% confidence interval, 0.57-1.09; P =0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96-3.74; P =0.067)., Conclusions: In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS)., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01132495., (© 2017 American Heart Association, Inc.)

Background: Fractional flow reserve (FFR), an index of the hemodynamic severity of coronary stenoses, is derived from invasive measurements and requires a pressure-monitoring guidewire and hyperemic stimulus. Angiography-derived FFR measurements (FFR angio ) may have several advantages. The aim of this study is to assess the diagnostic performance and interobserver reproducibility of FFR angio in patients with stable coronary artery disease., Methods and Results: FFR angio is a computational method based on rapid flow analysis for the assessment of FFR. FFR angio uses the patient's hemodynamic data and routine angiograms to generate a complete 3-dimensional coronary tree with color-coded FFR values at any epicardial location. Hyperemic flow ratio is derived from an automatic resistance-based lumped model of the entire coronary tree. A total of 203 lesions were analyzed in 184 patients from 4 centers. Values derived using FFR angio ranged from 0.5 to 0.97 (median 0.85) and correlated closely (Spearman ρ=0.90; P <0.001) with the invasive FFR measurements, which ranged from 0.5 to 1 (median 0.84). In Bland-Altman analyses, the 95% limits of agreement between these methods ranged from -0.096 to 0.112. Using an FFR cutoff value of 0.80, the sensitivity, specificity, and diagnostic accuracy of FFR angio were 88%, 95%, and 93%, respectively. The intraclass coefficient between 2 blinded operators was 0.962 with a 95% confidence interval from 0.950 to 0.971, P <0.001., Conclusions: There is a high concordance between FFR angio and invasive FFR. The color-coded display of FFR values during coronary angiography facilitates the integration of physiology and anatomy for decision making on revascularization in patients with stable coronary artery disease., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03005028., (© 2017 American Heart Association, Inc.)

Background: The correlation between angiographic assessment of coronary stenoses and fractional flow reserve (FFR) is weak. Whether and how risk factors impact the diagnostic accuracy of angiography is unknown. We sought to evaluate the diagnostic accuracy of angiography by visual estimate and by quantitative coronary angiography when compared with FFR and evaluate the influence of risk factors (RF) on this accuracy., Methods and Results: In 1382 coronary stenoses (1104 patients), percent diameter stenosis by visual estimation (DS VE ) and by quantitative coronary angiography (DS QCA ) was compared with FFR. Patients were divided into 4 subgroups, according to the presence of RFs, and the relationship between DS VE , DS QCA , and FFR was analyzed. Overall, DS VE was significantly higher than DS QCA ( P <0.0001); nonetheless, when examined by strata of DS, DS VE was significantly smaller than DS QCA in mild stenoses, although the reverse held true for severe stenoses. Compared with FFR, a large scatter was observed for both DS VE and DS QCA . When using a dichotomous FFR value of 0.80, C statistic was significantly higher for DS VE than for DS QCA (0.712 versus 0.640, respectively; P <0.001). C statistics for DS VE decreased progressively as RFs accumulated (0.776 for ≤1 RF, 0.750 for 2 RFs, 0.713 for 3 RFs and 0.627 for ≥4 RFs; P =0.0053). In addition, in diabetics, the relationship between FFR and angiographic indices was particularly weak (C statistics: 0.524 for DS VE and 0.511 for DS QCA )., Conclusions: Overall, DS VE has a better diagnostic accuracy than DS QCA to predict the functional significance of coronary stenosis. The predictive accuracy of angiography is moderate in patients with ≤1 RFs, but weakens as RFs accumulate, especially in diabetics., (© 2017 American Heart Association, Inc.)