Abstract
Background: The relationship between sex differences and long-term outcomes after fractional flow reserve (FFR)- and instantaneous wave-free ratio (iFR)-guided deferral of revascularization has yet to be elucidated.
Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on FFR in a multicenter registry), this study included 432 lesions from 385 patients (men, 323 lesions in 286 patients; women, 109 lesions in 99 patients) with paired data of FFR and iFR. The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. The median FFR value was lower in men than in women (0.85 [0.81, 0.88] vs. 0.87 [0.83, 0.91], P=0.002), but the iFR value was comparable between men and women (0.94 [0.90, 0.98] vs. 0.93 [0.89, 0.98], P=0.26). The frequency of discordance between FFR and iFR was comparable between men and women (19.5% vs. 23.9%, P=0.34), although with different discordance patterns (P=0.036). The cumulative incidence of 5-year TVF did not differ between men and women after adjustment for baseline characteristics (13.9% vs. 6.9%, adjusted hazard ratio 1.82 [95% confidence interval: 0.44–7.56]; P=0.41).
Conclusions: Despite sex differences in the results for physiological indexes, the 5-year TVF in deferred lesions did not differ between men and women after adjustment for baseline characteristics.
Invasive physiological indices for assessing epicardial coronary lesions have become widely used in clinical practice. Fractional flow reserve (FFR) is a standard physiological index and has been validated in numerous studies.1 Recently, the non-hyperemic pressure ratio, such as the instantaneous wave-free ratio (iFR), has been introduced and subsequent clinical trials have shown non-inferiority of an iFR-guided strategy to an FFR-guided strategy for 1- and 5-year outcomes.2–4 As such, the latest guidelines recommend both FFR and iFR assessment before revascularization unless there is objective evidence of ischemia.1,5
Previous studies have demonstrated that the FFR value is higher in women than men, regardless of similar stenosis severity,6–9 a result that could be primarily explained by sex differences in microvascular circulation, myocardial mass, coronary height, vessel size, plaque characteristics, and diastolic function.6–9 However, despite these differences potentially affecting the iFR value, a post hoc analysis of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate stenosis to guide Revascularization) study demonstrated that the iFR value did not differ between women and men, unlike FFR; the FFR-guided strategy was associated with a higher rate of revascularization in men but not in women.8 Notably, the FFR- and iFR-guided strategies showed comparable 1-year clinical outcomes in both sexes.8 That study’s results suggested the safety and efficacy of FFR and iFR assessment regardless of sex, but further investigations are required because paired FFR and iFR data for the same patient were unavailable. Also, whether sex differences would influence long-term outcomes after deferral of revascularization based on physiological assessment is not yet fully understood. The present study aimed to investigate the effect of sex differences on the results for physiological indexes (e.g., discordance between FFR and iFR) and long-term outcomes after deferring revascularization in patients with chronic coronary syndrome (CCS).
Methods
Study Population
This post hoc analysis of the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients with Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry; UMIN000014473), a prospective multicenter registry designed to investigate clinical outcomes of Japanese patients with deferral of revascularization based on FFR in real-world clinical practice. The study protocol and 2- and 5-year clinical outcomes have been previously described.10,11 In brief, the registry included 1,263 patients with 1,447 angiographically intermediate coronary artery lesions in whom revascularization was deferred based on FFR measurement at 28 Japanese centers (Supplementary Appendix). Patients with (1) acute myocardial infarction (AMI), (2) cardiogenic shock, (3) chronic total occlusion lesion, (4) graft lesion, or (5) limited life expectancy due to comorbidity were excluded. For the present study, we sought to enroll patients with paired FFR and iFR data at the index measurement. Those with unstable angina and CCS class III were also excluded from the present analysis. The study protocol was approved by the local ethics committee at all participating centers and was in accordance with the Declaration of Helsinki. All patients provided written informed consent.
Quantitative and Qualitative Angiographic Analyses
Coronary angiography was performed after intracoronary administration of 0.2 mg nitroglycerin. Quantitative and qualitative coronary angiographic analyses were performed in a core laboratory (ENDOCORE, Fukuoka, Japan) by independent analysts blinded to the clinical information. The lesion location was divided either into proximal (referred as segments 1, 2, 5, 6, 7, 11, and 13) or distal (3, 4, 8, 9, 12, 14, and 15) segments according to the American Heart Association classification.12
Physiological Assessment
A commercially available coronary pressure wire (Prestige, Volcano Ltd., Cordova, CA, USA) was used to measure physiologic indices. After administrating intracoronary nitrate (100 or 200 μg), the pressure sensor was positioned at the distal segment of the target lesion. Maximum hyperemia was induced by intravenous infusion of adenosine (150–180 μg) via the forearm or femoral vein or intracoronary injection of adenosine (40–80 μg), papaverine (8–12 mg), or nicorandil (2 mg). FFR was calculated as the ratio of the mean distal coronary pressure to the mean aortic pressure during maximum hyperemia. iFR was calculated as the ratio of the mean distal coronary pressure to the mean aortic pressure during the wave-free period.2–4
Study Endpoints and Definitions
The primary study endpoint was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel MI (TVMI), and clinically driven target vessel revascularization (CDTVR) on a lesion basis. Secondary endpoints included (1) individual outcomes of the primary endpoint on a lesion and patient basis and (2) 5-year TVF on a patient basis.12 Death was regarded as cardiac death unless other non-cardiac causes could be identified. MI was defined according to the Academic Research Consortium definition.12 TVR was defined as a repeated percutaneous coronary intervention (PCI) or repeated coronary artery bypass grafting on the target vessel. TVR was considered clinically indicated if (1) the angiographic percentage diameter stenosis (%DS) of the target lesion was ≥50% by qualitative coronary angiographic assessment, in the presence of ischemic signs or symptoms or (2) the %DS was ≥70 by qualitative coronary angiographic assessment, irrespective of ischemic signs or symptoms.12
Data Collection and Clinical Follow-up
All baseline and clinical follow-up data were prospectively collected using a dedicated electronic case report form. Site investigators at each institution obtained the data at outpatient clinic visits or by telephone contacts with the patients, relatives, or referring physicians at 12, 24, 36, 48 and 60 months after the index procedure. All clinical events were adjudicated by an independent clinical events committee.
Statistical Analysis
All results are expressed as median (lower and upper quartiles) for continuous variables with and without normal distribution. Continuous variables were compared between the groups using the unpaired t test or Mann-Whitney U test, based on the data distribution. Categorical variables were compared between groups with the chi-square test or Fisher’s exact test, as appropriate. Cumulative incidences of study endpoint after physiological assessment were estimated by the Kaplan-Meier method and compared by the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the men group relative to the women group for the outcome measures were estimated through a multivariable Cox model and an inverse probability weighted (IPW) Cox model with the clinically relevant variables listed in Tables 1 and 2 as covariates. Weights for the IPW methods were estimated through a logistic model for probabilities of the men group conditional on the same covariates. The marginal Cox proportional hazard regression was used in the per-lesion analysis to account for clustering of data obtained on multiple lesions within the same patient. The interaction effects between sex and the subgroup with FFR value (≤0.80 or >0.80), iFR value (≤0.89 or >0.89), age (≤70 or >70 years), diabetes mellitus, and %DS (≤50 or >50) were assessed for 5-year TVF.
Table 1.
Baseline Patient Characteristics
| |
Men
(n=286) |
Women
(n=99) |
P value |
| Age*, years |
70 (64, 77) |
73 (69, 78) |
<0.001 |
| Body mass index, kg/m2 |
24.3 (22.1, 26.4) |
23.1 (21.4, 25.9) |
0.085 |
| ≤22.0* |
69 (24) |
38 (38) |
0.009 |
| Hypertension* |
221 (77) |
71 (72) |
0.28 |
| Dyslipidemia* |
174 (61) |
71 (72) |
0.054 |
| Diabetes mellitus* |
116 (41) |
40 (40) |
1.0 |
| Current smoking* |
137 (48) |
9 (9.1) |
<0.001 |
| Hemodialysis* |
11 (3.8) |
4 (4.0) |
0.57 |
| Prior myocardial infarction* |
81 (28) |
15 (15) |
0.010 |
| Prior percutaneous coronary intervention* |
168 (59) |
42 (42) |
0.007 |
| Prior coronary artery bypass grafting* |
16 (5.6) |
1 (1.0) |
0.041 |
| Prior cerebrovascular disease* |
14 (4.9) |
10 (10) |
0.089 |
| CCS class |
|
|
0.69 |
| Asymptomatic |
112 (39) |
39 (39) |
|
| Class I |
149 (52) |
54 (55) |
|
| Class II |
25 (8.7) |
6 (6.1) |
|
| Left ventricular ejection fraction, % |
63 (52, 71) |
69 (63, 77) |
<0.001 |
| <40%* |
19/226 (8.4) |
0/79 (0) |
0.003 |
| Baseline medications |
| Aspirin* |
223 (78) |
69 (70) |
0.10 |
| P2Y12 inhibitor* |
177 (62) |
49 (50) |
0.034 |
| Anticoagulant |
37 (13) |
5 (5.1) |
0.038 |
| Calcium channel blocker |
149 (52) |
60 (61) |
0.16 |
| ACEi/ARB* |
162 (57) |
44 (44) |
0.047 |
| β-blocker* |
83 (29) |
19 (19) |
0.064 |
| Insulin |
13 (4.5) |
3 (3.0) |
0.38 |
| Oral hypoglycemic agent |
90 (32) |
28 (28) |
0.61 |
| Statin* |
156 (55) |
65 (66) |
0.060 |
| Nitrous acid |
70 (25) |
24 (24) |
1.0 |
Data are expressed as median (lower and upper quartiles) or number (%). *Variables used for multivariable and inverse provability weighted Cox models comparing hazard ratios of male and female patients for the study endpoints (see Table 3). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCS, Canadian Cardiovascular Society.
Table 2.
Lesion and Procedural Characteristics
| |
Men
(n=323) |
Women
(n=109) |
P value |
| Physiological indices |
| Fractional flow reserve* |
0.85 (0.81, 0.88) |
0.87 (0.83, 0.91) |
0.002 |
| Instantaneous wave-free ratio* |
0.94 (0.90, 0.98) |
0.93 (0.89, 0.98) |
0.26 |
| Target vessel* |
| Left main coronary artery |
13 (4.0) |
0 (0) |
0.045 |
| Left anterior descending coronary artery |
164 (51) |
61 (56) |
0.38 |
| Left circumflex artery |
60 (19) |
21 (19) |
0.89 |
| Right coronary artery |
88 (27) |
27 (25) |
0.71 |
| Bifurcation lesion* |
99 (32) |
32 (30) |
0.81 |
| Calcified lesion* |
60 (19) |
27 (25) |
0.22 |
| Tortuous lesion* |
55 (18) |
21 (19) |
0.66 |
| ACC/AHA type |
| A/B1/B2*/C* |
29 (9)/83 (26)/
143 (44)/68 (21) |
12 (11)/24 (22)/
49 (45)/24 (22) |
0.84 |
| In-stent restenosis* |
22 (6.8) |
7 (6.4) |
1.0 |
| QCA data |
| Reference vessel diameter, mm |
2.77 (2.43, 3.31) |
2.64 (2.21, 3.00) |
0.026 |
| ≤2.5 mm* |
104 (34) |
43 (41) |
0.24 |
| Minimum lumen diameter, mm |
1.55 (1.28, 1.85) |
1.53 (1.27, 1.84) |
0.35 |
| Diameter stenosis, % |
45 (36, 52) |
42 (33, 52) |
0.17 |
| ≥50%* |
96 (32) |
30 (29) |
0.63 |
| Lesion length, mm |
11.1 (9.0, 14.2) |
10.0 (8.8, 14.9) |
0.58 |
| ≥20 mm* |
18 (6) |
10 (9) |
0.26 |
Data are expressed as median (lower and upper quartiles) or number (%). *Variables used for multivariable and inverse provability weighted Cox models comparing hazard ratios of men and women for the study endpoints (see Table 3). ACC/AHA, American College of Cardiology/American Heart Association; QCA, quantitative coronary angiography.
All statistical analyses were performed by 2 physicians (T.I. and S.K.) using the IBM SPSS Statistics package ver. 26 (IBM Corp., Armonk, NY, USA) and R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org). All inferential statistics were accompanied by 2-sided P values to indicate incompatibility with null associations.
Results
Study Population
After excluding 878 patients (no iFR data, n=862; unstable angina, n=12; CCS class III, n=4), 385 patients (men, n=286; women, n=99) were enrolled (Supplementary Figure 1). The 5-year clinical follow-up was completed in 94.6% of patients.
Baseline Clinical Characteristics
Baseline patient characteristics are shown in Table 1. Men were older, with a higher prevalence of current smoking, prior MI, and prior PCI. In terms of lesion and procedural characteristics, reference vessel diameter and minimum lumen diameter were significantly larger in men than women, whereas %DS did not differ between the 2 groups (Table 2).
Physiological Results
The median FFR value was lower in men than in women (0.85 [0.81, 0.89] vs. 0.87 [0.83, 0.91], P=0.003), especially in lesions with %DS <50% (0.84 [0.81, 0.89] vs. 0.86 [0.83, 0.91], P=0.017). In contrast, the median iFR value did not differ between men and women (0.94 [0.90, 0.98] vs. 0.93 [0.89, 0.98], P=0.26), regardless of the %DS (Table 2, Figure 1). Figure 2 demonstrates the distribution of lesions according to physiological indexes and sex. The frequency of discordance between FFR and iFR was comparable between men and women (19.5% vs. 23.9%, P=0.34), and the FFR+/iFR− and the FFR−/iFR+ patterns were dominant in men and women, respectively. The FFR/iFR discordant pattern was significantly different between men and women (P=0.036).
Clinical Events of Deferred Lesions
Cumulative 5-year incidence of TVF was numerically higher in men than in women but did not reach statistical significance after adjustment for baseline characteristics (13.9% vs. 6.9%; IPW-adjusted HR 3.05 [95% CI: 0.60–15.4], P=0.18) (Table 3, Figure 3). Cardiac death, CDTVR, and TVMI did not differ between men and women (Table 3, Figure 3). Also, similar outcomes were observed on a patient level (Supplementary Table, Supplementary Figure 2). Figure 4 shows the subgroup analysis of the effect of sex differences on 5-year TVF. In lesions with %DS <50%, female sex tended to be associated with a lower risk of TVF, but not with statistical significance for the interaction term. Regardless of the concordance and discordance between FFR and iFR, 5-year TVF did not differ between men and women (13.2% vs. 6.6%, P=0.099; 16.3% vs. 8.0%, P=0.27, respectively) (Supplementary Figure 3). In addition, the 1-year land-mark analyses of TVF and CDTVR are shown in Supplementary Figure 4. The cumulative incidence of any revascularization was numerically higher in men than in women, but did not reach statistical significance (Supplementary Figure 5).
Table 3.
Adjusted Risk of Clinical Events Through 5 Years
| Outcomes |
Cumulative 5-year
incidence |
Crude HR |
Multivariable
adjustment† |
IPW adjustment† |
| Men |
Women |
HR (95% CI) |
P value |
HR (95% CI) |
P value |
HR (95% CI) |
P value |
| TVF |
13.9% |
6.9% |
2.18
(0.98–4.85) |
0.056 |
1.82
(0.44–7.56) |
0.41 |
3.05
(0.60–15.4) |
0.18 |
| Cardiac death |
1.3% |
2.1% |
0.65
(0.12–3.67) |
0.67 |
1.00
(0.043–23.3) |
1.00 |
1.50
(0.13–17.7) |
0.75 |
| CDTVR |
12.8% |
6.9% |
2.01
(0.90–4.50) |
0.088 |
1.35
(0.38–4.85) |
0.65 |
2.34
(0.59–9.52) |
0.23 |
| TVMI |
0.9% |
2.0% |
0.46
(0.085–3.03) |
0.46 |
0.53
(0.004–74.7) |
0.80 |
0.28
(0.036–2.12) |
0.22 |
*Based on robust sandwich variance estimates that cluster lesions within the same patients.†
Adjusted for covariates listed in Tables 1 and 2 as regressors of multivariable Cox and inverse probability weighted models. CDTVR, clinically driven target vessel revascularization; CI, confidence interval; HR, hazard ratio; IPW, inverse probability weighting; TVF, target vessel failure; TVMI, target vessel-related myocardial infarction.
Discussion
The main findings of the present study can be summarized as follows: (1) the median FFR value was higher in women than in men, whereas the median iFR value was comparable between men and women; (2) the cumulative 5-year incidence of TVF did not differ between men and women after adjustment for baseline characteristics; and (3) the FFR/iFR discordant pattern was different between men and women (Figure 5).
FFR is a standard invasive method to evaluate the functional significance of epicardial coronary artery stenosis.1 Previous studies report that the FFR value is higher in men than in women with the same stenosis severity.6–9 The underlying mechanism of this phenomenon includes a higher resting coronary flow, a smaller cardiac mass, and less high-risk coronary plaque in women than in men.6–9 In the present study, the median FFR value was higher in women than in men, especially when %DS was <50. Consistently, Hoshino et al reported that the median FFR value was significantly higher in women than in men in lesions with %DS <50, but did not differ in those with %DS ≥50.13 In contrast to FFR, the median iFR value was comparable between men and women, irrespective of the coronary stenosis severity, which was in line with previous studies.8,13 A potential explanation for these differences is that hyperemic coronary flow might be relatively lower in women than men due to the smaller cardiac mass and higher resting coronary flow,6–9 although the present study could not evaluate this. Our results highlighted sex differences in the relationship between angiographic stenosis severity and physiological indexes (i.e., FFR and iFR).
Despite the different number of functionally significant lesions per patient, FFR and iFR-guided strategies have demonstrated comparable 1-year outcomes in men and women.8 Similarly, the subanalysis of the FAME (FFR versus Angiography for Multivessel Evaluation) study showed that although women had a lower proportion of functionally significant lesions, a FFR-guided strategy equally reduced 2-year major adverse cardiac events in men and women as compared with an angiography-guided strategy.6 Those findings indicated that sex differences in the proportion of functionally significant lesions might not contribute to clinical outcomes. However, little evidence is available regarding the clinical effect of sex differences on long-term (>2 years) outcomes after FFR-guided deferral of revascularization. The current study demonstrated that the cumulative 5-year incidence of TVF was numerically higher in men than women but did not reach statistical significance after adjustment for baseline characteristics, regardless of the FFR values (>0.80 or ≤0.80). A similar trend was observed in the cumulative incidence of any revascularization. Meanwhile, a previous study reported that the incidence of a 5-year patient-oriented composite outcome (i.e., all-cause death, any MI, and any revascularization) after FFR-guided deferral of revascularization was higher in men than in women among patients with FFR >0.80; the any revascularization rate was significantly higher in men than women, mainly derived from non-target vessels.13 These differences might be partially explained by the fact that (1) the present study population consisted solely of Japanese subjects; (2) the previous study included non-culprit lesions of acute coronary syndrome; and (3) the previous study had a higher prevalence of multivessel disease than the present study. Nevertheless, given both studies were retrospectively conducted, the results should be considered inconclusive. Randomized controlled trials are mandatory to assess the long-term clinical outcomes after FFR-guided deferral of revascularization between men and women.
In a post hoc analysis of the DEFINE-FLAIR study, FFR- and iFR-guided strategies showed comparable outcomes at 1 year between men and women, although with sex differences in the revascularization rate in the FFR group.8 Meanwhile, whether sex differences would affect the long-term outcome after iFR-guided deferral of revascularization is still unclear. The present study demonstrated that the 5-year TVF rate after deferral of revascularization was numerically higher in men than women, regardless of the iFR values (>0.89 or ≤0.89); the subgroup analysis did not show a significant interaction between sex and iFR. These differences might be explained by the fact that the present study did not include patients who underwent revascularization based on FFR or iFR. Indeed, previous studies reported comparable outcomes of FFR- and iFR-guided revascularization between men and women, possibly due to recent advances in PCI techniques and medical devices.6,8 Because the revascularization decision-making was based on FFR in the present study, the effect of sex on long-term outcomes of iFR-guided strategy should be addressed as soon as possible.
Discordance between FFR and iFR is observed in ≈20% of cases, primarily caused by differences in coronary flow reserve (CFR) between the 2 indexes.14–16 Although the index of microcirculatory resistance is similar between men and women, CFR is lower in women than in men due to their higher resting blood flow.15 The current study demonstrated that the FFR+/iFR− and FFR−/iFR+ patterns were dominant in men and women, respectively, in line with the previous study.16 Recently, Lee et al reported that discordant lesions were associated with a higher incidence of cardiac events after deferring revascularization than concordant lesions at 5 years.17 However, the effect of sex differences on the long-term outcomes in concordant and discordant lesions has not been thoroughly investigated. In the current study, 5-year TVF was numerically higher but not statistically significant in men than in women, irrespective of concordant or discordant lesions. Given that these results should be interpreted cautiously because of the small study population, we need more clinical data to assess the clinical effect of sex differences in discordant lesions.
Study Limitations
There are several limitations to note. First, this was a post hoc analysis of the J-CONFIRM registry. In addition, iFR was measured only in 31% of patients in this registry. Although we performed multivariable and IPW Cox models to adjust for differences in baseline characteristics between groups, the potential of bias is inevitable, which might have affected the conclusions. Second, we did not evaluate microcirculatory functions such as CFR and microvascular resistance. Third, our results do not apply to patients with acute coronary syndrome because all patients presented with CCS in this study. Fourth, the present study population was relatively small, so our results should be considered hypothesis-generating. Further studies are necessary to investigate the association between sex differences and long-term outcomes after deferral of revascularization based on physiological indexes (FFR and iFR). Finally, extrapolating our results outside Japan requires caution because the study population consisted solely of Japanese subjects.
Conclusions
Sex differences affected the results for physiological indexes in Japanese patients with CCS. However, the 5-year TVF in deferred lesions did not differ between men and women after adjustment for baseline clinical characteristics.
Acknowledgment
We appreciate the efforts of the investigators in the 28 participating centers.
Funding Sources
This work was supported by Abbott Vascular Japan, Phillips Japan, and Boston Scientific Japan.
Disclosures
S.K. receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan; H.M. serves as advisory board member for Zeon Medical and receives lecture fees from Abbott Vascular Japan, Boston Scientific Japan, and Phillips Japan; Y.K. receives lecture fees from Abbott Vascular Japan and Phillips Japan; Y.S. receives lecture fees from Abbott Vascular Japan and Phillips Japan; T.A. receives lecture fees from Abbott Vascular Japan and Phillips Japan; N.T. serves as advisory board member for Abbott Vascular Japan and Boston Scientific Japan; H.Y. receives lecture fees from Boston Scientific Japan. K.T. is a member of Circulation Reports’ Editorial Team. The other authors report no conflicts.
IRB Information
This study was approved by the Institutional Review Board of Kokura Memorial Hospital (Reference no. 18041151).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-23-0100
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