As previously demonstrated [
8‐
12], iFR/FFR discordance was observed approximately 20% of cases in the present study. Despite such physiological differences, the 3V FFRFRIENDS study reported that clinical outcomes were similar among the discordant population of non-LMD [
25]. Conversely, a sub-analysis of the DEFNE-FLAIR study focusing only on LAD territory demonstrated that iFR-guided deferral was associated with significantly lower MACE as compared with FFR-guided deferral [
26]. Regarding hard event, more recent reports focusing on the pooled 5 year mortality in the DEFINE-FLAIR and iFR-SWEDEHEART trials demonstrated significantly higher mortality in the iFR-arm [
27,
28]. However, it was reported that the difference was not derived from the deferral group but from the revascularization group, which indicated that the value of epicardial coronary revascularization (
i.e. PCI and CABG) might be substantially different for the iFR- or FFR-positive patients despite guideline-based interchangeable recommendation [
29]. Furthermore, we have to recognize those trials fundamentally excluded LMD as well.
Accordingly, these conflicting reports provoke an even greater discussion in LMD because the LM stem subtends the largest myocardial territory in the coronary artery system [
30]. A recent report from the DEFINE-LM registry demonstrated that outcomes in patients of physiologically significant (iFR≤0.89) LMD treated by medical therapy alone were not clinically acceptable, even with contemporary optimal medical therapy (MACE: ∼30% in 4 years) [
3]. This study also suggested that a physiologically significant iFR should not be ignored regardless of reassuring results of other forms of ischemia assessment (
i.e. negative findings for significant ischemia on non-invasive testing, FFR, or intravascular ultrasound).
This latter point is further supported by the current analysis, which also suggests a higher predictive power of iFR
LM in deferred patients with LMD (Fig.
4A and Supplemental Fig. S2). Furthermore, the direct comparison of clinical outcomes in the log-rank test for the groups classified by iFR
LM and FFR
LM showed significantly higher event rates in iFR
LM-positive deferral group, though the sample size was relatively small to be conclusive (Supplemental Fig. S3). Accordingly, the present study demonstrates the importance of physiological assessment with iFR in the contemporary management of LMD (at least, prior to the FFR measurement). In our hypothetical insights, these differences in clinical outcomes might be attributed to the high rate of cardiovascular events of the deferred LMD as natural history [
11]. Given that coronary microvascular dysfunction is better correlated with the lower iFR than lower FFR [
31,
32], this was considered to be a potential mechanism for worse outcomes in the FFR-guided deferral patients in the previously reported sub-analysis of the DEFINE-FLAIR focusing on the LAD [
26]. Similarly, in the most proximal disease of the LMD subtending the largest myocardial territory [
30], the risk of cardiovascular events of the LMD with lower iFR and higher FFR would be enhanced by the influence of microvascular dysfunction, which would hamper the ability of maintaining cardiac system and could cause adverse cardiovascular events [
33]. In fact, the overall difference of AUC between iFR
LM and FFR
LM in the deferral group was mainly attributed to the different predictability for hard cardiovascular events (cardiac death and LM-MI) in the present study (Fig.
4). However, as mentioned above, comprehensive understandings for the different outcomes between iFR and FFR could not be easily explained by the single study. Therefore, deeper investigations for this topic (which might include LMD and non-LMD as well as the assessment of coronary microvascular dysfunction) would be necessary for the current body of knowledge.