Physiologic Lesion Assessment to Optimize Multivessel Disease

Purpose of Review Multivessel coronary artery disease, defined as significant stenosis in two or more major coronary arteries, is associated with high morbidity and mortality. The diagnosis and treatment of multivessel disease have evolved in the PCI era from solely a visual estimation of ischemic risk to a functional evaluation during angiography. This review summarizes the evidence and discusses the commonly used methods of multivessel coronary artery stenosis physiologic assessment. Recent Findings While FFR remains the gold standard in coronary physiologic assessment, several pressure-wire-based non-hyperemic indices of functional stenosis have been developed and validated as well as wire-free angiographically derived quantitative flow ratio. Identifying and treating functionally significant coronary atherosclerotic lesions reduce symptoms and major adverse cardiovascular events. Summary Coronary physiologic assessment in multivessel disease minimizes the observer bias in visual estimates of stenosis, changes clinical management, and improves patient outcomes.


Introduction
Since its inception, coronary angiography has been a standard for the diagnosis and management of coronary artery disease. Multivessel coronary artery disease, defined as significant stenosis in two or more major coronary arteries, is associated with the highest morbidity and mortality. Significant lesions are denoted visually by 70% luminal diameter narrowing on angiography. However, visual stenosis assessment is plagued by interobserver variability and imprecision. Operators cannot accurately predict physiologic significance, especially for intermediate lesions in the range of 50 to 70% diameter stenosis ( Fig. 1) [1,2]. Moreover, treating functionally significant coronary atherosclerotic lesions reduces major adverse cardiovascular events (MACE) and symptoms [3][4][5]. Thus, the focus of this review is to summarize the evidence and commonly used methods for physiologic assessment of multivessel disease.

Types of Physiologic Assessment
Although fractional flow reserve (FFR) is the gold standard in invasive physiologic assessment of coronary stenosis, it remains underutilized due to several factors including operator reluctance to delay procedures, hospital costs, conceptual skepticism, and side effects of hyperemic pharmacologic agents. Non-hyperemic pressure ratios (NHPR) using the resting distal/aortic pressure over either the whole cardiac cycle or confined to diastole only were developed as an alternative to FFR (Fig. 2, Table 1). The simplest of the NHPRs is the resting pressure ratio of the mean distal/ aortic pressure over the whole cardiac cycle, Pd/Pa, which has an 80-85% concordance with FFR using a threshold value of ≤ 0.91 [6]. Further refining the NHPR measurements, the first diastolic sub-cycle index, the instantaneous wave-free ratio (iFR), has been supported by large randomized clinical studies showing non-inferiority to FFR for physiology-guided revascularization [7]. As one might expect in comparison to FFR, omitting adenosine for routine iFR use results in reduced patient discomfort, time, and cost [8,9]. Newer NHPR methodologies like resting full-cycle ratio (RFR™, Abbott), diastolic hyperemia-free ratio (DFR™, Boston Scientific), and diastolic pressure ratio (dPR™, Acist and Opsens Medical) have been found to be numerically identical to iFR and thus interchangeable for clinical use (Fig. 3) [10][11][12].

Rationale for Physiologic Assessment of Coronary Stenoses
Given that myocardial ischemia is an important prognostic factor for patients with coronary artery disease [13], defining ischemia-causing stenosis is critical, particularly in patients with multivessel disease. However, because of the complexity of anatomy and overlap of ischemic territories and other factors, angiographic and nuclear stress imaging assessment in patients with multivessel disease often cannot discern which lesions are important nor identify the degree of myocardial ischemia present. Defining ischemia-causing stenosis not only changes patient management strategies but also impacts clinical outcomes.
Improved outcomes have been associated with physiological assessment for multivessel coronary artery disease ( Table 2). For example, in a 5-year follow-up to the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study, major adverse cardiovascular events in the FFR-guided and angiography-guided PCI groups were similar (28% vs 31%, relative risk 0.91, 95% CI 0.75-1.10; p = 0.31) despite a higher number of stents placed in the angiography group, suggesting that a similar outcome can be achieved with fewer stents used selectively for lesions of hemodynamic significance [14]. The FAME 2 trial aimed to clarify if FFR-guided PCI in addition to optimal medical therapy is superior to optimal medical therapy alone for patients with stable coronary artery disease, with multivessel disease consisting of 26% and 22% of patients, respectively. [15] Not only was the trial stopped prematurely due to a significantly lower rate of death, myocardial infarction, or urgent revascularization in the FFR-guided PCI group  Non-hyperemic pressure ratio derivations. Instantaneous wavefree ratio (iFR) is defined as average Pd/Pa during the wave-free period (WFP) (pink shaded area). The WFP was calculated beginning 25% of the way into diastole and ending 5 ms before the end of diastole. Diastolic pressure ratio (dPR) is defined as average Pd/Pa during entire diastole. Diastolic hyperemia-free ratio (DFR) is defined as average Pd/Pa during Pa less than mean Pa with negative slope. Resting full-cycle ratio (RFR) is defined as the lowest filtered mean Pd/Pa during the entire cardiac cycle (adapted from Kogame et al. J Am Coll Cardiol Intv 2020;13:1617-1638, with permission from Elsevier) [54] of the study at 2 years but these results were sustained at 5 years. [16••] Further evidence of improved outcomes was observed in the SYNTAX II trial, which was a comprehensive strategy of three-vessel disease management using the SYNTAX Score II, iFR/FFR-guided revascularization, and intravascular ultrasound-guided implantation. Results showed reduced major adverse cardiac and cerebrovascular events compared to PCI performed in comparable patients from the SYNTAX I trial (HR 0.58, 95% CI 0.39-0.85, P = 0.006) [17].
Based on physiologic assessment, changes in patient management (medical vs PCI vs CABG) may explain the In the 3 V-FFR FRIENDS (3-Vessel Fractional Flow Reserve for the Assessment of Total Stenosis Burden and Its Clinical Impact in Patients with Coronary Artery Disease) study, Lee and colleagues routinely examined 3-vessel FFR measurements (i.e., summed FFR of three major vessels) in patients with multivessel disease to understand the influence of total atherosclerotic burden on clinical outcomes. Patients with high total physiologic atherosclerotic burden (defined as a low 3 V-FFR value < 2.72) were associated with a higher MACE at 2 years compared to low total physiologic atherosclerotic burden (defined as a high 3 V-FFR value ≥ 2.72), which was mainly a result of higher rate of ischemia-driven revascularization [22]. In a subset of patients identified to have insignificant angiographic stenosis (percentage of diameter stenosis < 50% by visual assessment) with deferred intervention (8.7% of study group), those patients with lesions having a low FFR (≤ 0.80) showed a significantly higher risk of MACE compared to patients with a high FFR (> 0.80) at 2 years (3.3% versus 1.2%, hazard ratio: 3.371; 95% CI, 1.346-8.442; P = 0.009) [23]. Low FFR and iFR  [54] were both associated with future risk of MACE in deferred lesions [24].

STEMI and Non-culprit Physiologic Assessment
For patients with STEMI and multivessel disease, a commonly raised question is whether revascularization should be directed at the culprit only or at all significant stenoses during or soon after the index procedure. Most studies evaluating complete revascularization in STEMI patients used visualization estimates from coronary angiography regarding lesion severity for decision-making. The first two trials to incorporate routine FFR-guided revascularization were the DANAMI-3-PRIMULTI and COMPARE-ACUTE trials. In the DANAMI-3-PRIMULTI trial, patients presenting with STEMI who had more than one visually significant stenosis in the non-infarct-related artery underwent randomization to no further therapy or FFR-guided completed revascularization during index hospitalization. While there was a significant reduction in future revascularization procedures, there was no difference in all-cause mortality or non-fatal myocardial infarciton [25]. The COMPARE-ACUTE trial (Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction) found a lower risk of MACE or cerebrovascular events in the FFR-guided group driven primarily by a lower risk of revascularization [26], reaching the same conclusion as the prior trial. After the release of this study's results in 2017, the European Society of Cardiology guidelines subsequently recommended that PCI for non-culprit lesions should be considered (class IIa) for the treatment of patients with STEMI and multivessel disease [27]. Subsequent evaluation in the COMPELTE trial demonstrated consistent results with previous trials of reduced risk of cardiovascular death or myocardial infarction, granted that physiologic lesion assessment was limited to intermediate lesions which consisted of < 1% of non-culprit lesion stenosis [28]. With these results, FFR-guided complete revascularization may not necessarily improve death and myocardial infarction but likely reduce repeat revascularization, suggesting indirect beneficial effects on quality of life and healthcare cost-utility.
Contrary to the aforementioned trials, the FLOWER-MI (Flow Evaluation to Guide Revascularization in Multivessel ST Elevation Myocardial Infarction) trial suggested that a FFR-guided strategy did not significantly reduce outcomes of death, MI, or urgent revascularization when compared to angiography-guided revascularization strategy. [29] However, the observed event rates in both arms of the study were much lower than expected, underpowering the study, resulting in a wide confidence interval, and leading to inconclusive results.
Given the conflicting results of studies in this specific population, questions regarding the true value of FFR in the acute coronary syndrome population have arisen. The FFR guidance for complete non-culprit revascularization (Full-Revasc) trial is a large, multi-center, randomized clinical trial designed to evaluate the effect of FFR-guided complete revascularization of non-culprit lesions during index hospitalization on total mortality, non-fatal MI, and unplanned revascularization. Enrollment completed in September 2019 and the follow-up is still ongoing [30•]. Additionally, the iFR-guided multivessel revascularization during percutaneous coronary intervention for acute myocardial infarction (iMODERN) trial is ongoing and will compare an iFRguided intervention of non-culprit lesions during acute intervention with a deferred stress perfusion CMR-guided strategy [31].

Diffuse Disease and Serial Lesion Physiologic Assessment
Advanced atherosclerotic coronary disease often presents as diffuse and/or serial lesions which complicates simple physiologic assessment. In serial or tandem lesions, individual stenosis FFR cannot be determined because of lesion interaction and limited maximal lesion hyperemia. The contribution of each lesion to the total resistance during maximal hyperemia can be challenging to deconstruct and measure by FFR. In contrast, NHPRs, like iFR, do not require hyperemia and theoretically do not have as much lesion interaction. Performing a pressure-wire pullback study can superimpose iFR on the angiogram to create a blueprint of functionally significant coronary stenosis, differentiating diffuse from focal disease (Fig. 4). For diffuse disease, the distributed pressure gradient may be gradual along the entire vessel whereas focal areas of sharp pressure change identify the most physiologically discrete lesions. Stent placement in these specific areas may maximize post-PCI blood flow with the appropriate amount of stent usage. Compared with angiography alone, iFR pullback altered revascularization procedural planning in 31% of patients [32••, 33]. In addition, iFR pullback recordings that identified predominantly physiologically focal versus diffuse disease was an important factor for FFR/iFR discordance, with focal disease associated with FFR + /iFR-and diffuse disease associated with FFR-/iFR + results [34•]. Hyperemic pressure pullback gradient, a metric of pressure drop over 20 mm measured by a pressure-wire pullback device with a set speed of 1 mm/s, can also characterize pathophysiological patterns of focal versus diffuse disease with similar results [35].

Post-PCI Physiology
While pre-PCI physiology has become routine for functional lesion assessment, physiologic measurements are only occasionally performed post-PCI in clinical practice, despite the presence of residual ischemia in up to 24% of patients [36]. In a similar fashion, recent data suggest that a greater physiological improvement in lesion stenosis corresponds to greater symptomatic relief and a lower event rate [37]. In patients who received functionally complete revascularization (CR), instead of angiographic-based revascularization, lower post-PCI FFR was associated with an increased risk of target vessel failure (hazard ratio, 1.091 [95% CI, 1.032-1.153]; P = 0.002) [38]. Likewise, patients who received functionally incomplete revascularization (IR) showed a higher incidence of MACE at 2 years than those with functionally complete revascularization (functional IR vs CR, 14.6% vs 4.2%; hazard ratio: 4.09; 95% confidence interval: 1.82 to 9.21; p < 0.001) [39].

Future Directions
Future directions in coronary physiologic assessment of multivessel disease will likely incorporate regular use of imaging modalities like CT-FFR and angiographic-derived FFR such as quantitative flow ratio (QFR) among others. In the SYNTAX III Revolution trial, a comprehensive heart team decision on optimal medical therapy (CABG, PCI, or equipoise between CABG and PCI) by coronary CT-FFR for multivessel disease showed a high agreement with the decision by conventional coronary angiography, allowing for adequate decision-making and procedural planning in up to 20% of patients on non-invasive physiologic assessment alone [40][41][42].
Despite the availability and accuracy of pressure-wirebased hyperemic and non-hyperemic measures of coronary physiology, their routine use remains limited. Functional coronary stenoses assessment by wire-free angiographically derived 3D reconstruction and computational flow dynamic calculations has led to the development of angiographic FFR such as QFR (Fig. 5). Two high-quality angiographic projections are used to reconstruct a 3D coronary tree and frame count analysis allows for computation of simulation models (fixed flow, contrast flow, and adenosine flow) to identify functionally significant stenosis [43]. Several studies have validated the accuracy and high correlation of QFR with FFR as a diagnostic reference [44][45][46]. Furthermore, QFR incorporation into functional SYNTAX score improves the prognostication and revascularization strategy choice compared to anatomic assessment alone in patients with left main or multivessel coronary artery disease [47]. QFR computation may also be a reliable tool to guide revascularization of non-infarct coronary arteries in the acute setting for patients with STEMI [48,49]. Other indices of functional assessment including FFR derived by angiography along (FFR angio ) and three-dimensional quantitative coronary angiography (3D-QCA)-based FFR (vFFR) also show high accuracy when compared to pressure-wire-based FFR in diagnosing functionally significant stenosis [50•, 51]. Finally, the interpretation of wire-based physiologic measurements can be made more accurate and reproducible with the use of artificial intelligence, which may ultimately be applied for decisionmaking irrespective of the data source [52,53].

Conclusions
Physiologic assessment of multivessel coronary artery disease minimizes the observer bias in visual estimates of stenosis, particularly for intermediate severity stenosis. Strong clinical evidence and guideline recommendations support routine use of physiologic assessment for more accurate identification and treatment for ischemia-related stenosis. Building on FFR, novel techniques to assess physiology with non-hyperemic indices like iFR and angiographically derived FFR have a growing body of evidence for routine use. A physiologic-guided approach will likely provide optimal revascularization strategies, objectively assess the adequacy of post-intervention, and will be associated with improved outcomes. As the techniques and evidence for physiologic coronary assessment continue to grow, these tools will undoubtedly shift the focus of contemporary treatment from anatomic to functional revascularization in patients with multivessel coronary disease.

Compliance with Ethical Standards
Conflict of Interest Morton Kern is a consultant and speaker for Abbott Vascular/St. Jude, Acist Medical Inc., Philips Inc., and Opsens Inc. Gautam Kumar has received research grants from Acist. Arnold Seto has received research grants from Philips and Acist Medical. The other author declared no conflict of interest.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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