Methods

From January 2008 to December 2011, patients with angiographically confirmed significant LMCA disease or 3-vessel disease, in which revascularization was deemed to be clinically indicated, were consecutively enrolled in this study from the Asan Left Main and Multivessel Registry. Significant left main disease was defined as the angiographic diameter stenosis of >50%. We excluded patients who underwent previous CABG or concomitant valvular or aortic surgery, those who had an acute myocardial infarction (MI) 24 hours before revascularization or presented with cardiogenic shock, and those who had a contraindication to the placement of a DES. Patients who did not receive revascularization because of poor clinical or coronary anatomical condition or who refused percutaneous or surgical procedures were also excluded. Our center’s institutional review board approved the use of clinical data for this study, and all patients provided written informed consent for enrollment in our registry.

Since January 2010, clinical protocols of our institute were revised to mandate its use during coronary intervention, and thereby, all operators in our institution routinely use FFR for assessing the functional severity of intermediate coronary stenosis (visual estimated diameter stenosis, 50% to 80%) during coronary intervention without objective evidence of ischemia before PCI. All patients having routine FFR measurement were applied in this manner. Accordingly, data of study patients before routine FFR use (from January 2008 to December 2009) and those after routine FFR use (from January 2010 to December 2011) were obtained. FFR was measured with a coronary pressure wire (St. Jude Medical, Minneapolis, Minnesota) as described previously. PCI was performed in coronary stenosis with FFR <0.75, if PCI was feasible and was deferred in those with FFR >0.80. For FFR values between 0.75 and 0.80, revascularization was performed at the operator’s discretion. The choice between PCI and CABG was at the physician’s discretion, primarily based on the angiography results. Patients whose revascularizations were intentionally deferred by attending physicians based on the angiographic or invasive/noninvasive functional studies were included in the medical treatment group. Stent implantation was performed according to the standard guidelines and techniques. During the study period, DES was the default stent for patients with coronary artery stenosis. Each PCI patient received a loading dose of 200 mg aspirin and 300 mg clopidogrel before the procedure. After DES implantation, standard dual antiplatelet therapy consisting of 100 mg/day aspirin and 75 mg/day clopidogrel was recommended for at least 6 months, and patients at high risk of ischemic complications were administered clopidogrel for a longer period. CABG was performed using standard bypass techniques.

The primary outcome of interest was the composite of all-cause death, MI, stroke, and any repeat revascularization (Major adverse cardiovascular and cerebral event [MACCE]). The principal secondary end points were the composite of death, MI, and stroke and individual components of these composite endpoints. Deaths were considered cardiac unless an unequivocal, noncardiac cause was established. MI was defined as an increase in the creatine kinase MB concentration to >5 times the upper limit of the normal range and any of the following: (1) new pathologic Q waves or new bundle branch block, (2) angiographically documented new graft or new native coronary occlusion, or (3) new loss of viable myocardium or new regional wall motion abnormalities, if occurring within 48 hours after the procedure or any increase in creatine kinase MB concentration to greater than the upper limit of the normal range plus ischemic symptoms or signs, if occurring >48 hours after the procedure. Repeat revascularization included target vessel revascularization, regardless of whether the procedure was clinically or angiographically driven and nontarget vessel revascularization. Stroke, as indicated by neurologic deficits, was established by a neurologist on the basis of imaging studies. All outcomes of interest were carefully verified and adjudicated by independent clinicians.

All analyses were performed using R software, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS software, version 19.0 (IBM Corp., Armonk, New York) by an independent statistician (S-BH). All reported p values are 2 sided, and p values <0.05 were considered statistically significant. All continuous variables are expressed as mean ± SD, and categorical variables are expressed as a number (percentage). Continuous variables were compared using the t test, the Mann-Whitney U test, or analysis of variance test (among 3 group comparisons), and categorical variables were compared using the chi-square or Fisher’s exact test, as appropriate. To reduce the effect of selection bias and potential confounding, we used the propensity score (PS) matching method to adjust for baseline characteristics of patients. PS was estimated nonparametrically using variables that are known to be related to both group assignments and outcome variables. 1:1 PS matching was performed by a nearest neighbor matching without replacement. The considered caliper size was 0.1. Pairs on the PS logit were matched within a range of 0.1 SDs of logit-transformed PS. The PS logit distributions for each cohort showed sufficient overlaps with caliber size 0.1. The balance difference of covariates was measured by their standardized differences in means. For the matched pair comparison, the Wilcoxon signed-rank test for continuous variables and the McNemar’s test for categorical variables were used. The Cox proportional hazards regression model with robust SEs that accounts for the clustering of the pairs was used to compare the clinical outcomes between the 2 groups. The proportional hazards assumption was confirmed by examination of log (−log [survival]) curves and by testing of partial (Schoenfeld) residuals. When the proportional hazards assumption is violated, we fitted an Aalen’s additive hazard model. In the additive hazard model, the results were consistent with primary analysis. R packages of timereg and MatchIt were used to fit the additive hazard model and to construct matched cohort and for balance checking.

Results

We enrolled 2,612 patients, including 1,264 who underwent CABG, 1,229 who underwent PCI, and 119 in whom revascularization was not performed. In addition, we obtained data before (1,467 patients) and after routine (1,145 patients) FFR use ( Figure 1 ). Treatment strategies are shown in Figure 2 . After routine FFR use, the proportion of patients receiving CABG decreased, whereas that of patients receiving PCI and in whom revascularization was deferred increased. Similarly, this trend was observed in the subgroup of LMCA disease or 3-vessel disease.

The rate of FFR during PCI.

Changes in treatment strategy in all patients (A) , left main disease (B) , and three vessel disease (C) .

Patient characteristics are listed in Table 1 . Before routine FFR use, a higher number of patients in the CABG group had diabetes, peripheral vascular disease, and history of stroke; less hyperlipidemia and MI presentation; and lower ejection fraction than that after routine FFR use. After routine FFR use, a higher number of patients in the CABG group had history of congestive heart failure and peripheral vascular disease; less hypertension; and lower weight and ejection fraction. After routine FFR use, more patients had hyperlipidemia, previous MI, previous congestive heart failure, peripheral vascular disease, and less hypertension than before routine FFR use ( Supplementary Table 1 ).

After PS matching, there were 488 and 314 matched pairs of patients between the CABG and PCI groups, before and after routine FFR use, respectively, and 915 matched pairs of patients before and after routine FFR use, with no significant differences between groups for any of the covariates ( Supplementary Tables 2 and 3 ). Revascularization was not performed in a total of 119 patients, the reasons for which are listed in Supplementary Table 4 . Procedural characteristics are shown in Figure 1 and listed in Supplementary Table 5 . Supplementary Figure 1 showed the summary of FFR-measured patients (lesions) and outcomes. FFR was measured in 323 patients and 450 lesions (15 before the routine FFR measurement and 308 after the routine FFR measurement). Of them, 64 patients were deferred without any revascularizations after FFR measurement. At 1 year, only 1 repeated revascularization occurred in deferred patients. Of the 259 patients (358 lesions) who received any revascularization after FFR measurement, 158 lesions were deferred and 191 lesions were revascularized (CABG was performed in 9 patients). At 1 year, 3 deaths (1 cardiac and 2 noncardiac death) occurred and repeated revascularizations occurred in 10 patients (12 lesions), of which only 3 repeated revascularizations were associated with deferred lesion after FFR measurement. Supplementary Table 6 demonstrated reasons for FFR not measured from 2010 to 2011. Tight stenosis (visual estimated diameter stenosis >80%) or total occlusion was the most frequent cause. After routine use of FFR, ∼92% were second-generation DES, and few and short stents were placed in each patient. In the CABG group, more conduits were used, and off-pump CABG was more frequently performed.

Complete 1-year follow-up data were obtained for 2,605 patients (99.7%). At 1-year follow-up, 64 patients (2.5%) died, of which 24 (0.9%) were cardiovascular-related deaths. Seven patients (0.3%) had an MI and 68 (2.6%) had a repeat revascularization.

Regarding clinical outcomes, unadjusted event rates are shown in Figure 3 and listed in Table 2 . Before routine FFR use, the rate of MACCE at 1 year was significantly higher in the PCI group, mainly because of the high rate of repeat revascularization. The composite of death, MI, and stroke was not significantly different between groups. However, there was no significant difference in the rates of MACCE and the composite of death, MI, and stroke at 1 year before and after routine FFR use. The repeat revascularization rate was still significantly higher in the PCI group, although it was reduced. The 1-year event rate in the medical therapy group was only 0% and 1.2% before and after the routine FFR use, respectively. Figure 4 and Table 3 summarizes the rates of clinical outcomes in the PS-matched population. The risks of MACCE and repeat revascularization were significantly higher in the PCI group before routine FFR use but did not differ significantly 1 year after the routine FFR use. The risk of composite of death, MI, or stroke was not significantly different between the PCI and CABG groups before and after FFR.

Kaplan-Meier curve for the composite of death, myocardial infarction, or repeat revascularization (A) , the composite of death, myocardial infarction, or stroke (B) , and repeat revascularization (C) in the CABG and PCI groups before and after routine use of FFR in the crude population.

Table 2

Clinical outcomes in the crude population at 1 year

Variables	Before Routine FFR (Year 2008–2009)			P-value	After Routine FFR (Year 2010–2011)			P-value
	CABG (N = 770)	PCI (N = 663)	Medical Therapy (N = 34)		CABG (N = 494)	PCI (N = 566)	Medical Therapy (N = 85)
MACCE ∗	36 (4.7%)	49 (7.4%) †	0	0.034	24 (4.9%)	30 (5.3%)	2 (2.4%)	0.50
Death	21 (2.7%)	13 (2.0%)	0	0.42	16 (3.2%)	13 (2.3%)	1 (1.2%)	0.43
Cardiac death	11 (1.4%)	7 (1.1%)	0	0.66	11 (2.2%)	10 (1.8%)	0	0.37
Noncardiac death	10 (1.3%)	5 (0.8%)	0	0.50	5 (1.0%)	3 (0.5%)	1 (1.2%)	0.61
Myocardial infarction	3 (0.4%)	0	0	0.26	2 (0.4%)	2 (0.4%)	0	0.84
Stroke	5 (0.6%)	1 (0.2%)	0	0.31	5 (1.0%)	1 (0.2%)	0	0.13
Repeat revascularization	8 (1.0%)	36 (5.5%) †	0	<0.001	4 (0.8%)	18 (3.2%) †	1 (1.2%)	0.021
Target vessel	8 (1.0%)	29 (4.4%)	–	<0.001	4 (0.8%)	13 (2.3%)	–	0.06
Target lesion	8 (1.0%)	27 (4.1%)	–	<0.001	4 (0.8%)	8 (1.4%)	–	0.36
New lesion	4 (0.5%)	9 (1.4%)	–	0.10	1 (0.2%)	11 (1.9%)	–	0.008
The composite of death, MI, or stroke	28 (3.6%)	13 (2.0%)	0	0.10	23 (4.7%)	15 (2.7%)	1 (1.2%)	0.10

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