In this large, core laboratory–based analysis, the overall linear correlation between both iFR and Pd/Pa and FFR was moderate (R = 0.66 and 0.69, respectively), with an overall diagnostic accuracy of ~80% for both nonhyperemic indices (using the optimal ROC-determined cutoff points of 0.90 and 0.92 to predict an FFR ≤0.80). The diagnostic accuracy was independent of vessel, embedded versus core laboratory–generated ECG gating signal, use of intravenous versus intracoronary adenosine to induce hyperemia, and clinical site. Accepting FFR as the reference method (in the absence of outcome studies with iFR or Pd/Pa), this level of accuracy is insufficient to use either parameter for procedural guidance in all cases because ~20% of therapeutic decisions would be discordant from FFR.
Although iFR and Pd/Pa are imperfect surrogates of FFR close to the clinically used cutoff value of 0.80, they may still provide acceptable accuracy at greater or lesser degrees of functional stenosis severity. The fundamental principle of FFR, justifying pressure-derived estimation of coronary flow impairment, is that the translesional pressure ratio approximates flow when microvascular resistance is minimized, requiring the use of a potent vasodilator. However, microvascular resistance is influenced by many factors, including capacitive, inertial, and resistive forces as well as the complex effects of systolic contraction. Nonhyperemic pressure ratios may theoretically have adequate concordance with hyperemic pressure measurements when there is a large baseline gradient (i.e., obvious impairment of coronary flow) or no gradient at all (i.e., absence of any resting flow disturbance). In this regard, a recent retrospective analysis of almost 500 patients demonstrated a good correlation between Pd/Pa and FFR with an area under the curve of 0.86. When only translesional resting pressure ratios of <0.88 and >0.95 were considered, the PPV and NPV increased to >95%, with more than half of the study population falling in these categories. The present larger, multicenter, core laboratory–based analysis shows that if 90% accuracy compared with the FFR reference standard is accepted at the margins (the pre-specified precision limit for therapeutic interchangeability in the present study), use of iFR and Pd/Pa might avoid hyperemia in 65% and 48% of lesions, respectively. If 95% accuracy is required, however, use of iFR and Pd/Pa might avoid hyperemia in only 29% and 36% of lesions, respectively. In addition, the percentage of lesions falling into the adenosine-free zone will vary based on the spectrum of lesions being studied. If only intermediate lesions are investigated (i.e., with an FFR near 0.80 in a greater proportion of patients), the adenosine-free zone may be smaller compared with the findings of the current study.
A secondary goal of the present study was to compare and contrast iFR and Pd/Pa. By restricting measurements to a specific segment of diastole in which the maximum achievable coronary flow occurs during resting conditions, iFR has a theoretical advantage compared with Pd/Pa. However, using FFR as the reference standard, we found no significant differences between iFR and Pd/Pa with respect to sensitivity, specificity, PPV, NPV, or diagnostic accuracy. Although modest differences were noted between the iFR and Pd/Pa versus FFR regression patterns, the overall similar results are consistent with a prior retrospective analysis by Johnson et al.. Prospective studies are required to determine whether the differences between iFR and Pd/Pa are practically or clinically relevant.
The present study has several strengths but also some limitations. Prior studies examining the relationship between iFR, Pd/Pa, and FFR showed significant variability and thus reached strikingly different conclusions. In this regard, it is reassuring to note that by applying a rigorous study methodology, common inclusion and exclusion criteria, and a standardized physiology assessment methodology, the data from these prior studies showed relatively little variation, with diagnostic accuracy ranging from 79% to 83%. We have applied linear models to our data, although the complete physiological relationship between FFR and iFR or rest Pd/Pa may best be described by a curvilinear relationship. RESOLVE is the first coronary physiology study that used a core laboratory for analysis of hyperemic and resting pressure–derived indices of the severity of stenosis. Surprisingly, 19% of measurements were found to be suboptimal and were excluded from the analysis (perhaps explaining the reduced site-to-site variability in the present report compared with previously reported individual studies). Future clinical trials should consider including core laboratory analysis to assess the validity of hemodynamic measurements, as is currently the standard for quantitative coronary angiography and intravascular ultrasonography. An additional strength is the size of the present study, encompassing all iFR studies published to date as well as several nonpublished clinical experiences, which provides incremental power to accurately locate point estimates while reducing CI width and affording subgroup analysis. However, the present retrospective analysis is limited by nonuniform patient and lesion characteristics at each site and varying FFR acquisition protocols. Despite the fact that all studies underwent rigorous analysis by an independent core laboratory to eliminate potential erroneous measurements and minimize variability, we cannot fully exclude selection bias and other sources of inconsistencies. A final pullback of the pressure wire into the guiding catheter confirming the absence of pressure drift was not required and was performed in only a small minority of cases.
As with any diagnostic test FFR, iFR and Pd/Pa have inherent variability. On the basis of 3 randomized trials showing superior clinical outcomes with FFR guidance compared with angiographic guidance alone, FFR is justifiably accepted as the standard in both US and European guidelines for invasive physiological lesion assessment and clinical decision making. On the basis of the present report and consistent with prior studies, the universal adoption of iFR or Pd/Pa with use of a single cutoff point cannot be recommended. However, using a hybrid approach wherein Pd/Pa or iFR are accepted at the 2 outer tails of the spectrum with FFR-based decisions required in the gray area in between may be feasible and might avoid the use of hyperemia in approximately 48% to 65% of lesions, respectively, if ≥90% correlation with an FFR cutoff ≤0.80 is accepted. Although there will always be a trade-off for greater diagnostic accuracy (e.g., if >99% accuracy compared with FFR is desired, the adenosine-free zone would shrink to <20% of patients), a small (≤10%) degree in variability between nonhyperemic physiological measurements and FFR in a large proportion of patients may be acceptable to many physicians in daily clinical practice given the cost, inconvenience, and potential side effects associated with administration of adenosine and the relatively low major adverse cardiac event rate around the FFR 0.80 cut point, where most classification errors are likely to occur. However, the iFR and Pd/Pa cutoff values identified in the present retrospective study require validation, and prospective randomized trials are required to determine whether a hybrid strategy results in noninferior clinical outcomes to the routine use of FFR.