Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment

Background Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR). Objectives The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial. Methods MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex. Results A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06). Conclusions iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral.

T he instantaneous wave-free ratio (iFR) (1) is an index of stenosis severity that has been demonstrated to be noninferior to fractional flow reserve (FFR) when guiding coronary revascularization (2,3). iFR does not require adenosine and can be performed in a significantly shorter time than FFR (2). In the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) study, iFR was found to defer revascularization in a significantly higher proportion of patients (2). Although iFR was found to be    Before physiological measurements were made, intracoronary nitrates were administered to control vasomotor tone. FFR and iFR measurements were then performed in all appropriate vessels in the routine manner using a coronary pressure guidewire.
Pre-specified treatment cutpoints were an FFR of 0.80 and an iFR of 0.89. Revascularization was performed when the physiological value was equal to or lower than these pre-specified thresholds, and revascularization was deferred when it was above these thresholds.
LAD territory patients are defined as patients undergoing physiological assessment, which included LAD assessment in which the LAD was deferred based on the iFR or FFR measurement ( Figure 1). Non-LAD territory patients are defined as patients undergoing physiological assessment that did not include LAD assessment in which intervention was deferred in at  Revascularization was considered to be unplanned when it was not the index procedure and was not identified at the time of the index procedure as a staged procedure to occur within 60 days. Additionally, unplanned revascularization required symptoms consistent with ischemia. All events were independently adjudicated.
STATISTICAL ANALYSIS. The objective of this study was to compare event rates between physiology techniques (iFR vs. FFR) in patients for whom revascularization was deferred, separately in LAD territory patients and non-LAD territory patients.
Baseline and procedural characteristics of patients were analyzed in the following manner. Categorical and binary variables were compared between groups using chi-square tests. Continuous variables were compared using Student's t-test, or Wilcoxon signedrank test in case of non-normal distributions.
For MACE and its components, a time-to-event analysis was performed by Cox survival modeling.
Participants who withdrew from the study before reaching 1 year of follow-up and who were event-free at their last visit were censored at their time of last visit. Testing of validity of proportional hazard assumption was done using Schoenfeld residuals.
There were no signs of violations of proportional hazards assumption.
Results are reported using hazard ratios (HRs), 95% 2-sided confidence intervals (CIs) and cumulative hazard curves. Analyses were performed in an unadjusted manner. In addition, adjustment for age and sex was performed. Indeed, despite randomization at the trial level, sex was found to be imbalanced between iFR and FFR groups in this study of deferred patients. Moreover, iFR patients were slightly younger than FFR patients, although this difference did not reach statistical significance. Results are presented as adjusted for age and sex in text, and both as unadjusted and adjusted in the tables.    Abbreviations as in Table 1. Bar charts outlining clinical events in patients with LAD stenoses deferred on the basis of intracoronary physiology. The orange bars denote patients whose treatment was guided by iFR, and the blue bars denote patients whose treatment was guided by FFR. iFR-guided deferral was associated with significantly lower rates of unplanned revascularization (right, p ¼ 0.03). This was driven by numerically greater rates of target vessel revascularization with FFR (p ¼ 0.06). iFR-guided deferral was associated with numerically lower rates of myocardial infarction (MI) (left, p ¼ 0.06). This was driven by numerically greater rates of target vessel MI with FFR (p ¼ 0.08). There was no difference in periprocedural MI (p ¼ 1.00). Abbreviations as in Figure 1.   FFR has been previously studied in this distribution of patients, there has been some concern as to its safety and, therefore, utility in guiding revascularization (11).

RESULTS
Within DEFINE-FLAIR, in non-LAD lesions, FFRguided deferral had similar outcomes to iFR-guided deferral. For LAD lesions, there was a trend toward better outcomes in those with iFR-guided deferral than those with FFR-guided deferral. The difference Sen et al.   Figure 1. The same could also apply to iFR; however, the agreement between iFR and CFR has been demonstrated to be significantly closer than that of FFR and CFR (17). Therefore, the proportion of patients in whom iFR is normal and CFR abnormal is lower, possibly explaining the lower event rate in the iFR-deferred patients (15).
iFR-BASED DEFERRAL. Physicians are correct to question the safety of any technique proposed as an alternative to one that is accepted as safe. The LAD has been highlighted as a territory in which reliance on nonhyperemic indexes may be particularly dangerous (5,6). This is because the LAD supplies a large amount of myocardium, and any index of stenosis severity will need to also reflect the amount of