Between January 2003 and June 2011, PCI was performed in 5,929 patients at Samsung Medical Center. A total of 3,208 patients underwent elective PCI for stable ischemic heart disease (SIHD). After excluding patients with coronary computed tomography alone or no stress testing, or those with pharmacologic stress echocardiography of nuclear study prior to PCI, 959 patients who had EST within 6 months prior to PCI were selected. For study purposes, the 291 patients who did not have a positive result of pre-PCI EST (173 patients with suboptimal heart rate and 118 patients with ST depression less than 1 mm) were excluded. Among the remaining 668 patients, 396 patients who did not undergo follow-up EST within 24 months after PCI, 2 patients who underwent EST by modified Bruce protocol, and 14 patients who had nonfatal myocardial infarction (MI) or any revascularization before follow-up EST (Supplementary Figure 1) were excluded. Post-PCI EST was performed as routine follow-up protocol of the patients under institutional policy. Finally, a total of 256 eligible patients were divided into 2 groups according to the functional completeness of revascularization: 1) the functional complete revascularization (CR) group had positive EST before PCI and negative EST after PCI (n=149); and 2) the functional incomplete revascularization (IR) group had positive EST both before and after PCI (n=107).

Clinical, angiographic and procedural data were recorded prospectively by independent research personnel. Patients were routinely followed up at 1, 6, and 12 months after index procedure and annually thereafter. Further information was collected by telephone contact and medical records if necessary. Follow-up was considered complete if the patient's death was confirmed by the National Population Registry of the Korea National Statistical Office using a unique personal identification number, or if the patient was contacted at the planned follow-up interval. The Institutional Review Board and Ethics Committee approved this study and waived the requirement for written informed consent for access to an institutional PCI registry (2016-03-020).

Angiographic disease severity was assessed by Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score and residual disease burden after PCI was assessed by residual SYNTAX score in an independent core laboratory by a blinded investigator. In patients with functional IR, post-PCI coronary angiograms were reviewed by 2 independent investigators to explore potential reasons for positive post-PCI EST results.

The EST was performed according to the Bruce protocol using a conventional treadmill. A 12-lead electrocardiogram (ECG) was recorded and monitored continuously with a computerized system (Quinton Q-Stress; Quinton Cardiology, Inc. Bothell, WA, USA) during exercise and rest. The ECG was reviewed by cardiology fellows and senior cardiologists. The test was discontinued in the event of exercise-limiting symptoms including dyspnea, chest pain, fatigue, or significant abnormalities in vital signs. The target heart rate was determined as 85% of maximum predicted heart rate (220 − age), but was not used as a predetermined endpoint for premature termination of the test. A positive result was defined as horizontal or down-sloping ST depression ≥1 mm (0.1 mV) at 60 to 80 milliseconds after the J point,7) by using the largest value of ST-deviation during exercise or recovery phase. In patients with baseline ECG abnormalities, 3 or more consecutive beats in the same lead with a stable ECG baseline were analyzed. In case of unstable baseline, an average magnitude of consecutive beats was analyzed, and if required, computer-assisted ECG were included in analysis. In patients with baseline ST segment change, an additional ST depression from baseline level was analyzed. In patients with resting ST segment elevation, a magnitude of ST depression below baseline PQ segment was used for interpretation. The Duke score was calculated as follows: duration of exercise in minutes − (5 × the maximal ST-segment deviation from baseline during or after exercise, in millimeters) − (4 × angina index). The angina index was defined as 0 if the patient had no angina during exercise, 1 if the patient had non-limiting angina, and 2 if angina was the reason for the patient stopping the exercise.8) Duke treadmill score was calculated regardless of EST result for comparison.

Out of 256 patients, 27 patients who showed definite ST segment depression in pre-PCI EST did not reach target heart rate without ST depression on post-PCI EST during their maximal exercise. Those patients were considered as having negative EST.

The primary outcome was change in exercise duration after PCI and was calculated as the difference in exercise duration between pre-PCI and post-PCI ESTs. Secondary outcomes were major adverse cardiac events (MACE, a composite of all-cause death, any spontaneous MI, and any ischemia-driven revascularization) and individual components of MACE at 3 years of follow-up. Spontaneous MI was defined as elevated cardiac enzyme levels, such as troponin I or myocardial band fraction of creatine kinase, greater than the upper limit of the normal range with either ischemic symptoms or electrocardiographic changes indicating ischemia after index procedure.9) Periprocedural MI was not included as a clinical event. Ischemia-driven revascularization included all target and non-target revascularization with either PCI or coronary artery bypass graft surgery. Ischemia-driven revascularization was defined as a revascularization procedure with at least one of the following: 1) Recurrence of angina; 2) Positive non-invasive test other than EST; and 3) Positive invasive physiologic test.

Continuous variables were presented as mean±standard deviation or median (Q1–Q3) according to the normal distribution. To compare differences of variables between groups, Student's t-test or the Mann-Whitney U test was used for continuous variables, and χ² test was used for categorical variables. To compare continuous variables between pre-PCI and post-PCI EST within the same group, paired t-test was used. To determine the significance of relationship between exercise duration increment and post-PCI EST result, multivariable linear regression was performed using clinically relevant variables including age, sex, hypertension, diabetes, previous PCI, previous MI, baseline (pre-PCI) exercise duration, and days from PCI to post-PCI EST. Linear regression analysis was used to evaluate the association of a change in exercise duration with pre-PCI Duke treadmill score or pre-PCI SYNTAX score.

As a sensitivity analysis, a propensity score-adjusted multivariable regression was performed for comparison of exercise increment between the 2 groups. Propensity score was estimated by multivariable logistic regression analysis using all baseline clinical characteristics and disease extent. Estimated propensity score was added to the multivariable adjusted variables.

Event rates were calculated based on Kaplan-Meier censoring estimates and presented with the cumulative incidence, and the log-rank test was used to compare survival curves between groups. Multivariate Cox proportional hazard regression was used to calculate adjusted hazard ratio (HR_adj) and 95% confidence interval (CI) to compare between-group differences. In multivariate linear regression and multivariate Cox proportional hazard model, clinically relevant variables including age, sex, hypertension, diabetes mellitus, previous PCI and previous MI were included. The assumption of proportionality was assessed graphically by the log-minus-log plot, and Cox proportional hazard models for all clinical outcomes satisfied the proportional hazards assumption.

All probability values are 2-sided and p values <0.05 were considered statistically significant. R software version 3.4.0 (R Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analyses.

A total of 256 patients eligible for analysis met the following inclusion criteria: 1) positive result of pre-PCI EST; 2) elective PCI for SIHD; 3) available post-PCI EST results; and 4) no clinical event of MI or any revascularization before post-PCI EST (Supplementary Figure 1). Among the total population, 149 patients were classified as the functional CR group based on negative conversion of post-PCI EST whereas 107 patients were classified as the functional IR group based on remaining positive results in post-PCI EST. Baseline characteristics were not significantly different between the 2 groups, except higher prevalence of hypertension and previous PCI in the functional IR group (Tables 1 and 2). Both groups showed minimal residual stenosis after PCI with similar residual SYNTAX score. Among patients with functional IR, potential reasons for positive post-PCI EST results were suspected due to residual focal stenosis with angiographic %DS≥50% including chronic total occlusion and compromised side branch (25.2%), suspected diffuse atherosclerosis in angiography without focal stenosis (67.3%), and unknown or suspected combined microvascular disease (7.5%).

Details of EST are shown in Table 3. In pre-PCI EST, about 60% of patients in both functional CR and IR groups showed exercise-limiting or non-limiting chest pain during EST without between-group difference. The median exercise duration before PCI was similar between the functional CR and IR groups (540 [Q1–Q3, 414, 602] seconds vs. 480 [Q1–Q3, 402, 589] seconds, p=0.091). Pre-PCI Duke treadmill score represented that the study population was moderate-risk population, and there was no signfiicant difference between the 2 groups.

The median time interval of post-PCI EST after the index procedure was 269 days (Q1–Q3, 166, 393) with median 10 days difference between the 2 groups (median 274 vs. 264 days for functional CR and IR group, respectively, p=0.012). After PCI, the functional CR group had significantly greater relief of exercise-induced chest pain and less incidence of significant ST-segment change during exercise. Median exercise duration was significantly higher in the funtional CR group than in the functional IR group (612 [Q1–Q3, 540, 661] seconds versus 540 [Q1–Q3, 441, 600] seconds, p<0.001). In addition, the Duke treadmill score was also significantly higher in the functional CR group than in the functional IR group.

When the amount of change in exercise duration and Duke treadmill score was compared between the 2 groups, the functional CR group showed a significantly higher increment in exercise duration (62.0 [Q1–Q3, 12.0, 141.0] seconds vs. 30.0 [Q1–Q3, −11.0, 103.5] seconds, p=0.011) as well as Duke treadmill score (Figure 1). The increment in exercise duration was also significantly different after adjustment of baseline covariables between the functional CR and IR groups (β_adj=40.1 seconds, p<0.001), and the consistent result was observed in sensitivity analysis (β_adj=44.4 seconds, p<0.001). The increment of exercise duration had a significant inverse relationship with pre-PCI Duke treadmill score (p<0.001). However, there was no significant relationship between the increment of exercise duration and pre-PCI SYNTAX score (p=0.282) (Figure 2).

The functional CR group showed a significantly lower risk of MACE (6.2% vs. 26.1%; HR_adj, 0.18; 95% CI, 0.08–0.40; p<0.001), mainly driven by a significantly lower incidence of ischemia-driven revascularization than the functional IR group (Figure 3 and Table 4). The cause of ischemia-driven revascularization was due to refractory chest pain despite OMT with objective signs of lesion progression in 92.3% (24/26 events) of patients in the functional IR group and in 71.4% (5/7 events) of patients in the functional CR group.