Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry

Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow... Abstract Aims The optimal fractional flow reserve (FFR) cut-off value for revascularization is debated. We evaluated the prognosis for deferred and performed revascularization in coronary stenosis with FFR values in the grey zone (0.75–0.80). Methods and results This study included 1334 native coronary stenosis with grey-zone FFR values in 1334 patients from the prospective multicentre Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve registry. Revascularization was deferred for 683 patients (deferred group) and performed for 651 (performed group). The primary outcome, a composite of death, target-vessel myocardial infarction (MI), and target vessel revascularization (TVR) occurred in 55 (8.1%) patients in the deferred group and 55 (8.4%) in the performed group [adjusted hazard ratio (aHR) 1.05, 95% confidence interval (CI) 0.67–1.66; P = 0.79] during a median follow-up of 2.9 years (interquartile range 1.5–4.1 years). Overall mortality and spontaneous MI did not differ between the groups (mortality 2.5% vs. 2.0%; aHR 0.82, 95% CI 0.34–2.00; P = 0.66; spontaneous MI 0.7% vs. 0.5%; aHR 1.85, 95% CI 0.35–9.75; P = 0.47). Myocardial infarction was significantly higher in the performed group (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. Target vessel revascularization was significantly higher in the deferred group (5.7% vs. 3.7%; aHR 2.17, 95% CI 1.17–4.02; P = 0.01). Conclusion For coronary stenosis with grey-zone FFR, revascularization was not associated with better clinical outcomes. The higher likelihood of periprocedural MI with revascularization was offset by the higher likelihood of TVR with deferral. Trial registration Clinicaltrials.gov identifier: NCT01366404. Fractional flow reserve, Coronary artery disease, Grey zone Introduction Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) has shown better clinical outcomes than conventional angiography-guided PCI.1–8 The optimal FFR cut-off value for revascularization is debated. With FFR ≤0.80, revascularization for coronary stenosis is associated with improved clinical outcomes, whereas with FFR ≥0.75, medical treatment has been shown to result in favourable long-term outcomes.2,3 However, there has been controversy over revascularization decision-making for coronary stenosis with FFR between 0.75 and 0.80, the so-called grey zone. Several studies have reported the outcomes of revascularization vs. deferral for coronary stenosis with grey-zone FFR values, with conflicting results.9–15 However, these studies were hampered by limited numbers of patients and short follow-up periods. Clinically relevant information regarding the appropriate management for this uncertain subset requires a large multicentre cohort study with long-term follow-up. In this study, we compared long-term outcomes of deferral vs. revascularization for 1334 coronary stenosis with grey-zone FFR values included in a multicentre, prospective registry. Methods The Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve (IRIS-FFR) registry is a prospective, multicentre registry designed for investigating the prognosis of coronary stenosis assessed using FFR in routine clinical practice. The inclusion and exclusion criteria of the registry have been previously described.16 In brief, the registry consecutively enrolled all patients who underwent FFR measurement for at least one coronary lesion. The main exclusion criteria were thrombolysis in myocardial infarction (MI) flow < three, bypass graft, overt heart failure, technical unsuitability for FFR evaluation, and short life expectancy (<2 years). For this substudy, we enrolled patients with a de novo native coronary artery stenosis with an FFR value in the grey zone (0.75–0.80). To eliminate the clustering effects of lesions within the same patient, we selected one lesion per patient, preferentially choosing those with lower FFR values, or left anterior descending arterial lesions when the FFR values were equal for two or more lesions. The study protocol was approved by the institutional review board or ethics committee of each participating centre, and all patients provided written informed consent. Fractional flow reserve measurement and revascularization Fractional flow reserve was measured after coronary angiography with a commercially available coronary pressure (Pd) wire, as previously described.16 After the administration of intracoronary nitroglycerin (100 or 200 µg), the pressure wire was positioned in the distal segment of the target vessel. It was recommended that hyperaemia should be induced by intravenous adenosine infusion (140 or 200 µg/kg/min) via a central or large antecubital vein. The proximal aortic pressure (Pa) and distal Pd were measured during sustained hyperaemia, and FFR was calculated as the mean value of Pd/Pa. For FFR values between 0.75 and 0.80, the decision regarding revascularization was at the operator’s discretion. All the revascularization procedures for PCI or bypass surgery were performed using standard techniques.7,8 Second-generation drug-eluting stents were routinely used. Routine follow-up angiography after the index procedure was highly discouraged. Quantitative coronary angiography and intravascular ultrasound Quantitative coronary angiography was performed using standard techniques and automated edge-detection algorithms (CAAS-5, Pie Medical, Maastricht, Netherlands). Diameter stenosis, minimal lumen diameter, lesion length, and reference lumen diameter were measured.17 The decision to conduct an intravascular ultrasound (IVUS) measurement was at the discretion of the operator. Intravascular ultrasound images obtained at the index procedure was analysed in accordance with standard methods.18 Minimal lumen area (MLA) and external elastic membrane (EEM) area at the MLA site were measured. The plaque burden was calculated as (plaque + media area)/EEM area × 100 (%).Quantitative coronary angiography analysis and IVUS analysis were conducted at the Core Laboratory of the CardioVascular Research Foundation (Seoul, Korea). Outcomes and definitions The primary outcome was a major adverse cardiac event [MACE, a composite of death from any cause, target vessel MI and target vessel revascularization (TVR)]. Target vessel MI was defined as follows: (i) within the first 48 h of the index revascularization procedure, ischaemic symptoms and signs, with the creatinine kinase MB (CK-MB) fraction concentration elevated to more than five times the upper normal limit; or (ii) ≥48 h after the procedure, any elevation of CK-MB level above the upper normal limit related to the FFR-measured vessels, accompanied by ischaemic symptoms.19 In the post hoc analysis, periprocedural MI was defined as an elevation of the CK-MB fraction to more than 10 times the upper normal limit. Target vessel revascularization was defined as any PCI or bypass surgery of the index vessel with FFR measurement. All outcomes of interest were confirmed by source documentation collected at each hospital, and were centrally adjudicated by an independent clinical events committee. Data and follow-up The data were collected using a web-based dedicated case report form. Members of the academic co-ordinating centre (Clinical Research Center, Asan Medical Center, Seoul, South Korea) monitored and verified the data in the participating hospitals. Clinical 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 visit. Statistical analysis Baseline characteristics are presented as a number (%) for categorical variables and mean ± standard deviation for continuous variables. Differences between groups were analysed using the Student’s t-test or the Mann–Whitney U-test for continuous variables and the χ2 test or the Fisher’s exact test for categorical variables, as appropriate. Survival curves were constructed using Kaplan–Meier estimates and compared with the log-rank test. Multivariable Cox proportional hazard regression models were used to adjust for the differences in the baseline characteristics between the groups.20 Additional adjustments were made with propensity score matching and weighted Cox proportional hazards regression models with inverse probability of treatment weighting (IPTW). The propensity score was computed by a logistic regression model, and the matching was performed using the nearest neighbour method, with a calliper width of 0.2 standard deviation.21–23 In the matched cohorts, survival curves were constructed using Kaplan–Meier estimates and compared using a Cox proportional hazard regression model. The statistical analyses were performed using SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) and R version 3.2.3 (R Foundation for Statistical Computing, Vienna, Austria). P-values <0.05 were considered statistically significant. Results Between August 2009 and October 2016, 10 881 lesions from 7735 patients were prospectively enrolled in the IRIS-FFR registry, of which 1388 de novo native coronary lesions in 1334 patients were with an FFR value in the grey zone (0.75–0.80). Among these, 1334 lesions were selected (one per patient) for the patient-level analysis (Figure 1). After FFR assessment, revascularization was deferred for 683 lesions (deferred group) and performed in 651 lesions (performed group). Figure 1 View largeDownload slide Study flowchart. aOne lesion per patient was selected, preferentially choosing lesions with a lower fractional flow reserve value and those in the left anterior descending artery. IVUS, intravascular ultrasound; QCA, quantitative coronary angiography. Figure 1 View largeDownload slide Study flowchart. aOne lesion per patient was selected, preferentially choosing lesions with a lower fractional flow reserve value and those in the left anterior descending artery. IVUS, intravascular ultrasound; QCA, quantitative coronary angiography. The mean age of the patients was 64 years; 76% were men, 78% had stable angina, 32% were diabetic, and 59% had multi-vessel coronary artery disease. The deferred group patients were more likely to be men, and have a history of previous PCI and were associated with higher FFR values, less multi-vessel disease, less frequent left main or proximal diseases, and less complex coronary artery disease (Table 1 and Supplementary material online, Table S1). Table 1 Patient and lesion characteristics in the overall and matched populations   Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18    Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18  ACC/AHA, American College of Cardiology/American Heart Association. Table 1 Patient and lesion characteristics in the overall and matched populations   Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18    Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18  ACC/AHA, American College of Cardiology/American Heart Association. Quantitative coronary angiography showed larger minimal lumen diameters and smaller diameter stenosis in the deferred group, whereas IVUS showed that the deferred group patients had fewer plaque ruptures, larger MLA, and smaller plaque burden than the performed group patients (Table 2). Table 2 Lesion characteristics at the index procedure by imaging analysis Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  MLA, minimal lumen area. Table 2 Lesion characteristics at the index procedure by imaging analysis Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  MLA, minimal lumen area. Outcomes for the overall population During a median follow-up of 2.9 (interquartile range 1.5–4.1) years, MACE occurred in 55 (8.1%) patients in the deferred group and 55 (8.4%) in the performed group [adjusted hazard ratio (aHR) 1.05, 95% confidence interval (CI) 0.67–1.66; P = 0.79]. 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) (Table 3). Indications for target lesion revascularization are summarized in Supplementary material online, Table S2. Figure 2 shows the Kaplan–Meier curves for the outcomes in the two groups. Independent predictors of MACE in the deferred and performed groups are shown in Supplementary material online, Tables S3 and S4. Table 3 Clinical outcomes in the deferred and performed groups   Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031    Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031  CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; IPTW, inverse probability-of-treatment weighting; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable; TVR, target vessel revascularization. a Major adverse cardiac events comprised death, target vessel myocardial infarction, and target vessel revascularization. b Adjusted by age, gender, clinical presentation, hypertension, diabetes, current smoking, hyperlipidaemia, history of percutaneous coronary intervention, chronic renal failure, lesion territory, lesion location, FFR value, diameter stenosis, lesion complexity, lesion length, and number of diseased vessels. Table 3 Clinical outcomes in the deferred and performed groups   Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031    Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031  CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; IPTW, inverse probability-of-treatment weighting; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable; TVR, target vessel revascularization. a Major adverse cardiac events comprised death, target vessel myocardial infarction, and target vessel revascularization. b Adjusted by age, gender, clinical presentation, hypertension, diabetes, current smoking, hyperlipidaemia, history of percutaneous coronary intervention, chronic renal failure, lesion territory, lesion location, FFR value, diameter stenosis, lesion complexity, lesion length, and number of diseased vessels. Figure 2 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the overall population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Figure 2 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the overall population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Outcomes for the propensity score-matched groups Propensity score matching to adjust for the differences in the baseline characteristics created 368 matched pairs of patients. The two groups were well balanced with no significant differences in baseline characteristics, except for the more frequent post-procedural use of antiplatelet agents and statin in the performed group (Table 1). The clinical outcomes showed a similar trend to those for the overall population. The risk of MACE, death, cardiac death, and spontaneous MI did not differ between the groups (Table 3, Figure 3). The results after adjustment by IPTW were consistent (Table 3). The clinical outcomes of the patients not included in the propensity score matching showed a similar trend (see Supplementary material online, Tables S5 and S6). Figure 3 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the matched population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Figure 3 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the matched population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Subgroup analyses In the subgroup analyses, the only difference in the effect on MACE between deferred and performed revascularization was with respect to MLA on IVUS (≤2.5 mm2 and >2.5 mm2), in which a trend towards a treatment by subgroup interaction was observed (P = 0.045 for the interaction; Figure 4). Even when a stricter definition of periprocedural MI was applied, the overall findings remained consistent (see Supplementary material online, Table S7). Figure 4 View largeDownload slide Subgroup analysis for major adverse cardiac events in the overall population. IVUS, intravascular ultrasound; LAD, left anterior descending artery. Figure 4 View largeDownload slide Subgroup analysis for major adverse cardiac events in the overall population. IVUS, intravascular ultrasound; LAD, left anterior descending artery. Discussion Data from this large, prospective, multicentre registry showed that the risk of a composite of death, target vessel MI and TVR for patients with grey-zone FFR values did not significantly differ between the patients whose revascularization was deferred and those for whom it was performed. The incidence of death and spontaneous MI did not differ between the groups. Although the risk of TVR tended to be higher for the deferred group, this was offset by a higher risk of periprocedural MI for the performed group. This trend remained consistent even after adjustment by propensity score matching and IPTW. This suggests that the medical treatment of lesions with grey-zone FFR values would be a reasonable and safe strategy. Revascularization may be considered in patients with medically refractory angina. Initially, the FFR cut-off value for revascularization was 0.75, with FFR values <0.75 having >99% positive predictive value for inducible myocardial ischaemia. Subsequent studies have reported that in a minority of patients, FFR between 0.75 and 0.80 was associated with flow-limiting stenosis.24,25 Currently, FFR of 0.80 is used in revascularization threshold to avoid a few significant stenosis being left untreated.1,2 Nevertheless, FFR values between 0.75 and 0.80 are still considered as being in the grey zone in revascularization decision-making.9–15 Therefore, for the treatment of those lesions, careful clinical judgement considering typicality of complaints, other test results, and the lesion characteristics was suggested.26 Revascularization for stenosis with grey-zone FFR values has been investigated in only three small retrospective observational studies (see Supplementary material online, Table S8). Courtis et al.9 reported that coronary revascularization was associated with a lower rate of MACE, mainly because of the reduction in target lesion revascularization. Conversely, Lindstaedt et al.10 showed that deferral of revascularization was associated with lower rates of MACE and the composite of cardiac death and MI. Recently, Adjedj et al.11 demonstrated that revascularization of stenosis with grey-zone FFR values tended to have a lower risk of overall mortality, and Agarwal et al.12 reported that revascularization was associated with lower rates of MACE and spontaneous MI. The IRIS-FFR registry includes the largest current cohort of prospectively enrolled coronary stenosis patients treated using contemporary medicine and interventional technology, with clinical events adjudicated by an independent committee. Furthermore, we controlled for selection bias between the groups in the present study using various statistical adjustments. This study could therefore provide valuable insights for daily catheterization laboratory practice. The results suggested that deferred revascularization could be the preferred initial treatment strategy for stenosis with grey-zone FFR values. In the deferred group, the annual death and target vessel MI rate was less than 1%. The annual incidence of TVR was less than 2%, which must be lower than that of contemporary PCI-related complications.27,28 Late TVR after index procedure was more frequent in the deferred group. However, it is noteworthy that in performed group, all patients already received PCI and 3.7% experienced late TVR. Therefore, more patients actually received stent implantation in performed group than deferred group between index procedure and follow-up. Although we exclusively used second-generation drug-eluting stents, the risk of periprocedural MI and repeated TVR was not negligible in the performed group, and performing revascularization was not observed to be superior to medical treatment for stenosis with grey-zone FFR values. These overall findings remained consistent even when we applied a stricter definition of periprocedural MI in a supplementary analysis. A recent meta-analysis showed that the outcome-derived FFR threshold for revascularization was located within the grey zone29 that was consistent with our findings. The morphological characteristics of the stenosis and the patient’s clinical context can affect clinical outcomes in coronary artery disease.15,30,31 Thus, for stenosis with grey-zone FFR values, some operators favour revascularization for high-risk patients and lesion characteristics, such as patients with diabetes or acute coronary syndrome. However, our subgroup analysis showed no differences in effect between deferred and performed revascularization on the risk of MACE across the subgroups including acute coronary syndrome. This would be due to that unfavourable clinical and lesion characteristics affected outcomes of both revascularized and deferred lesions. Interestingly, MLA showed a marginally significant interaction. However, these results had insufficient statistical power and should be interpreted with caution. A further large study is needed to test whether MLA measured using IVUS could guide revascularization decisions for stenosis with grey-zone FFR values. Limitation This study has several limitations. First, there was the inherent limitation of this being an observational study. Second, the clinical and lesion characteristics differed between the groups. These differences were adjusted through propensity score matching; nevertheless, some differences remained, particularly with regard to the use of post-procedural medications. Third, we selected one lesion per patient to eliminate clustering effects. Additional analysis with the all 1388 lesions showed similar trends (Supplementary Tables S9 and S10). Finally, the power of this study could be limited to detect small differences. Our findings warrant substantiation in larger studies with greater power. Although underpowered, this study is the largest cohort of prospectively enrolled patients with the longest follow-up duration that could give clinically relevant information for the debating issue. Conclusion In conclusion, this study based on a large, prospective, and multicentre registry demonstrated that revascularization was not associated with better clinical outcomes for coronary stenosis with grey-zone FFR values. A high risk of periprocedural MI in patients who underwent revascularization was offset by the high risk of TVR in the deferred group. Supplementary material Supplementary material is available at European Heart Journal online. Funding This work was supported by the CardioVascular Research Foundation, Ministry of Trade, Industry & Energy (MOTIE), and Korea Institute for Advancement of Technology (KIAT) through the Encouragement Program for The Industries of Economic Cooperation Region. Conflict of interest: none declared. References 1 Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van't Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med  2009; 360: 213– 224. Google Scholar CrossRef Search ADS PubMed  2 De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nüesch E, Jüni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med  2014; 371: 1208– 1217. Google Scholar CrossRef Search ADS PubMed  3 Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, Erbel R, Legrand V, Gwon HC, Remkes WS, Stella PR, van Schaardenburgh P, Bech GJ, De Bruyne B, Pijls NH. 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. Google Scholar CrossRef Search ADS PubMed  4 Park SJ, Ahn JM, Park GM, Cho YR, Lee JY, Kim WJ, Han S, Kang SJ, Park DW, Lee SW, Kim YH, Lee CW, Mintz GS, Park SW. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J  2013; 34: 3353– 3361. Google Scholar CrossRef Search ADS PubMed  5 Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, Champagne S, Belle L, Barreau D, Hanssen M, Besnard C, Dauphin R, Dallongeville J, El Hahi Y, Sideris G, Bretelle C, Lhoest N, Barnay P, Leborgne L, Dupouy P; Investigators of the Registre Francais de la FFR-R3F. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation  2014; 129: 173– 185. Google Scholar CrossRef Search ADS PubMed  6 Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J Koolen JJ, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med  1996; 334: 1703– 1708. Google Scholar CrossRef Search ADS PubMed  7 Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH; American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines, Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol  2011; 58:2550–2122. 8 Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J  2014; 35: 2541– 2619. Google Scholar CrossRef Search ADS PubMed  9 Courtis J, Rodés-Cabau J, Larose E, Déry J-P, Nguyen CM, Proulx G, Gleeton O, Roy L, Barbeau G, Noël B, DeLarochellière R, Bertrand OF. 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. Google Scholar CrossRef Search ADS PubMed  10 Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mügge A, Germing A. 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. Google Scholar CrossRef Search ADS PubMed  11 Adjedj J, De Bruyne B, Flore V, Di Gioia G, Ferrara A, Pellicano M, Toth GG, Bartunek J, Vanderheyden M, Heyndrickx GR, Wijns W, Barbato E. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation  2016; 133: 502– 508. Google Scholar CrossRef Search ADS PubMed  12 Agarwal SK, Kasula S, Edupuganti MM, Raina S, Shailesh F, Almomani A, Payne JJ, Pothineni NV, Uretsky BF, Hakeem A. Clinical decision-making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol  2017; 29: 371– 376. Google Scholar PubMed  13 Yamashita J, Tanaka N, Shindo N, Ogawa M, Kimura Y, Sakoda K, Murata N, Hokama Y, Hoshino K, Ikeda S, Yamashina A. 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. Google Scholar CrossRef Search ADS PubMed  14 Shiono Y, Kubo T, Tanaka A, Ino Y, Yamaguchi T, Tanimoto T, Yamano T, Matsuo Y, Nishiguchi T, Teraguchi I, Ota S, Ozaki Y, Orii M, Shimamura K, Kitabata H, Hirata K, Imanishi T, Akasaka T. 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. Google Scholar CrossRef Search ADS PubMed  15 Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, Davies JE. 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. Google Scholar CrossRef Search ADS PubMed  16 Ahn JM, Park DW, Shin ES, Koo BK, Nam CW, Doh JH, Kim JH, Chae IH, Yoon JH, Her SH, Seung KB, Chung WY, Yoo SY, Lee JB, Choi SW, Park K, Hong TJ, Lee SY, Han M, Lee PH, Kang SJ, Lee SW, Kim YH, Lee CW, Park SW, Park SJ, Investigators IF. Fractional flow reserve and cardiac events in coronary artery disease: data from a prospective registry. Circulation  2017; 135: 2241– 2251. Google Scholar CrossRef Search ADS PubMed  17 Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures. J Am Coll Cardiol  1988; 12: 529– 545. Google Scholar CrossRef Search ADS PubMed  18 Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG, O’Rourke RA, Abrams J, Bates ER, Brodie BR, Douglas PS, Gregoratos G, Hlatky MA, Hochman JS, Kaul S, Tracy CM, Waters DD, Winters WL. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). J Am Coll Cardiol  2001; 37: 1478– 1492. Google Scholar CrossRef Search ADS PubMed  19 Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasché P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; ESC Committee for Practice Guidelines. Third universal definition of myocardial infarction. Eur Heart J  2012; 33: 2551– 2567. Google Scholar CrossRef Search ADS PubMed  20 Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol  1995; 48: 1503– 1510. Google Scholar CrossRef Search ADS PubMed  21 Ho D, Imai K, King G, Stuart E. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw  2011; 42: 1– 28. Google Scholar CrossRef Search ADS   22 Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat  2011; 10: 150– 161. Google Scholar CrossRef Search ADS PubMed  23 Hansen B, Bowers J. Covariate balance in simple, stratified and clustered comparative studies. Stat Sci  2008; 23: 219– 236. Google Scholar CrossRef Search ADS   24 De Bruyne B, Pijls NH, Bartunek J, Kulecki K, Bech JW, De Winter H, Van Crombrugge P, Heyndrickx GR, Wijns W. Fractional flow reserve in patients with prior myocardial infarction. Circulation  2001; 104: 157– 162. Google Scholar CrossRef Search ADS PubMed  25 Samady H, Lepper W, Powers ER, Wei K, Ragosta M, Bishop GG, Sarembock IJ, Gimple L, Watson DD, Beller GA, Barringhaus KG. Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction. J Am Coll Cardiol  2006; 47: 2187– 2193. Google Scholar CrossRef Search ADS PubMed  26 Pijls NH, Tanaka N, Fearon WF. Functional assessment of coronary stenoses: can we live without it? Eur Heart J  2013; 34: 1335– 1344. Google Scholar CrossRef Search ADS PubMed  27 Bønaa KH, Mannsverk J, Wiseth R, Aaberge L, Myreng Y, Nygård O, Nilsen DW, Kløw NE, Uchto M, Trovik T, Bendz B, Stavnes S, Bjørnerheim R, Larsen AI, Slette M, Steigen T, Jakobsen OJ, Bleie Ø, Fossum E, Hanssen TA, Dahl-Eriksen Ø, Njølstad I, Rasmussen K, Wilsgaard T, Nordrehaug JE; NORSTENT Investigators. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med  2016; 375: 1242– 1252. Google Scholar CrossRef Search ADS PubMed  28 Kedhi E, Joesoef KS, McFadden E, Wassing J, van Mieghem C, Goedhart D, Smits PC. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet  2010; 375: 201– 209. Google Scholar CrossRef Search ADS PubMed  29 Johnson NP, Toth GG, Lai D, Zhu H, Acar G, Agostoni P, Appelman Y, Arslan F, Barbato E, Chen SL, Di Serafino L, Dominguez-Franco AJ, Dupouy P, Esen AM, Esen OB, Hamilos M, Iwasaki K, Jensen LO, Jimenez-Navarro MF, Katritsis DG, Kocaman SA, Koo BK, Lopez-Palop R, Lorin JD, Miller LH, Muller O, Nam CW, Oud N, Puymirat E, Rieber J, Rioufol G, Rodes-Cabau J, Sedlis SP, Takeishi Y, Tonino PA, Van Belle E, Verna E, Werner GS, Fearon WF, Pijls NH, De Bruyne B, Gould KL. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. J Am Coll Cardiol  2014; 64: 1641– 1654. Google Scholar CrossRef Search ADS PubMed  30 Depta JP, Patel JS, Novak E, Gage BF, Masrani SK, Raymer D, Facey G, Patel Y, Zajarias A, Lasala JM, Amin AP, Kurz HI, Singh J, Bach RG. Risk model for estimating the 1-year risk of deferred lesion intervention following deferred revascularization after fractional flow reserve assessment. Eur Heart J  2015; 36: 509– 515. Google Scholar CrossRef Search ADS PubMed  31 Doh JH, Nam CW, Koo BK, Park SH, Lee JH, Han JK, Yang HM, Lim HS, Yoon MH, Cho YK, Hur SH, Lee SY, Kim HS, Tahk SJ. Long-term patient-related and lesion-related outcomes after real-world fractional flow reserve use. J Invasive Cardiol  2015; 27: 410– 415. Google Scholar PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims The optimal fractional flow reserve (FFR) cut-off value for revascularization is debated. We evaluated the prognosis for deferred and performed revascularization in coronary stenosis with FFR values in the grey zone (0.75–0.80). Methods and results This study included 1334 native coronary stenosis with grey-zone FFR values in 1334 patients from the prospective multicentre Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve registry. Revascularization was deferred for 683 patients (deferred group) and performed for 651 (performed group). The primary outcome, a composite of death, target-vessel myocardial infarction (MI), and target vessel revascularization (TVR) occurred in 55 (8.1%) patients in the deferred group and 55 (8.4%) in the performed group [adjusted hazard ratio (aHR) 1.05, 95% confidence interval (CI) 0.67–1.66; P = 0.79] during a median follow-up of 2.9 years (interquartile range 1.5–4.1 years). Overall mortality and spontaneous MI did not differ between the groups (mortality 2.5% vs. 2.0%; aHR 0.82, 95% CI 0.34–2.00; P = 0.66; spontaneous MI 0.7% vs. 0.5%; aHR 1.85, 95% CI 0.35–9.75; P = 0.47). Myocardial infarction was significantly higher in the performed group (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. Target vessel revascularization was significantly higher in the deferred group (5.7% vs. 3.7%; aHR 2.17, 95% CI 1.17–4.02; P = 0.01). Conclusion For coronary stenosis with grey-zone FFR, revascularization was not associated with better clinical outcomes. The higher likelihood of periprocedural MI with revascularization was offset by the higher likelihood of TVR with deferral. Trial registration Clinicaltrials.gov identifier: NCT01366404. Fractional flow reserve, Coronary artery disease, Grey zone Introduction Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) has shown better clinical outcomes than conventional angiography-guided PCI.1–8 The optimal FFR cut-off value for revascularization is debated. With FFR ≤0.80, revascularization for coronary stenosis is associated with improved clinical outcomes, whereas with FFR ≥0.75, medical treatment has been shown to result in favourable long-term outcomes.2,3 However, there has been controversy over revascularization decision-making for coronary stenosis with FFR between 0.75 and 0.80, the so-called grey zone. Several studies have reported the outcomes of revascularization vs. deferral for coronary stenosis with grey-zone FFR values, with conflicting results.9–15 However, these studies were hampered by limited numbers of patients and short follow-up periods. Clinically relevant information regarding the appropriate management for this uncertain subset requires a large multicentre cohort study with long-term follow-up. In this study, we compared long-term outcomes of deferral vs. revascularization for 1334 coronary stenosis with grey-zone FFR values included in a multicentre, prospective registry. Methods The Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve (IRIS-FFR) registry is a prospective, multicentre registry designed for investigating the prognosis of coronary stenosis assessed using FFR in routine clinical practice. The inclusion and exclusion criteria of the registry have been previously described.16 In brief, the registry consecutively enrolled all patients who underwent FFR measurement for at least one coronary lesion. The main exclusion criteria were thrombolysis in myocardial infarction (MI) flow < three, bypass graft, overt heart failure, technical unsuitability for FFR evaluation, and short life expectancy (<2 years). For this substudy, we enrolled patients with a de novo native coronary artery stenosis with an FFR value in the grey zone (0.75–0.80). To eliminate the clustering effects of lesions within the same patient, we selected one lesion per patient, preferentially choosing those with lower FFR values, or left anterior descending arterial lesions when the FFR values were equal for two or more lesions. The study protocol was approved by the institutional review board or ethics committee of each participating centre, and all patients provided written informed consent. Fractional flow reserve measurement and revascularization Fractional flow reserve was measured after coronary angiography with a commercially available coronary pressure (Pd) wire, as previously described.16 After the administration of intracoronary nitroglycerin (100 or 200 µg), the pressure wire was positioned in the distal segment of the target vessel. It was recommended that hyperaemia should be induced by intravenous adenosine infusion (140 or 200 µg/kg/min) via a central or large antecubital vein. The proximal aortic pressure (Pa) and distal Pd were measured during sustained hyperaemia, and FFR was calculated as the mean value of Pd/Pa. For FFR values between 0.75 and 0.80, the decision regarding revascularization was at the operator’s discretion. All the revascularization procedures for PCI or bypass surgery were performed using standard techniques.7,8 Second-generation drug-eluting stents were routinely used. Routine follow-up angiography after the index procedure was highly discouraged. Quantitative coronary angiography and intravascular ultrasound Quantitative coronary angiography was performed using standard techniques and automated edge-detection algorithms (CAAS-5, Pie Medical, Maastricht, Netherlands). Diameter stenosis, minimal lumen diameter, lesion length, and reference lumen diameter were measured.17 The decision to conduct an intravascular ultrasound (IVUS) measurement was at the discretion of the operator. Intravascular ultrasound images obtained at the index procedure was analysed in accordance with standard methods.18 Minimal lumen area (MLA) and external elastic membrane (EEM) area at the MLA site were measured. The plaque burden was calculated as (plaque + media area)/EEM area × 100 (%).Quantitative coronary angiography analysis and IVUS analysis were conducted at the Core Laboratory of the CardioVascular Research Foundation (Seoul, Korea). Outcomes and definitions The primary outcome was a major adverse cardiac event [MACE, a composite of death from any cause, target vessel MI and target vessel revascularization (TVR)]. Target vessel MI was defined as follows: (i) within the first 48 h of the index revascularization procedure, ischaemic symptoms and signs, with the creatinine kinase MB (CK-MB) fraction concentration elevated to more than five times the upper normal limit; or (ii) ≥48 h after the procedure, any elevation of CK-MB level above the upper normal limit related to the FFR-measured vessels, accompanied by ischaemic symptoms.19 In the post hoc analysis, periprocedural MI was defined as an elevation of the CK-MB fraction to more than 10 times the upper normal limit. Target vessel revascularization was defined as any PCI or bypass surgery of the index vessel with FFR measurement. All outcomes of interest were confirmed by source documentation collected at each hospital, and were centrally adjudicated by an independent clinical events committee. Data and follow-up The data were collected using a web-based dedicated case report form. Members of the academic co-ordinating centre (Clinical Research Center, Asan Medical Center, Seoul, South Korea) monitored and verified the data in the participating hospitals. Clinical 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 visit. Statistical analysis Baseline characteristics are presented as a number (%) for categorical variables and mean ± standard deviation for continuous variables. Differences between groups were analysed using the Student’s t-test or the Mann–Whitney U-test for continuous variables and the χ2 test or the Fisher’s exact test for categorical variables, as appropriate. Survival curves were constructed using Kaplan–Meier estimates and compared with the log-rank test. Multivariable Cox proportional hazard regression models were used to adjust for the differences in the baseline characteristics between the groups.20 Additional adjustments were made with propensity score matching and weighted Cox proportional hazards regression models with inverse probability of treatment weighting (IPTW). The propensity score was computed by a logistic regression model, and the matching was performed using the nearest neighbour method, with a calliper width of 0.2 standard deviation.21–23 In the matched cohorts, survival curves were constructed using Kaplan–Meier estimates and compared using a Cox proportional hazard regression model. The statistical analyses were performed using SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) and R version 3.2.3 (R Foundation for Statistical Computing, Vienna, Austria). P-values <0.05 were considered statistically significant. Results Between August 2009 and October 2016, 10 881 lesions from 7735 patients were prospectively enrolled in the IRIS-FFR registry, of which 1388 de novo native coronary lesions in 1334 patients were with an FFR value in the grey zone (0.75–0.80). Among these, 1334 lesions were selected (one per patient) for the patient-level analysis (Figure 1). After FFR assessment, revascularization was deferred for 683 lesions (deferred group) and performed in 651 lesions (performed group). Figure 1 View largeDownload slide Study flowchart. aOne lesion per patient was selected, preferentially choosing lesions with a lower fractional flow reserve value and those in the left anterior descending artery. IVUS, intravascular ultrasound; QCA, quantitative coronary angiography. Figure 1 View largeDownload slide Study flowchart. aOne lesion per patient was selected, preferentially choosing lesions with a lower fractional flow reserve value and those in the left anterior descending artery. IVUS, intravascular ultrasound; QCA, quantitative coronary angiography. The mean age of the patients was 64 years; 76% were men, 78% had stable angina, 32% were diabetic, and 59% had multi-vessel coronary artery disease. The deferred group patients were more likely to be men, and have a history of previous PCI and were associated with higher FFR values, less multi-vessel disease, less frequent left main or proximal diseases, and less complex coronary artery disease (Table 1 and Supplementary material online, Table S1). Table 1 Patient and lesion characteristics in the overall and matched populations   Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18    Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18  ACC/AHA, American College of Cardiology/American Heart Association. Table 1 Patient and lesion characteristics in the overall and matched populations   Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18    Overall population   Matched population   Deferred group (n = 683)  Performed group (n = 651)  P-value  Deferred group (n = 368)  Performed group (n = 368)  P-value  Age (years), mean ± SD  64.2 ± 9.8  63.8 ± 9.9  0.52  64.5 ± 9.9  64.2 ± 9.9  0.73  Male gender, n (%)  535 (78.3)  478 (73.4)  0.042  285 (77.4)  275 (74.7)  0.44  Body mass index (kg/m2), mean ± SD  24.9 ± 3.1  25.1 ± 3.0  0.18  24.9 ± 3.2  24.9 ± 2.8  0.95  Acute coronary syndrome presentation, n (%)  125 (18.3)  163 (25.0)  0.003  71 (19.3)  73 (19.8)  0.85  Hypertension, n (%)  441 (64.6)  418 (64.2)  0.94  232 (63.0)  234 (63.6)  0.94  Diabetes, n (%)  220 (32.2)  203 (31.2)  0.73  112 (30.4)  119 (32.3)  0.63  Current smoking, n (%)  164 (24.0)  130 (20.0)  0.09  97 (26.4)  81 (22.0)  0.20  Hyperlipidaemia, n (%)  388 (56.8)  363 (55.8)  0.74  205 (55.7)  207 (56.2)  0.94  Previous percutaneous coronary intervention, n (%)  153 (22.4)  102 (15.7)  0.002  80 (21.7)  68 (18.5)  0.31  Previous stroke, n (%)  57 (8.3)  43 (6.6)  0.27  30 (8.2)  29 (7.9)  1.00  Chronic renal failure, n (%)  19 (2.8)  15 (2.3)  0.70  13 (3.5)  8 (2.2)  0.38  Left ventricular ejection fraction (%), mean ± SD  60.5 ± 11.4  60.8 ± 11.0  0.67  61.7 ± 6.9  61.5 ± 7.8  0.82  Discharge medication, n (%)               Aspirin  573 (84.0)  636 (98.3)  <0.001  319 (86.9)  357 (97.3)  <0.001   P2Y12 inhibitor  443 (65.0)  631 (97.5)  <0.001  252 (68.7)  353 (96.2)  <0.001   Statin  623 (91.2)  618 (95.4)  0.003  339 (92.1)  352 (95.9)  0.039   Beta-blocker  339 (49.6)  386 (59.6)  0.001  194 (52.7)  219 (59.7)  0.11   Calcium-channel blocker  372 (54.5)  362 (55.9)  0.78  204 (55.4)  198 (54.0)  0.92  Multi-vessel coronary artery disease  375 (54.9)  413 (63.4)  0.002  223 (60.6)  228 (62.0)  0.76  Lesion characteristics               Fractional flow reserve, mean ± SD  0.78 ± 0.02  0.77 ± 0.02  <0.001  0.78 ± 0.02  0.78 ± 0.02  0.14   Lesion territory, n (%)      0.001      0.98    Left main  20 (2.9)  48 (7.4)    15 (4.1)  17 (4.6)      Left anterior descending artery  513 (75.1)  448 (68.8)    258 (70.1)  262 (71.2)      Right coronary artery  72 (10.5)  86 (13.2)    49 (13.3)  47 (12.8)      Left circumflex artery  54 (7.9)  56 (8.6)    34 (9.2)  32 (8.7)      Others  24 (3.5)  13 (2.0)    12 (3.3)  10 (2.7)     Lesion location, n (%)      0.002      0.80    Proximal  315 (46.1)  362 (55.6)    193 (52.4)  191 (51.9)      Mid  264 (38.7)  215 (33.0)    125 (34.0)  132 (35.9)      Distal  81 (11.9)  65 (10.0)    38 (10.3)  37 (10.1)     Diameter stenosis, n (%)      <0.001      0.20    ≥70%  88 (12.9)  349 (53.6)    83 (22.6)  90 (24.5)      50–69%  446 (65.3)  295 (45.3)    270 (73.4)  271 (73.6)      30–49%  149 (21.8)  7 (1.1)    15 (4.1)  7 (1.9)      AHA/ACC B2C lesion  444 (65.0)  484 (74.3)  <0.001  249 (67.7)  262 (71.2)  0.34   Long lesion (>20 mm)  320 (46.9)  384 (59.0)  <0.001  180 (48.9)  199 (54.1)  0.18  ACC/AHA, American College of Cardiology/American Heart Association. Quantitative coronary angiography showed larger minimal lumen diameters and smaller diameter stenosis in the deferred group, whereas IVUS showed that the deferred group patients had fewer plaque ruptures, larger MLA, and smaller plaque burden than the performed group patients (Table 2). Table 2 Lesion characteristics at the index procedure by imaging analysis Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  MLA, minimal lumen area. Table 2 Lesion characteristics at the index procedure by imaging analysis Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  Lesion characteristics  Overall population   Matched population   Deferred group  Performed group  P-value  Deferred group  Performed group  P-value  Quantitative coronary angiography, mean ± SD  n = 292  n = 278    n = 163  n = 172     Lesion length (mm)  21.9 ± 12.7  21.8 ± 11.2  0.89  22.9 ± 14.0  20.8 ± 10.1  0.12   Reference lumen diameter (mm)  3.1 ± 0.5  3.1 ± 0.5  0.36  3.1 ± 0.5  3.1 ± 0.5  0.69   Minimal lumen diameter (mm)  1.5 ± 0.4  1.4 ± 0.4  0.004  1.5 ± 0.4  1.4 ± 0.4  0.03   Diameter stenosis (%)  50.9 ± 10.0  55.4 ± 10.0  <0.001  52.1 ± 10.7  55.8 ± 10.2  0.001  Intravascular ultrasound  n = 240  n = 266    n = 134  n = 167     Lesion length (mm), mean ± SD  35.6 ± 14.2  26.4 ± 11.3  <0.001  36.6 ± 13.6  25.8 ± 11.6  <0.001   Qualitative analysis, n (%)                Plaque rupture  27 (11.2)  59 (22.2)  <0.001  27 (11.2)  59 (22.2)      Thrombus  38 (15.8)  35 (13.2)  0.39  38 (15.8)  35 (13.2)      Severe calcification with calcium arc >180°  30 (12.5)  40 (15.0)  0.41  30 (12.5)  40 (15.0)     Single-plane analysis at MLA site, mean ± SD                External elastic membrane area (mm2)  11.1 ± 4.4  12.1 ± 5.0  0.015  11.6 ± 4.8  12.1 ± 5.1  0.35    Plaque plus media area (mm2)  8.3 ± 4.0  9.8 ± 4.6  <0.001  8.8 ± 4.3  9.8 ± 4.6  0.07    MLA (mm2)  2.8 ± 1.1  2.3 ± 0.9  <0.001  2.8 ± 1.1  2.3 ± 0.9  0.001    Plaque burden (%)  74.2 ± 10.7  79.1 ± 7.6  <0.001  75.8 ± 10.5  79.1 ± 7.3  0.002  MLA, minimal lumen area. Outcomes for the overall population During a median follow-up of 2.9 (interquartile range 1.5–4.1) years, MACE occurred in 55 (8.1%) patients in the deferred group and 55 (8.4%) in the performed group [adjusted hazard ratio (aHR) 1.05, 95% confidence interval (CI) 0.67–1.66; P = 0.79]. 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) (Table 3). Indications for target lesion revascularization are summarized in Supplementary material online, Table S2. Figure 2 shows the Kaplan–Meier curves for the outcomes in the two groups. Independent predictors of MACE in the deferred and performed groups are shown in Supplementary material online, Tables S3 and S4. Table 3 Clinical outcomes in the deferred and performed groups   Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031    Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031  CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; IPTW, inverse probability-of-treatment weighting; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable; TVR, target vessel revascularization. a Major adverse cardiac events comprised death, target vessel myocardial infarction, and target vessel revascularization. b Adjusted by age, gender, clinical presentation, hypertension, diabetes, current smoking, hyperlipidaemia, history of percutaneous coronary intervention, chronic renal failure, lesion territory, lesion location, FFR value, diameter stenosis, lesion complexity, lesion length, and number of diseased vessels. Table 3 Clinical outcomes in the deferred and performed groups   Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031    Total number of events (%)   Crude HR (95% CI)  P-value  Adjusted HR (95% CI)   Deferred group [n = 683; n (%)]  Performed group [n = 651; n (%)]  Multivariableb  P-value  Propensity matching  P-value  IPTW  P-value  Primary outcome   MACEa  55 (8.1)  55 (8.4)  0.81 (0.55–1.17)  0.26  1.05 (0.67–1.66)  0.79  0.95 (0.57–1.57)  0.83  0.97 (0.67–1.40)  0.86    FFR 0.75 (n = 216)  6 (9.1)  10 (6.7)  1.27 (0.46–3.49)  0.65                FFR 0.76 (n = 193)  5 (6.1)  11 (9.9)  0.53 (0.18–1.52)  0.23                FFR 0.77 (n = 215)  5 (5.4)  10 (8.1)  0.61 (0.21–1.79)  0.37                FFR 0.78 (n = 206)  10 (10.2)  10 (9.3)  0.99 (0.41–2.39)  0.99                FFR 0.79 (n = 221)  10 (8.1)  9 (9.3)  0.71 (0.29–1.76)  0.46                FFR 0.80 (n = 283)  19 (8.6)  5 (8.1)  0.96 (0.36–2.58)  0.94              Secondary outcome   Death from any cause  17 (2.5)  13 (2.0)  1.06 (0.52–2.19)  0.87  0.82 (0.34–2.00)  0.66  0.61 (0.23–1.60)  0.31  0.99 (0.51–1.91)  0.97    Cardiac death  9 (1.3)  4 (0.6)  1.82 (0.56–5.93)  0.32  1.09 (0.23–5.09)  0.91  0.84 (0.17–4.19)  0.84  1.15 (0.38–3.52)  0.81   MI  5 (0.7)  21 (3.2)  0.21 (0.08–0.55)  0.002  0.27 (0.09–0.80)  0.019  0.34 (0.11–1.07)  0.06  0.36 (0.16–0.82)  0.015    Periprocedural MI  0 (0.0)  18 (2.8)  NA  NA  NA  NA  NA  NA  NA  NA    Spontaneous MI  5 (0.7)  3 (0.5)  1.31 (0.31–5.50)  0.71  1.85 (0.35–9.75)  0.47  3.49 (0.39–31.24)  0.26  2.10 (0.51–8.59)  0.30   Death or MI  20 (2.9)  33 (5.1)  0.51 (0.29–0.88)  0.017  0.48 (0.25–0.95)  0.034  0.40 (0.18–0.89)  0.024  0.60 (0.36–1.01)  0.05   Death or spontaneous MI  20 (2.9)  16 (2.5)  1.02 (0.53–1.97)  0.96  0.90 (0.41–1.99)  0.80  0.72 (0.30–1.73)  0.46  1.09 (0.60–1.98)  0.78   Cardiac death or spontaneous MI  7 (1.0)  5 (0.8)  1.13 (0.36-3.56)  0.84  0.93 (0.21-4.12)  0.92  1.09 (0.29-4.06)  0.90  1.14 (0.40-3.23)  0.81   TVR  39 (5.7)  24 (3.7)  1.30 (0.78–2.16)  0.31  2.17 (1.17–4.02)  0.013  2.49 (1.16–5.34)  0.019  1.79 (1.05–3.04)  0.031  CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; IPTW, inverse probability-of-treatment weighting; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable; TVR, target vessel revascularization. a Major adverse cardiac events comprised death, target vessel myocardial infarction, and target vessel revascularization. b Adjusted by age, gender, clinical presentation, hypertension, diabetes, current smoking, hyperlipidaemia, history of percutaneous coronary intervention, chronic renal failure, lesion territory, lesion location, FFR value, diameter stenosis, lesion complexity, lesion length, and number of diseased vessels. Figure 2 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the overall population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Figure 2 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the overall population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Outcomes for the propensity score-matched groups Propensity score matching to adjust for the differences in the baseline characteristics created 368 matched pairs of patients. The two groups were well balanced with no significant differences in baseline characteristics, except for the more frequent post-procedural use of antiplatelet agents and statin in the performed group (Table 1). The clinical outcomes showed a similar trend to those for the overall population. The risk of MACE, death, cardiac death, and spontaneous MI did not differ between the groups (Table 3, Figure 3). The results after adjustment by IPTW were consistent (Table 3). The clinical outcomes of the patients not included in the propensity score matching showed a similar trend (see Supplementary material online, Tables S5 and S6). Figure 3 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the matched population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Figure 3 View largeDownload slide Kaplan–Meier curves for clinical outcomes in the matched population. (A) Major adverse cardiac events. (B) Death from any cause. (C) Myocardial infarction. (D) Target vessel revascularization. Subgroup analyses In the subgroup analyses, the only difference in the effect on MACE between deferred and performed revascularization was with respect to MLA on IVUS (≤2.5 mm2 and >2.5 mm2), in which a trend towards a treatment by subgroup interaction was observed (P = 0.045 for the interaction; Figure 4). Even when a stricter definition of periprocedural MI was applied, the overall findings remained consistent (see Supplementary material online, Table S7). Figure 4 View largeDownload slide Subgroup analysis for major adverse cardiac events in the overall population. IVUS, intravascular ultrasound; LAD, left anterior descending artery. Figure 4 View largeDownload slide Subgroup analysis for major adverse cardiac events in the overall population. IVUS, intravascular ultrasound; LAD, left anterior descending artery. Discussion Data from this large, prospective, multicentre registry showed that the risk of a composite of death, target vessel MI and TVR for patients with grey-zone FFR values did not significantly differ between the patients whose revascularization was deferred and those for whom it was performed. The incidence of death and spontaneous MI did not differ between the groups. Although the risk of TVR tended to be higher for the deferred group, this was offset by a higher risk of periprocedural MI for the performed group. This trend remained consistent even after adjustment by propensity score matching and IPTW. This suggests that the medical treatment of lesions with grey-zone FFR values would be a reasonable and safe strategy. Revascularization may be considered in patients with medically refractory angina. Initially, the FFR cut-off value for revascularization was 0.75, with FFR values <0.75 having >99% positive predictive value for inducible myocardial ischaemia. Subsequent studies have reported that in a minority of patients, FFR between 0.75 and 0.80 was associated with flow-limiting stenosis.24,25 Currently, FFR of 0.80 is used in revascularization threshold to avoid a few significant stenosis being left untreated.1,2 Nevertheless, FFR values between 0.75 and 0.80 are still considered as being in the grey zone in revascularization decision-making.9–15 Therefore, for the treatment of those lesions, careful clinical judgement considering typicality of complaints, other test results, and the lesion characteristics was suggested.26 Revascularization for stenosis with grey-zone FFR values has been investigated in only three small retrospective observational studies (see Supplementary material online, Table S8). Courtis et al.9 reported that coronary revascularization was associated with a lower rate of MACE, mainly because of the reduction in target lesion revascularization. Conversely, Lindstaedt et al.10 showed that deferral of revascularization was associated with lower rates of MACE and the composite of cardiac death and MI. Recently, Adjedj et al.11 demonstrated that revascularization of stenosis with grey-zone FFR values tended to have a lower risk of overall mortality, and Agarwal et al.12 reported that revascularization was associated with lower rates of MACE and spontaneous MI. The IRIS-FFR registry includes the largest current cohort of prospectively enrolled coronary stenosis patients treated using contemporary medicine and interventional technology, with clinical events adjudicated by an independent committee. Furthermore, we controlled for selection bias between the groups in the present study using various statistical adjustments. This study could therefore provide valuable insights for daily catheterization laboratory practice. The results suggested that deferred revascularization could be the preferred initial treatment strategy for stenosis with grey-zone FFR values. In the deferred group, the annual death and target vessel MI rate was less than 1%. The annual incidence of TVR was less than 2%, which must be lower than that of contemporary PCI-related complications.27,28 Late TVR after index procedure was more frequent in the deferred group. However, it is noteworthy that in performed group, all patients already received PCI and 3.7% experienced late TVR. Therefore, more patients actually received stent implantation in performed group than deferred group between index procedure and follow-up. Although we exclusively used second-generation drug-eluting stents, the risk of periprocedural MI and repeated TVR was not negligible in the performed group, and performing revascularization was not observed to be superior to medical treatment for stenosis with grey-zone FFR values. These overall findings remained consistent even when we applied a stricter definition of periprocedural MI in a supplementary analysis. A recent meta-analysis showed that the outcome-derived FFR threshold for revascularization was located within the grey zone29 that was consistent with our findings. The morphological characteristics of the stenosis and the patient’s clinical context can affect clinical outcomes in coronary artery disease.15,30,31 Thus, for stenosis with grey-zone FFR values, some operators favour revascularization for high-risk patients and lesion characteristics, such as patients with diabetes or acute coronary syndrome. However, our subgroup analysis showed no differences in effect between deferred and performed revascularization on the risk of MACE across the subgroups including acute coronary syndrome. This would be due to that unfavourable clinical and lesion characteristics affected outcomes of both revascularized and deferred lesions. Interestingly, MLA showed a marginally significant interaction. However, these results had insufficient statistical power and should be interpreted with caution. A further large study is needed to test whether MLA measured using IVUS could guide revascularization decisions for stenosis with grey-zone FFR values. Limitation This study has several limitations. First, there was the inherent limitation of this being an observational study. Second, the clinical and lesion characteristics differed between the groups. These differences were adjusted through propensity score matching; nevertheless, some differences remained, particularly with regard to the use of post-procedural medications. Third, we selected one lesion per patient to eliminate clustering effects. Additional analysis with the all 1388 lesions showed similar trends (Supplementary Tables S9 and S10). Finally, the power of this study could be limited to detect small differences. Our findings warrant substantiation in larger studies with greater power. Although underpowered, this study is the largest cohort of prospectively enrolled patients with the longest follow-up duration that could give clinically relevant information for the debating issue. Conclusion In conclusion, this study based on a large, prospective, and multicentre registry demonstrated that revascularization was not associated with better clinical outcomes for coronary stenosis with grey-zone FFR values. A high risk of periprocedural MI in patients who underwent revascularization was offset by the high risk of TVR in the deferred group. Supplementary material Supplementary material is available at European Heart Journal online. Funding This work was supported by the CardioVascular Research Foundation, Ministry of Trade, Industry & Energy (MOTIE), and Korea Institute for Advancement of Technology (KIAT) through the Encouragement Program for The Industries of Economic Cooperation Region. Conflict of interest: none declared. References 1 Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van't Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med  2009; 360: 213– 224. Google Scholar CrossRef Search ADS PubMed  2 De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nüesch E, Jüni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med  2014; 371: 1208– 1217. Google Scholar CrossRef Search ADS PubMed  3 Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, Erbel R, Legrand V, Gwon HC, Remkes WS, Stella PR, van Schaardenburgh P, Bech GJ, De Bruyne B, Pijls NH. 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. Google Scholar CrossRef Search ADS PubMed  4 Park SJ, Ahn JM, Park GM, Cho YR, Lee JY, Kim WJ, Han S, Kang SJ, Park DW, Lee SW, Kim YH, Lee CW, Mintz GS, Park SW. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J  2013; 34: 3353– 3361. Google Scholar CrossRef Search ADS PubMed  5 Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, Champagne S, Belle L, Barreau D, Hanssen M, Besnard C, Dauphin R, Dallongeville J, El Hahi Y, Sideris G, Bretelle C, Lhoest N, Barnay P, Leborgne L, Dupouy P; Investigators of the Registre Francais de la FFR-R3F. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation  2014; 129: 173– 185. Google Scholar CrossRef Search ADS PubMed  6 Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J Koolen JJ, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med  1996; 334: 1703– 1708. Google Scholar CrossRef Search ADS PubMed  7 Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH; American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines, Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol  2011; 58:2550–2122. 8 Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J  2014; 35: 2541– 2619. Google Scholar CrossRef Search ADS PubMed  9 Courtis J, Rodés-Cabau J, Larose E, Déry J-P, Nguyen CM, Proulx G, Gleeton O, Roy L, Barbeau G, Noël B, DeLarochellière R, Bertrand OF. 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. Google Scholar CrossRef Search ADS PubMed  10 Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mügge A, Germing A. 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. Google Scholar CrossRef Search ADS PubMed  11 Adjedj J, De Bruyne B, Flore V, Di Gioia G, Ferrara A, Pellicano M, Toth GG, Bartunek J, Vanderheyden M, Heyndrickx GR, Wijns W, Barbato E. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation  2016; 133: 502– 508. Google Scholar CrossRef Search ADS PubMed  12 Agarwal SK, Kasula S, Edupuganti MM, Raina S, Shailesh F, Almomani A, Payne JJ, Pothineni NV, Uretsky BF, Hakeem A. Clinical decision-making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol  2017; 29: 371– 376. Google Scholar PubMed  13 Yamashita J, Tanaka N, Shindo N, Ogawa M, Kimura Y, Sakoda K, Murata N, Hokama Y, Hoshino K, Ikeda S, Yamashina A. 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. Google Scholar CrossRef Search ADS PubMed  14 Shiono Y, Kubo T, Tanaka A, Ino Y, Yamaguchi T, Tanimoto T, Yamano T, Matsuo Y, Nishiguchi T, Teraguchi I, Ota S, Ozaki Y, Orii M, Shimamura K, Kitabata H, Hirata K, Imanishi T, Akasaka T. 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. Google Scholar CrossRef Search ADS PubMed  15 Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, Davies JE. 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. Google Scholar CrossRef Search ADS PubMed  16 Ahn JM, Park DW, Shin ES, Koo BK, Nam CW, Doh JH, Kim JH, Chae IH, Yoon JH, Her SH, Seung KB, Chung WY, Yoo SY, Lee JB, Choi SW, Park K, Hong TJ, Lee SY, Han M, Lee PH, Kang SJ, Lee SW, Kim YH, Lee CW, Park SW, Park SJ, Investigators IF. Fractional flow reserve and cardiac events in coronary artery disease: data from a prospective registry. Circulation  2017; 135: 2241– 2251. Google Scholar CrossRef Search ADS PubMed  17 Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures. J Am Coll Cardiol  1988; 12: 529– 545. Google Scholar CrossRef Search ADS PubMed  18 Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG, O’Rourke RA, Abrams J, Bates ER, Brodie BR, Douglas PS, Gregoratos G, Hlatky MA, Hochman JS, Kaul S, Tracy CM, Waters DD, Winters WL. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). J Am Coll Cardiol  2001; 37: 1478– 1492. Google Scholar CrossRef Search ADS PubMed  19 Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasché P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; ESC Committee for Practice Guidelines. Third universal definition of myocardial infarction. Eur Heart J  2012; 33: 2551– 2567. Google Scholar CrossRef Search ADS PubMed  20 Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol  1995; 48: 1503– 1510. Google Scholar CrossRef Search ADS PubMed  21 Ho D, Imai K, King G, Stuart E. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw  2011; 42: 1– 28. Google Scholar CrossRef Search ADS   22 Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat  2011; 10: 150– 161. Google Scholar CrossRef Search ADS PubMed  23 Hansen B, Bowers J. Covariate balance in simple, stratified and clustered comparative studies. Stat Sci  2008; 23: 219– 236. Google Scholar CrossRef Search ADS   24 De Bruyne B, Pijls NH, Bartunek J, Kulecki K, Bech JW, De Winter H, Van Crombrugge P, Heyndrickx GR, Wijns W. Fractional flow reserve in patients with prior myocardial infarction. Circulation  2001; 104: 157– 162. Google Scholar CrossRef Search ADS PubMed  25 Samady H, Lepper W, Powers ER, Wei K, Ragosta M, Bishop GG, Sarembock IJ, Gimple L, Watson DD, Beller GA, Barringhaus KG. Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction. J Am Coll Cardiol  2006; 47: 2187– 2193. Google Scholar CrossRef Search ADS PubMed  26 Pijls NH, Tanaka N, Fearon WF. Functional assessment of coronary stenoses: can we live without it? Eur Heart J  2013; 34: 1335– 1344. Google Scholar CrossRef Search ADS PubMed  27 Bønaa KH, Mannsverk J, Wiseth R, Aaberge L, Myreng Y, Nygård O, Nilsen DW, Kløw NE, Uchto M, Trovik T, Bendz B, Stavnes S, Bjørnerheim R, Larsen AI, Slette M, Steigen T, Jakobsen OJ, Bleie Ø, Fossum E, Hanssen TA, Dahl-Eriksen Ø, Njølstad I, Rasmussen K, Wilsgaard T, Nordrehaug JE; NORSTENT Investigators. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med  2016; 375: 1242– 1252. Google Scholar CrossRef Search ADS PubMed  28 Kedhi E, Joesoef KS, McFadden E, Wassing J, van Mieghem C, Goedhart D, Smits PC. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet  2010; 375: 201– 209. Google Scholar CrossRef Search ADS PubMed  29 Johnson NP, Toth GG, Lai D, Zhu H, Acar G, Agostoni P, Appelman Y, Arslan F, Barbato E, Chen SL, Di Serafino L, Dominguez-Franco AJ, Dupouy P, Esen AM, Esen OB, Hamilos M, Iwasaki K, Jensen LO, Jimenez-Navarro MF, Katritsis DG, Kocaman SA, Koo BK, Lopez-Palop R, Lorin JD, Miller LH, Muller O, Nam CW, Oud N, Puymirat E, Rieber J, Rioufol G, Rodes-Cabau J, Sedlis SP, Takeishi Y, Tonino PA, Van Belle E, Verna E, Werner GS, Fearon WF, Pijls NH, De Bruyne B, Gould KL. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. J Am Coll Cardiol  2014; 64: 1641– 1654. Google Scholar CrossRef Search ADS PubMed  30 Depta JP, Patel JS, Novak E, Gage BF, Masrani SK, Raymer D, Facey G, Patel Y, Zajarias A, Lasala JM, Amin AP, Kurz HI, Singh J, Bach RG. Risk model for estimating the 1-year risk of deferred lesion intervention following deferred revascularization after fractional flow reserve assessment. Eur Heart J  2015; 36: 509– 515. Google Scholar CrossRef Search ADS PubMed  31 Doh JH, Nam CW, Koo BK, Park SH, Lee JH, Han JK, Yang HM, Lim HS, Yoon MH, Cho YK, Hur SH, Lee SY, Kim HS, Tahk SJ. Long-term patient-related and lesion-related outcomes after real-world fractional flow reserve use. J Invasive Cardiol  2015; 27: 410– 415. Google Scholar PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Heart JournalOxford University Press

Published: Feb 24, 2018

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