Unprotected Left Main Percutaneous Coronary Intervention: Integrated Use of Fractional Flow Reserve and Intravascular Ultrasound

For several decades, bypass surgery has been regarded as the treatment of choice for patients with unprotected left main coronary artery (LMCA) disease.[1][1]–[2][2] However, because of easy anatomic accessibility and a relatively large vessel caliber, left main percutaneous coronary intervention

Identification of significant stenosis of LMCA is of critical prognostic importance. Nevertheless, an angiographic stenosis diameter of 50% is still considered a cutoff value for significant LMCA stenosis. Hamilos et al 27 were the first to demonstrate the considerable discrepancy between coronary angiography and fractional flow reserve (FFR) in the evaluation of intermediate LMCA stenosis. Among the 213 patients in their study, 62 patients (29.1%) showed a "visual functional mismatch" between angiographic significance and functional significance, 13 patients had a diameter stenosis >50% while the FFR was >0.80, and 49 patients had a diameter stenosis <50% while the FFR was <0.80. It is interesting to note that the prevalence of "reverse mismatch," which refers to angiographically insignificant but functionally significant stenosis, was dominant and as high as 79.0% among the mismatched patients. Figure 1 demonstrates the discrepancy between coronary angiography and FFR.
In addition, noninvasive functional testing such as myocardial perfusion imaging is often noncontributive in the diagnosis of patients with intermediate LMCA stenosis. Perfusion defects are often seen in only 1 vascular territory, or tracer uptake may be reduced in all vascular territories ("balanced ischemia") giving rise to false-negative studies, especially when the right coronary artery is significantly diseased. 28 This is another reason why we should measure FFR for intermediate LMCA stenosis.
Therefore, the decision about whether the treatment of intermediate LMCA stenosis should be performed or deferred should not be determined by coronary angiogram alone, and

Complementary Roles of Intravascular Ultrasound in Functional Evaluation of LMCA Stenosis
Because of the limitations of the conventional coronary angiogram in assessing the severity of LMCA stenosis, there have been several attempts to compare the anatomical parameter assessed by intravascular ultrasound (IVUS) with the corresponding FFR measurement.
Jasti et al 33 reported that an MLA of 5.9 mm 2 had the highest sensitivity and specificity (93% and 95%, respectively) for determining a significant LM stenosis, compared with FFR as the gold standard. Recently, clinical application of an MLA criterion for treatment decision making for intermediate LMCA stenosis was tested. 37 In the LITRO study, a total of 354 patients with intermediate LMCA stenoses were enrolled.
In patients with an MLA<6 mm 2 , revascularization were performed, and in patients with an MLA≥6 mm 2 , revascularization was deferred. In a 2-year follow-up period, there were no statistical between-group differences regarding the incidence of death (2.3% versus 4.5%, respectively; P=0.5) and any event (12.7% versus 19.4%, respectively; P=0.3). Therefore, they suggested an MLA ≥6 mm 2 was a safe value for deferring revascularization of the LMCA.
We recently addressed these issues in 55 patients with isolated intermediate LMCA stenosis who underwent preinterventional IVUS and FFR measurements to determine the IVUS MLA criterion corresponding to an FFR<0.80. 38 We found that the IVUS MLA value within the LMCA that best predicted FFR<0.80 was <4.8 mm 2 (89% sensitivity, 83% specificity, 86% accuracy; AUC 0.90, 95% CI 0.788 to 0.964, P<0.001). It is interesting to note that that the positive predictive value of IVUS-measured MLA<4.8 mm 2 is acceptably high at 82%, in contrast with non-LMCA stenosis ( Figure 3). 38 This might be explained by the simplicity of morphological characteristics of pure LM lesions, uniformly large vessel size, short lesion length, and lack of side branch and other anatomical factors that could potentially affect FFR. Therefore, in the evaluation of intermediate LMCA stenosis, anatomical parameter provided by IVUS appeared to be correlated well with functional significance of LMCA stenosis.

How to Perform Unprotected LMCA Stenting
From a technical perspective, it would be easy to perform a single-stent procedure for ostial and shaft LM disease; published long-term clinical outcomes are excellent. [39][40][41] The current PCI guideline was updated as mentioned before. 23,24 For LMCA bifurcation disease, unresolved technical issues remain. The single-stent technique clearly shows more favorable long-term clinical outcomes compared with the 2-stent technique, even in bifurcation LM disease. [42][43][44][45] Therefore, in real practice, the single-stent crossover technique has been used more frequently, in as many as %60% of all LMCA bifurcation treatments. 42 Selection of a single-or 2-stent technique should be based on disease involvement of the LCX ostium, because side-branch compromise after stent crossover is frequent in the setting of significant ostial disease of the side branch (Table 4). Thus, to determine the choice of a single-or 2-stent strategy, IVUS provides accurate information for both main-and side-branch disease status and vascular remodeling in LMCA bifurcation lesions. In addition, if possible, direct imaging from the LCX is necessary for accurate assessment of the side branch, including its ostium, because IVUS evaluation of a sidebranch ostium from the main vessel is only moderately reliable. 46 After main-stent crossover from the proximal left anterior descending artery (LAD) to LM, geometric changes in the LCX ostium were related mainly to carina shift, reduction of MLA, and increased eccentricity of the external elastic membrane and carina angle between the LAD and the LCX (Figure 4). 47 However, an important issue is being unable to predict the functional significance of the stenosis with only the degree of jailed LCX ostium, no matter how big or small. Therefore, in cases in which the LCX ostium is significantly compromised (>50%) after simple crossover stent implantation from LM to LAD, we should consider FFR measurement first before further treatment of the LCX.

IVUS Minimal Stent Area Criteria Optimizing the Clinical Outcomes
Optimal stent expansion was considered one of the most important factors in preventing restenosis or adverse clinical outcomes. 48,49 However, there are no data suggesting the optimal minimal stent area (MSA) cutoff for prediction of   restenosis and long-term clinical outcome after DES implantation for LMCA stenosis.
Recently, we studied the optimal IVUS-MSA criteria for prevention of in-stent restenosis (ISR) in 403 patients undergoing sirolimus-eluting stent implantation for LMCA disease. 50 We classified the LMCA into 4 segments: the LCX ostium, LAD ostium, polygon of confluence (POC), and LMCA above the POC. The best IVUS-MSA criteria that predicted angiographic ISR on a segmental basis were 5.0 mm 2 for the LCX ostium, 6.3 mm 2 for the LAD ostium, 7.2 mm 2 for the POC, and 8.2 mm 2 for the proximal LMCA above the POC ( Figure 5). 50 Using these criteria, 133 patients (33.8%) experienced underexpansion ≥1 of the prespecified segments. In addition, underexpansion was more frequent in the 2-stent group than in the single-stent group (54% versus 27%, respectively, P=0.001). In the 2-stent group, the LCX ostium was the most common site of underexpansion (37%), which may explain the greater risk of ISR when LMCA bifurcation lesions are treated with a 2-stent strategy. Overall, angiographic ISR was more frequent in lesions with underexpansion than in lesions without underexpansion (24.1% versus 5.4%, respectively; P=0.001). Even in the 2-stent group, lesions with complete expansion at all sites showed only 6% of the ISR rate, which was similar to that of the single-stent group (6.3%) or in nonbifurcation LMCA lesions (4.5%). Furthermore, a smaller IVUS-MSA predicted angiographic ISR 9 months after DES implantation for treatment of LMCA disease, and poststenting underexpansion was an independent predictor of 2-year adverse clinical outcomes, especially repeat revascularization.

Impact of IVUS Guidance for LMCA Stenting
Although IVUS guidance has been useful in stenting unprotected LMCA stenoses, its impact on long-term mortality is still unclear. In 201 matched pairs from the MAIN-COMPARE registry, there was a tendency of lower risk for 3-year mortality with IVUS guidance compared with angiography guidance (6.0% versus 13.6%, respectively; log-rank P=0.063; hazard ratio 0.54). 26 In particular, for 145 matched pairs of patients receiving DES, the 3-year mortality was significantly lower for IVUS guidance compared with angiography guidance (4.7% versus 16.0%, respectively; log-rank P=0.048; hazard ratio 0.39). It is interesting to note that the mortality rate started to diverge beyond 1 year after the procedure. In contrast, the use of IVUS did not reduce the risk of mortality in 47 matched pairs of patients receiving a bare-metal stent (8.6% versus 10.8%, respectively; log-rank P=0.35; hazard ratio 0.59). Therefore, despite inherent limitations of nonrandomized registry design, this study indicated that IVUS guidance may play a role in reducing very late stent thrombosis and subsequent long-term mortality.
IVUS guidance has provided more information on negative remodeling, reference vessel size, and morphologic complexity of ostial or bifurcation lesions in preintervention evaluation, stent underexpansion, incomplete lesion coverage, small stent area, large residual plaque, and incomplete stent apposition in postinterventional evaluation. [51][52][53] For LMCA lesions, in particular, the use of IVUS is helpful in determining treatment strategy and in optimizing the stent procedure. Therefore, we strongly recommend mandatory use of IVUS in PCI for unprotected LMCA. Evaluate anatomic features favoring single stent cross over stenting (see Table 4.) Evaluate MSA in every segment of LMCA (see

Conclusions
FFR-guided PCI can help to select appropriate patients and lesions for treatment, avoid unnecessary procedures, reduce medical costs, and improve clinical outcomes. Furthermore, IVUS can be used to secure the PCI procedure by preinterventional lesion assessment and postinterventional stent optimization. We propose the concept of the integrated use of FFR and IVUS in LMCA stenting ( Figure 6). Despite several limitations of this approach including cost, procedural time, and availability of trained personnel, FFR-guided complex PCI, which is supported by IVUS, can give us better insights into LMCA disease and may improve the clinical outcomes of patients who undergo LMCA stenting.