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The type of vulnerable coronary plaque known as thin-capped fibroatheroma (TCFA), identified by virtual histology intravascular ultrasound (VH-IVUS), is associated with major adverse cardiovascular events (MACE), especially those in which restenosis does not play a critical role, according to a study published in the August 2011 issue of JACC: Cardiovascular Imaging.

The finding raises the possibility that, with further validation, use of the sophisticated imaging technique at the time of PCI may help predict which lesions are most likely to rupture in the future, triggering recurrent events. 

For the VIVA (Virtual Histology in Vulnerable Atherosclerosis) study, investigators led by Martin R. Bennett, MD, PhD, of the University of Cambridge (Cambridge, United Kingdom), prospectively enrolled 170 patients with stable angina (n = 100) or ACS (n = 70) who were scheduled for PCI. All underwent 3-vessel VH-IVUS before and after PCI. 

After a median follow-up of 625 days (interquartile range, 463-990 days) in 167 patients, 18 MACE (composite of death, MI, and unplanned revascularization) occurred in 16 patients, comprising 14 revascularizations, 2 MIs, and 2 deaths.

Both Plaques and Patients Analyzed

In an analysis of 1,096 lesions (excluding the 2 patients who died), 19 resulted in MACE; 13 were nonrestenotic events, while 6 were driven by in-stent restenosis. Of the 13 nonculprit lesions that resulted in nonrestenotic MACE, 9 were located in different vessels from the original stent and 4 were in the same vessel.

Specifically, of 931 nonculprit lesions identified, 13 resulted in MACE (1.4%). Six of the 165 culprit lesions (3.6%) resulted in MACE.

On univariate analysis, TCFA was the only nonculprit lesion plaque type associated with nonrestenotic events. Other, plaque-based factors linked with nonrestenotic events included plaque burden greater than 70% and remodeling index (lesion arterial area/reference arterial area; table 1).

Table 1. Nonculprit Lesion Characteristics Associated with Nonrestenotic MACE

 
Similar patterns were seen for traits associated with total MACE, although culprit lesion was an additional contributor (table 2).

Table 2. Lesion Characteristics Associated with Total MACE

In whole-patient analysis that included both clinical and PCI-related factors as well as grayscale and VH-IVUS-related variables, the only nonculprit lesion factor tied to nonrestenotic MACE was 3-vessel noncalcified TCFA (HR 1.79; 95% CI 1.20-2.66; P = 0.004). No clinical factors or stent-related or conventional IVUS parameters were associated with nonrestenotic MACE.

Despite the fact that nonrestenotic MACE rates for noncalcified TCFA were lower for nonculprit than culprit lesions, the authors stress, the predominance of nonculprit lesions meant that 68% of MACE nonetheless occurred due to nonculprit lesions.

VIVA, PROSPECT Concur

Dr. Bennett and colleagues write that despite many differences, the current study “shows remarkably similar findings” to the recently published PROSPECT study, which also used multimodal IVUS to assess the natural history of coronary atherosclerosis. These similarities include that TCFAs are quite common—accounting for 60.2% of nonculprit lesions in VIVA and for 22.0% in PROSPECT—and such vulnerable plaque is the only nonculprit lesion subtype associated with MACE.

In an accompanying editorial, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), and colleagues likewise underline the consistency between the 2 studies, saying that they “not only validate the clinical utility of VH-IVUS to detect vulnerable plaques but also the concept itself, as a pathological and clinical entity, as linked by the imaging tool.”

Dr. Bennett and colleagues agree, concluding that their paper demonstrates VH-IVUS “can identify plaques at increased risk of subsequent events, raising the possibility of better risk stratification at the time of PCI.”

Among VIVA’s limitations, the editorial notes, is the fact that the clinical characteristics, angiographic findings, and pharmacological treatments of the patient cohort are not reported. Both PROSPECT and VIVA leave several key questions unanswered, it adds, including the stability of vulnerable plaque over time, optimal treatment for TCFA identified by VH-IVUS, and whether patients should be screened for TCFA using the imaging technique. Moreover, it is unclear whether the accuracy of core lab VH-IVUS measurements could be replicated at clinical sites.

The editorial nonetheless concludes, “VH-IVUS has been validated as a tool capable of providing incremental discrimination to identify patients and lesions at risk for future MACE.”

Not All Vulnerable Plaques Are Trouble

“It is rewarding that the PROSPECT findings have been validated by in independent group,” Steven P. Marso, MD, of the University of Missouri-Kansas City (Kansas City, MO), told TCTMD in a telephone interview. But he pointed to several differences between the studies—most notably the more liberal definition of TCFA in the current paper.

“The TCFA detection algorithm was threefold more sensitive in VIVA,” he observed, which highlights a sticking point in research on vulnerable plaque. “We all think that TCFAs are high risk, but in fact some never rupture and some rupture but don’t result in clinical events. It’s a matter of specificity. We need enhanced methods of risk stratification to identify which TCFAs are truly high risk.”

That may require more refined measurement of TCFA fibrous caps—down to the 20- to 50-micron level, Dr. Marso suggested. Current IVUS technology cannot achieve that resolution, but optical coherence tomography might. Other approaches that deserve attention include using IVUS to assess plaque stress or developing algorithms to quantify the area of necrotic core, he suggested. Meanwhile, measuring inflammatory biomarkers has so far proved disappointing, Dr. Marso noted.

He added that studies using serial imaging are needed to understand the variability in plaque progression—or regression—over time.

Certainly for now, VH-IVUS should be considered a research tool, Dr. Marso said. But if operators incidentally notice nonculprit TCFAs along with the trio of high-risk lesion characteristics identified in VIVA in patients with established CAD, they should at least provide aggressive medical therapy and follow those patients carefully because they are at high risk of recurrent events, he advised.

Events Rare Despite TCFA

In a telephone interview with TCTMD, Robert L. Wilensky, MD, of the University of Pennsylvania School of Medicine (Philadelphia, PA), said these data confirming PROSPECT at least show that VH-IVUS is ahead of other invasive imaging modalities in identifying traits that predict plaque behavior.

“As these natural history studies emerge, it is interesting that the percentage of patients who experience acute events attributable to TCFAs is exceedingly small,” he said. “In both PROSPECT and VIVA, almost all we see is disease progression that would lead to revascularization.

One reason may be that medical therapy today is quite good, Dr. Wilensky commented, and that raises the question: Instead of focusing on ACS patients where the culprit lesion has already been treated, should more attention be paid to identifying patients who are at high risk but do not yet have manifest disease, to provide primary prevention?

Given the high percentage of TCFAs and low event rates, treating all such lesions is neither beneficial nor cost-effective, he said. Nonetheless, some select subgroups may warrant VH-IVUS assessment, he added, suggesting that younger women, who tend to have more recurrent events than men or older women, and younger diabetics may fit that category.

Like Dr. Marso, Dr. Wilensky stressed that a better understanding of the natural course of TCFAs is needed. “But for that I think noninvasive modalities are the future,” he said, adding that adaptations of CT and PET, or a combination of the 2, show promise in identifying lesions that deserve invasive evaluation.

Study Details

VH-IVUS was performed after administration of glyceryl trinitrate. Data were acquired with 20 MHz Eagle-Eye Gold catheters (Volcano Corporation, Rancho Cordova, CA) using motorized pull-back at 0.5 mm/sec. Data were captured on S5 consul software version 3.1 (Volcano Corporation), and analysis was performed offline by a core laboratory using Volcano Image Analysis software version 3.0.394. Thus, VH-IVUS analysis did not influence PCI procedure or subsequent management. 

Note: The editorialists are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD. One of them, Gary S. Mintz, MD, is the editor-in-chief of TCTMD.

2. Stone GW, Maehara A, Mintz GS. The reality of vulnerable plaque detection. J Am Coll Cardiol Img. 2011;4:902-904.

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