Chang-Wook Nam

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Anatomic and Functional Evaluation of Bifurcation Lesions Undergoing Percutaneous Coronary Intervention

Background—We sought to investigate the mechanism of geometric changes after main branch (MB) stent implantation and to identify the predictors of functionally significant “jailed” side branch (SB) lesions. Methods and Results—Seventy-seven patients with bifurcation lesions were prospectively enrolled from 8 centers. MB intravascular ultrasound was performed before and after MB stent implantation, and fractional flow reserve was measured in the jailed SB. The vessel volume index of both the proximal and distal MB was increased after stent implantation. The plaque volume index decreased in the proximal MB (9.1±3.0 to 8.4±2.4 mm3/mm, P=0.001), implicating plaque shift, but not in the distal MB (5.4±1.8 to 5.3±1.7 mm3/mm, P=0.227), implicating carina shifting to account for the change in vessel size (N=56). The mean SB fractional flow reserve was 0.71±0.20 (N=68) and 43% of the lesions were functionally significant. Binary logistic-regression analysis revealed that preintervention % diameter stenosis of the SB (odds ratio=1.05; 95% CI, 1.01 to 1.09) and the MB minimum lumen diameter located distal to the SB ostium (odds ratio=3.86; 95% CI, 1.03 to 14.43) were independent predictors of functionally significant SB jailing. In patients with ≥75% stenosis and Thrombolysis In Myocardial Infarction grade 3 flow in the SB, no difference in poststent angiographic and intravascular ultrasound parameters was found between SB lesions with and without functional significance. Conclusions—Both plaque shift from the MB and carina shift contribute to the creation/aggravation of an SB ostial lesion after MB stent implantation. Anatomic evaluation does not reliably predict the functional significance of a jailed SB stenosis. Clinical Trial Registration:http://www.clinicaltrials.gov. Unique Identifier: NCT00553670.

Optimal Intravascular Ultrasound Criteria and Their Accuracy for Defining the Functional Significance of Intermediate Coronary Stenoses of Different Locations

OBJECTIVES We performed this study to determine the optimal intravascular ultrasound (IVUS) criteria and to evaluate their accuracy for defining the functional significance of intermediate coronary stenoses in different locations of the coronary tree. BACKGROUND Presence of myocardial ischemia is the most important prognostic factor in patients with coronary artery disease and is determined by both the lesion severity and the amount of myocardium supplied. METHODS IVUS and fractional flow reserve (FFR) measurements were performed in 267 intermediate lesions located at the proximal or mid part of major epicardial coronary arteries. Optimal IVUS criteria and their diagnostic accuracy for functionally significant stenoses (FFR <0.8) were assessed. RESULTS FFR was <0.8 in 88 lesions (33%). The determinants of FFR were minimum lumen area (MLA) and lesion location. The diagnostic accuracy of MLA was highly variable according to the location of lesions. The best cutoff value of MLA to define the functional significance was 3.0 mm(2) (area under the curve [AUC]: 0.81, 95% confidence interval [CI]: 0.68 to 0.91) for proximal left anterior descending artery (LAD) lesions and 2.75 mm(2) for mid-LAD lesions located before the second diagonal branch (AUC: 0.76, 95% CI: 0.66 to 0.84). However, the appropriate MLA to predict the functional significance of lesions could not be found in other segments. CONCLUSIONS When IVUS parameters are used to determine the functional significance of lesions in patients with intermediate coronary artery stenoses, different criteria should be used according to lesion location. In segments or vessels with anatomic variations, IVUS cannot be used for functional assessment of a stenosis. (Comparison of Fractional Flow Reserve and Intravascular Ultrasound; NCT01133015).

Outcomes of percutaneous coronary intervention in intermediate coronary artery disease: fractional flow reserve-guided versus intravascular ultrasound-guided.

OBJECTIVES This study sought to evaluate the long-term clinical outcomes of a fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy compared with intravascular ultrasound (IVUS)-guided PCI for intermediate coronary lesions. BACKGROUND Both FFR- and IVUS-guided PCI strategies have been reported to be safe and effective in intermediate coronary lesions. METHODS The study included 167 consecutive patients, with intermediate coronary lesions evaluated by FFR or IVUS (FFR-guided, 83 lesions vs. IVUS-guided, 94 lesions). Cutoff value of FFR in FFR-guided PCI was 0.80, whereas that for minimal lumen cross sectional area in IVUS-guided PCI was 4.0 mm(2). The primary outcome was defined as a composite of major adverse cardiac events including death, myocardial infarction, and ischemia-driven target vessel revascularization at 1 year after the index procedure. RESULTS Baseline percent diameter stenosis and lesion length were similar in both groups (51 +/- 8% and 24 +/- 12 mm in the FFR group vs. 52 +/- 8% and 24 +/- 13 mm in the IVUS group, respectively). However, the IVUS-guided group underwent revascularization therapy significantly more often (91.5% vs. 33.7%, p < 0.001). No significant difference was found in major adverse cardiac event rates between the 2 groups (3.6% in FFR-guided PCI vs. 3.2% in IVUS-guided PCI). Independent predictors for performing intervention were guiding device: FFR versus IVUS (relative risk [RR]: 0.02); left anterior descending coronary artery versus non-left anterior descending coronary artery disease (RR: 5.60); and multi- versus single-vessel disease (RR: 3.28). CONCLUSIONS Both FFR- and IVUS-guided PCI strategy for intermediate coronary artery disease were associated with favorable outcomes. The FFR-guided PCI reduces the need for revascularization of many of these lesions.

Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis.

BACKGROUND The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093).

Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation.

AIMS Adoption of fractional flow reserve (FFR) remains low (6-8%), partly because of the time, cost and potential inconvenience associated with vasodilator administration. The instantaneous wave-Free Ratio (iFR) is a pressure-only index of stenosis severity calculated without vasodilator drugs. Before outcome trials test iFR as a sole guide to revascularisation, we evaluate the merits of a hybrid iFR-FFR decision-making strategy for universal physiological assessment. METHODS AND RESULTS Coronary pressure traces from 577 stenoses were analysed. iFR was calculated as the ratio between Pd and Pa in the resting diastolic wave-free window. A hybrid iFR-FFR strategy was evaluated, by allowing iFR to defer some stenoses (where negative predictive value is high) and treat others (where positive predictive value is high), with adenosine being given only to patients with iFR in between those values. For the most recent fixed FFR cut-off (0.8), an iFR of <0.86 could be used to confirm treatment (PPV of 92%), whilst an iFR value of >0.93 could be used to defer revascularisation (NPV of 91%). Limiting vasodilator drugs to cases with iFR values between 0.86 to 0.93 would obviate the need for vasodilator drugs in 57% of patients, whilst maintaining 95% agreement with an FFR-only strategy. If the 0.75-0.8 FFR grey zone is accounted for, vasodilator drug requirement would decrease by 76%. CONCLUSION A hybrid iFR-FFR decision-making strategy for revascularisation could increase adoption of physiology-guided PCI, by more than halving the need for vasodilator administration, whilst maintaining high classification agreement with an FFR-only strategy.

Clinical and Physiological Outcomes of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients With Serial Stenoses Within One Coronary Artery

OBJECTIVES This study was performed to evaluate the physiological and clinical outcomes of fractional flow reserve (FFR)-guided revascularization strategy with drug-eluting stents in serial stenoses within the same coronary artery. BACKGROUND Identifying a functionally significant stenosis is difficult when several stenoses exist within 1 coronary artery. METHODS A total of 131 patients (141 vessels and 298 lesions) with multiple intermediate stenoses within the same coronary artery were assessed by FFR with pullback pressure tracings. In vessels with an FFR <0.8, the stenosis that caused the largest pressure step-up was stented first. Major adverse cardiac events were assessed during follow-up. RESULTS FFR was measured 239 times and there were no procedure-related complications. There was a weak negative correlation between FFR and angiographic percent diameter stenosis (r = -0.282, p < 0.001). In total, 116 stents were implanted and revascularization was deferred in 61.1% (182 of 298) of lesions. When the vessels with an initial FFR <0.8 were divided into 2 groups according to FFR after first stenting (FFR ≥0.8 vs. FFR <0.8), there were no differences in baseline angiographic and physiological parameters between the 2 groups. During the mean follow-up of 501 ± 311 days, there was only 1 target vessel revascularization due to in-stent restenosis. There were no events related to deferred lesions. CONCLUSIONS FFR-guided revascularization strategy using pullback pressure tracing in serial stenoses was safe and effective. This strategy can reduce unnecessary intervention and maximize the benefit of percutaneous coronary intervention with drug-eluting stents in patients with multiple stenoses within 1 coronary artery.

Safety and efficacy of a novel hyperaemic agent, intracoronary nicorandil, for invasive physiological assessments in the cardiac catheterization laboratory.

AIMS Maximal hyperaemia is a key element of invasive physiological studies and adenosine is the most commonly used agent. However, infusion of adenosine requires additional venous access and can cause chest discomfort, bronchial hyper-reactivity, and atrioventricular conduction block. The aim of this study was to evaluate the feasibility and efficacy of intracoronary (IC) nicorandil as a novel hyperaemic agent for invasive physiological studies. METHODS AND RESULTS We enrolled 210 patients who underwent fractional flow reserve (FFR) measurement. Hyperaemic efficacy of the following methods was compared: IC bolus injection of adenosine; intravenous (i.v.) infusion of adenosine (140 μg/kg/min); and IC bolus of nicorandil (1 and 2 mg). In 70 patients, the index of microcirculatory resistance was also measured. Hyperaemic efficacy of IC nicorandil 2 mg was non-inferior to that of i.v. adenosine infusion (FFR: 0.82 ± 0.10 vs. 0.82 ± 0.10; P for non-inferiority < 0.001). There was a strong correlation between FFRs measured by i.v. adenosine and IC nicorandil (R² = 0.934). Nicorandil produced fewer changes in blood pressure, heart rate and PR interval, and less chest pain than adenosine (all P-values < 0.05). Atrioventricular block occurred in 12 patients with IC adenosine, 4 patients with i.v. adenosine and none with IC nicorandil. The index of microcirculatory resistance was 18.3 ± 8.7 with i.v. adenosine and 17.2 ± 7.6 with IC nicorandil (P = 0.126). CONCLUSION This study suggests that IC bolus injection of nicorandil is a simple, safe, and effective way to induce steady-state hyperaemia for invasive physiological evaluations. Clinicaltrials.gov number: NCT01331902.

Coronary Artery Axial Plaque Stress and its Relationship With Lesion Geometry : Application of Computational Fluid Dynamics to Coronary CT Angiography

OBJECTIVES The purpose of this study was to characterize the hemodynamic force acting on plaque and to investigate its relationship with lesion geometry. BACKGROUND Coronary plaque rupture occurs when plaque stress exceeds plaque strength. METHODS Computational fluid dynamics was applied to 114 lesions (81 patients) from coronary computed tomography angiography. The axial plaque stress (APS) was computed by extracting the axial component of hemodynamic stress acting on stenotic lesions, and the axial lesion asymmetry was assessed by the luminal radius change over length (radius gradient [RG]). Lesions were divided into upstream-dominant (upstream RG > downstream RG) and downstream-dominant lesions (upstream RG < downstream RG) according to the RG. RESULTS Thirty-three lesions (28.9%) showed net retrograde axial plaque force. Upstream APS linearly increased as lesion severity increased, whereas downstream APS exhibited a concave function for lesion severity. There was a negative correlation (r = -0.274, p = 0.003) between APS and lesion length. The pressure gradient, computed tomography-derived fractional flow reserve (FFRCT), and wall shear stress were consistently higher in upstream segments, regardless of the lesion asymmetry. However, APS was higher in the upstream segment of upstream-dominant lesions (11,371.96 ± 5,575.14 dyne/cm(2) vs. 6,878.14 ± 4,319.51 dyne/cm(2), p < 0.001), and in the downstream segment of downstream-dominant lesions (7,681.12 ± 4,556.99 dyne/cm(2) vs. 11,990.55 ± 5,556.64 dyne/cm(2), p < 0.001). Although there were no differences in FFRCT, % diameter stenosis, and wall shear stress pattern, the distribution of APS was different between upstream- and downstream-dominant lesions. CONCLUSIONS APS uniquely characterizes the stenotic segment and has a strong relationship with lesion geometry. Clinical application of these hemodynamic and geometric indices may be helpful to assess the future risk of plaque rupture and to determine treatment strategy for patients with coronary artery disease. (Evaluation of FFR, WSS, and TPF Using CCTA; NCT01857687).