Editor's Note: This is Part II of a two-part Expert Analysis. Go to Part I.

Even though there are many uses of intravascular ultrasound (IVUS) in the catheterization laboratory, the interventional cardiologist has only two fundamental questions and only two basic decisions when performing a percutaneous coronary intervention (PCI):

1. Is a lesion significant and ischemia producing and, therefore, should it be treated?
2. Has the PCI been optimized?

There is a wealth of published literature on the use of IVUS to guide metallic stent implantation but no significant studies on IVUS-guided implantation of bioresorbable vascular scaffolds. Therefore, this discussion of IVUS will focus on bare-metal stent (BMS) and metallic drug-eluting stent (DES) implantation.

Is a Lesion Significant?

Three randomized clinical trials (RCTs), DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia), FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), and FAME 2 (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2), established fractional flow reserve (FFR) as the gold standard to assess the significance of a non-left main coronary artery (LMCA) lesion. Many studies have attempted to identify IVUS criteria that are equivalent to FFR or noninvasive ischemia testing. Although the IVUS minimum lumen area (MLA) was the parameter that best correlated with ischemia, reported thresholds of IVUS MLA cut-offs ranged from 2.1 to 4.4 mm², the thresholds were smaller in Asian studies than in Western studies, and the "most common" cut-off was approximately 3.0 mm². Overall, IVUS studies showed a relatively high negative-predictive value (72-96%) but a low positive-predictive value (39-73%), indicating that although it may be acceptable to defer an intervention in selected situations based on MLA size, IVUS should never be used to justify an intervention.¹ IVUS has been "corrected" for vessel size, but IVUS has not been able to factor in the amount of subtended viable myocardium.

Conversely, there is relative equipoise regarding the use of FFR versus IVUS to assess an intermediate LMCA lesion; and both FFR and IVUS have limitations. IVUS must be performed from both the left anterior descending (LAD) and left circumflex (LCX) back to the LMCA to 1) define the MLA within the LMCA and 2) assess accurately disease at the LAD and LCX ostia (an MLA >4.0 mm² and a plaque burden <50% at the LCX ostium is rarely associated with an FFR <0.8 after single stent crossover²). Conversely, FFR may have limitations in the setting of a significant concomitant LAD stenosis. Deferring revascularization based on an FFR >0.80 or an IVUS MLA >6.0 mm² is associated with similar long-term outcomes.^3-5 Although IVUS versus FFR reports in Korean patients suggest that 4.8 mm² is a better MLA cut-off than 6.0 mm² in LMCA lesions,⁶ the worst outcomes in Western patients were associated with an IVUS MLA of 5.0-6.0 mm².³

Calcification

Severe calcification limits stent expansion, and stent under-expansion is associated with adverse events.⁷ There is general agreement that the greater the arc and length of IVUS-associated lesion calcium the greater the likelihood of under-expansion, there are no published or agreed-upon criteria for recommending lesion modification prior to stent implantation. And IVUS cannot measure calcium thickness, which may be an important limit to stent expansion. On the other hand, and most of the time, iterative IVUS imaging in conjunction with repeated high-pressure adjunctive balloon inflations can be used to correct post-procedure stent under-expansion even in the setting of significant calcification. Nevertheless, it is easier to prevent stent under-expansion than it is to struggle to correct it.

IVUS studies have shown that localized calcium deposits or the transition from calcified to non-calcified plaque (or to normal vessel wall) are foci for PCI-associated dissections. More extensive dissections occur in segments of arteries that are heavily calcified, and stent implantation into calcified lesions is more often associated with stent fracture.

How Do I Optimize Acute Stent Results With IVUS?

During PCI, IVUS can be used to select stent size, identify optimal proximal and distal stent edge landing zones and select stent length using motorized transducer pullback to measure the distance between the proximal and distal landing zones, and determine whether to cover the aorto-ostial junction when stenting an LMCA or proximal right coronary artery lesion. The ability of IVUS to visualize true vessel size permits upsizing a stent to maximize final stent dimensions (Figure 1) with no apparent downside; true vessel size is larger than lumen dimensions because of accumulated plaque and positive remodeling. Optimal landing zones are the largest lumens with the smallest plaque burden in the same coronary artery segment, ideally a plaque burden <50%. Similarly, the aorto-ostial junction should be covered if the plaque burden is >50%. Conversely, an aggressive stent-sizing strategy should be avoided in lesions with IVUS-detected negative remodeling because of the risk of perforation.

Figure 1

After either BMS or DES implantation, the IVUS predictors of early stent thrombosis (ST) or of in-stent restenosis are stent under-expansion (or, in the setting of primary PCI in ST-segment elevation myocardial infarction [STEMI] patients, a small lumen area caused by tissue thrombus protrusion) and inflow/outflow track disease (significant dissections, significant edge plaque burden or edge stenoses, and geographical miss), but not acute stent malapposition as long as the stent is well-expanded.⁸ Under-expansion refers to the size of the stent (assessed best using the absolute rather than the relative minimum stent area), and malapposition refers to the contact of the stent with the vessel wall; the two terms and concepts are not interchangeable. It should be noted, however, that these predictors—particularly the fact that acute malapposition is not a predictor of ST or in-stent restenosis after metallic stent implantation—might not apply to bioresorbable vascular scaffolds. In addition, the majority of acute malapposition resolves during follow-up and does not persist from the time of implantation; therefore, malapposition that is detected at the time of very late ST probably develops during the follow-up period. Although bigger is better regarding stent expansion and less is more with respect to stent edge plaque burden, acceptable procedural endpoints are a minimum stent area and stent-edge plaque burden that maximize the probability of long-term stent patency while minimizing the risk of clinical events.

Better Outcomes With IVUS Guidance

Two meta-analyses of seven randomized IVUS versus angiographic-guided BMS implantation trials showed that IVUS guidance reduced restenosis, repeat revascularization, and major adverse cardiac events (MACE) but not death or myocardial infarction; ST was not reported.^9,10

Five meta-analyses of the published IVUS versus angiographic-guided DES studies (the most recent included 29,068 patients from 17 registries and 3 RCTs), as well as propensity-score-matching substudies and subanalyses of high-risk lesions and unstable patient subsets, showed that IVUS guidance reduced overall MACE including early and late ST and myocardial infarction and mortality during follow-up of at least 1 year (Figure 2).^11-16 These meta-analyses did not include eight additional publications (four randomized and four registry studies). Seven of eight reported better outcomes with IVUS guidance,^17-24 and four of the seven were randomized studies. It should be noted that the eighth study also showed no outcomes benefit to intracoronary physiology.²⁴ Meta-analysis of the eight randomized IVUS-guided versus angiography-guided DES implantation studies showed that IVUS guidance was associated with a reduction in the risk of MACE by 41%, mortality by 54%, ST by 51%, and ischemia-driven target lesion revascularization by 40% (Figure 2).¹⁶ Furthermore, seven studies (one of which was randomized, three of which were propensity-score matched) showed a benefit to IVUS-guided DES implantation when treating LMCA lesions (Figure 3).

Figure 2: Meta-Analyses of IVUS Versus Angiography-Guided DES

Figure 3: MACE in Seven Studies of IVUS Versus Angiography-Guided DES for LMCA Disease

Three RCTs deserve particular mention. In one trial of percutaneous chronic total occlusion revascularization, 402 patients were randomized to IVUS versus angiographic guidance after guidewire crossing. According to the intention-to-treat analysis, IVUS guidance was associated with a lower MACE of 2.6 versus 7.1%, p = 0.035, along with a reduction in death/myocardial infarction and repeat revascularization.²⁰ The per-protocol differences in MACE—comparing PCI procedures that were actually guided by IVUS with those that were guided by angiography alone—were even greater: 2.2 versus 8.4%, p = 0.005. In the IVUS-XPL trial, 1,400 patients with long lesions were randomized to IVUS versus angiographic guidance. All patients were treated with the same metallic DES. IVUS guidance was associated with a lower MACE rate of 2.9 versus 5.8% (intention-to-treat), p = 0.007. In the subgroup of IVUS-guided patients with a post-intervention MLA greater than the distal reference lumen area, the MACE rate was only 1.5%.²¹ The most likely explanation is that studies showing that angiographic guidance achieved, on average, only 75% of the predicted minimum stent diameter and 67% of the predicted minimum stent area.^25,26 The randomized MOZART (Minimizing Contrast Utilization With IVUS Guidance in Coronary Angioplasty) trial showed that IVUS guidance can minimize contrast use (median of 20.0 ml) even when compared with a contrast-conservation, angiography-guided stent implantation strategy (median of 64.5 ml, p < 0.0001).²⁷ This has been extended to IVUS-guided stent implantation without the use of contrast, which can be particularly important in patients with renal insufficiency.²⁸

An Italian economic study showed that IVUS was cost effective in the first year post-DES implantation, became cost saving in the second year, and was the dominant strategy, especially in high risk patients (i.e., those with diabetes mellitus, renal insufficiency, or acute coronary syndromes).²⁹

Equipment Considerations

As of this writing, there are five companies that make IVUS equipment: BostonScientific, Volcano (now owned by Philips), Terumo (not available in the United States), Infraredx (now owned by Nipro), and ACIST. All five manufacture an IVUS catheter containing a rotating-transducer within a short-monorail imaging sheath to create cross-sectional IVUS images, although Volcano also makes a synthetic aperture array long-monorail IVUS catheter. Although the image presentation may vary among companies and although the IVUS console and software controls certainly do vary, there is no clinically meaningful difference among them. All commercially available IVUS technologies produce equally valid diagnostic information, especially in the setting of PCI. It is a matter of personal preference; however, it should be noted that catheters, motor drive or patient interface units, and consoles are not interchangeable among companies.

With the exception of calcium detection (discussed above), grayscale IVUS has limitations in assessing tissue composition. For this reason, three radiofrequency-IVUS technologies have been developed by Volcano, Terumo, and BostonScientific to improve on tissue characterization. In the context of guiding and optimizing PCI, there are little or no data to indicate that these radiofrequency-IVUS technologies improve acute or long-term patient outcomes above and beyond grayscale IVUS itself.

IVUS Versus Optical Coherence Tomography

There have been, however, a paucity of head-to-head IVUS versus optical coherence tomographic (OCT) data; and the available data have been limited to acute outcomes. In one small 70-patient randomized, blinded, comparison of IVUS versus OCT study with crossover imaging, IVUS guidance was associated with greater stent expansion (minimum stent area of 7.1 vs. 6.1 mm², p = 0.04) and a smaller stent-edge plaque burden (proximal edge 37.1 vs. 45.7%, p = 0.001; distal edge 33.3 vs. 40.3%, p < 0.001) compared with OCT.³⁰ Although ILUMIEN II (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention) showed no difference in percent expansion between IVUS and OCT,³¹ the currently available data from the randomized OPINION (Optical Frequency Domain Imaging Versus Intravascular Ultrasound in Percutaneous Coronary Intervention) trial showed a trend toward larger maximum balloon diameters (3.28 vs. 3.15 mm, p = 0.072) and a greater post-procedure in-stent angiographic minimum lumen diameter (2.63 vs. 2.56 mm, p = 0.058) with less contrast use (138 vs. 164 ml, p < 0.001) in the IVUS versus the OCT arm.³² OCT predictors of stent-related events have been similar to IVUS: under-expansion and inflow/outflow track disease.^33,34 The threefold greater sensitivity of OCT- versus IVUS-detected acute stent malapposition has not translated into a clinically important predictor of early or late ST or restenosis.

Conclusion

In order for patients to benefit from either IVUS- or OCT-guided stent implantation, it is necessary for the interventional cardiologist to be able to fulfill three basic requirements:

1. Proper image acquisition
2. Accurate image interpretation, which requires that images be acquired properly
3. Correct decision-making based on accurate image interpretation

Particularly with a new method like OCT, but also with a more mature technology like IVUS, training and education are critical.

Thus, the question of IVUS versus OCT is wrong and, in fact, belies the true conundrum. Although there are clear differences between the two technologies—resolution and surface detail favoring OCT, penetration and media-to-media sizing favoring IVUS, fine details favoring OCT, the bulk of clinical data favoring IVUS—better questions are IVUS or OCT versus angiography alone and why these technologies are so underutilized given the evidence that has been presented in both of our cases and the fact that the major determinants of optimal stent implantation can be assessed better by either IVUS or OCT than by angiography alone.

References

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Keywords: Acute Coronary Syndrome, Angiography, Angioplasty, Balloon, Coronary, Constriction, Pathologic, Coronary Vessels, Cross-Sectional Studies, Diabetes Mellitus, Drug-Eluting Stents, Intention to Treat Analysis, Myocardial Infarction, Myocardium, Percutaneous Coronary Intervention, Renal Insufficiency, Stents, Thrombosis, Tomography, Optical Coherence

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