PROSPECT II, COMBINE (OCT–FFR) and PROSPECT ABSORB: After revascularization of culprit lesions, assessment of coronary plaque size and composition matter!
Reported from the TCT Congress 2020
PROSPECT II, COMBINE (OCT–FFR) and PROSPECT ABSORB trials were presented at TCT Connect 2020. Hector Garcia-Garcia provides a summary of the key messages.
As shown in the PROSPECT II and the COMBINE studies presented at #TCT2020, in high-risk populations, treating only the culprit lesions is not enough, residual large plaque burden and lipid-rich lesions pose a high risk of future events. In previous studies, the presence of small lumen area completed the trifecta (triple “LLL”) which has been frequently associated with poor clinical cardiovascular outcomes in the follow-up (Figure 1).
Figure 1. Triple LLL – large plaque size, lipid-rich and small lumen area, associated with major cardiovascular events in the follow-up
The PROSPECT II and COMBINE studies used intravascular imaging, IVUS/NIRS and OCT respectively, to characterize, by means of IVUS, the plaque size; and with NIRS and OCT, the lipid content of the lesions; of note, NIRS detects lipid in a quantitative manner and OCT in a semiquantitative fashion. In addition, the OCT enables assessment of the overlying fibrous cap in these lipid-rich plaques and thereby it offers the fibrous cap thickness information to categorize thin (<65 microns) capped fibroatheroma (TCFA).
In a population presenting with acute coronary syndromes, the PROSPECT II study (n=898) found that 8% of MACE was related to untreated plaques vs only 4.6% MACE event rate for culprit lesions at median follow-up of 3.7 years. In the multivariable analysis, plaque burden more than 70% and LCBI >324 were independent predictors of MACE. On the other hand, in a diabetic population, investigators of the COMBINE study found that more than 25% of all FFR (-) lesions had high-risk plaque characteristics (i.e. TCFA) as defined by OCT. In the multivariable analysis for MACE, TCFA was the strongest predictor of myocardial infarction, revascularization and rehospitalizations for unstable angina. Dr Fuster (chair of the session @TCT2020) concluded as follows: “We have learned that high-risk plaques are high risk”.
Why have we not been screening for triple LLL lesions?
The PROSPECT II study just confirmed again what we knew since nearly a decade ago and have been hearing multiple times since then.
This is a summary of the evidence showing that the presence of these high-risk plaque characteristics (triple LLL – large plaque size, lipid-rich and small lumen area), alone or combined, was associated with major cardiovascular events in the follow-up (Figure 1).
First, clinical studies which use IVUS virtual histology. In 2010, Stone et al. reported the PROSPECT trial1 which was a natural history study of acute coronary syndrome patients. All patients underwent PCI in their culprit lesion at baseline, followed by an angiogram and IVUS virtual histology of the three major coronary arteries. A TCFA with a minimum lumen area of ≤4 mm2 and a large plaque burden (≥70%) had a 17.2% likelihood of causing an event within three years. Interestingly, the anticipated high frequency of acute thrombotic cardiovascular events did not occur, with only a 1% rate of myocardial infarction and no deaths directly attributable to non-culprit vessels over 3 years of follow-up. These results suggest that non-culprit, yet obstructive coronary plaques are most likely to be associated with increasing symptoms rather than thrombotic acute events, with 8.5% of patients presenting with worsening angina and 3.3% with unstable angina.
Similarly, in 2014 we reported in the ATHEROREMO-IVUS study2, that the presence of IVUS virtual histology-derived TCFA lesions (adjusted HR: 1.98, 95% CI: 1.09-3.60; P = 0.026) and lesions with a plaque burden of ≥70% (adjusted HR: 2.90, 95% CI: 1.60-5.25; P < 0.001) were independently associated with a higher MACE rate. The VIVA study3 concluded as well that patients with a TCFA, as assessed by virtual histology, had an increased risk of subsequent events.
Second, clinical studies which use IVUS near-infrared spectroscopy derived lipid core burden index (LCBI). We reported ATHEROREMO-NIRS in 20144 that in CAD patients with an LCBI equal to or above the median, in a nonculprit coronary artery, had a 4-fold risk of adverse cardiovascular events during 1-year follow-up. Thereafter, we extended its follow up (median 4.1 years) and pooled it with the data from IBIS-3(5), in this report we established a statistically significant and independent continuous relationship between higher MaxLCBI 4mm values and a higher risk of MACE.
Each 100 units increase of MaxLCBI 4mm was associated with a 19% increase in MACE [HR 1.19, 95% confidence intervals (95% CI): 1.07–1.32, P = 0.001]. Other groups confirmed our initial observations6,7. Undoubtedly, the landmark study for IVUS-NIRS preceding PROSPECT II is the Lipid Rich Plaque study8 which found that in patients with a maxLCBI 4mm more than 400, the unadjusted HR for nonculprit-MACE was 2·18 (p<0·0001) and adjusted HR was 1·89 (p=0·0021). At the plaque level, for segments with a maxLCBI 4mm more than 400, the unadjusted HR for nonculprit-MACE was 4·22 (p<0·0001) and adjusted HR was 3·39 (p<0·0001).
Taking all these reports together, the number of studied patients is much higher than for many of the class IA recommendations and therefore I call for a mention in the upcoming societal guidelines about screening for nonculprit lesions with the presence of the triple LLL characteristics.
What if we ever find high-risk coronary lesions?
The quest for identifying coronary lesions before they cause an acute myocardial infarction or sudden death – so-called high-risk or vulnerable plaques - has been going on for many decades. Echoing Dr Fuster conclusion remarks at TCT2020 session, we know that high-risk plaques actually are associated with clinical events in the follow-up. What is next then?
In the same session, we have also learned about the results of treating them with a local scaffold. The PROSPECT ABSORB study, a total of 182 were randomized to receive either ABSORB BVS + guideline-directed medical treatment (GDMT) or just GDMT. The primary powered effectiveness endpoint was the IVUS-derived minimum lumen area (MLA) at protocol-driven 25-month follow-up. The MLA in the BVS group was 6.9 vs. 3.0 mm2 (P<0.0001). Even more exciting news came from the primary (non-powered) safety endpoint which was randomized target lesion failure (TLF; cardiac death, target vessel-related MI or clinically-driven TLR) at 24 months. In the BVS group TLF was 4.3% vs. 10.7% in the GDMT group (OR 0.38, 95%CI 0.11-1.30).
As discussed above, triple LLL lesions often have a thin fibrous cap overlying the lipid-rich core. The notion that the implantation of a local device may passivate these plaques was described in 20129 using a self-expanding nitinol device. In this lesion subset, the use of a metallic device was deemed not necessary since these lesions do not require a device with high radial force to maintain the lumen open but just a device to cover the lesion to create a new layer (i.e. neo cap) of fibrous tissue. Therefore, it was thought that a polymeric device would serve this purpose.
The foundational observations using BVS were made by Dr Brugaletta in 201210. Using OCT, the documentation of a neointimal layer overlying the native disease was obtained and was hypothesized that this “de novo” cap may be used to seal a thin-cap fibroatheroma.
In figure 2 modified from11, we proposed how the natural history of coronary disease by local implantation of a bioresorbable scaffold can be achieved. From left to right: Intimal thickening (a), intimal xanthoma (b), pathological intimal thickening (c), fibroatheroma (d), thin-capped fibroatheroma (e). As coronary disease progresses does the endothelial function worsen. After the implantation of the scaffold, it can be seen that the 3-dimensional (3D) structure of the device can be delineated by means of optical coherence tomography (OCT) (f). In histology, it can be appreciated the polymeric struts overlying on the vessel wall (black arrow). On the 2D OCT image, the squared-shape struts are translucent and therefore their whole thickness can be appreciated (f′). At 5 o clock, the metallic marker can be seen (*). As time goes by, the struts are integrated into the vessel wall and cover by neointima (g and g′).
Figure 2. Scaffold implantation
Final thoughts and potential future directions
- Not all patients make it to the cath lab to screen them for triple LLL lesions. Alternatively, we can use computer tomography angiography (CTA), a non-invasive imaging tool, which is able to provide similar information. We have created, therefore, comprehensive CT-based scores (such as CT-Leaman score) that have been also proved to be associated with future CV events.
- Even if patients are in the cath lab, intravascular imaging is costly and there is no reimbursement coverage in most of countries. I believe that with the current evidence a strong case can be made towards the relevant payers to justify reimbursement.
- Even if they were reimbursed, interventional cardiology community has not yet embraced them and therefore training, and education are poor. EuroPCR, TCT and other dedicated courses every year make education and training available to the community, so we should take advantage of this.
- Triple LLL lesions should continue to be treated with the best GDMT until new studies investigating local therapy show unequivocally that it is safe and effective.
References
- Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A Prospective Natural-History Study of Coronary Atherosclerosis. N Engl J Med. 2011 Jan 20;364(3):226–35.
- Cheng JM, Garcia-Garcia HM, de Boer SPM, Kardys I, Heo JH, Akkerhuis KM, et al. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. European Heart Journal. 2014 Mar 7;35(10):639–47.
- Calvert PA, Obaid DR, O’Sullivan M, Shapiro LM, McNab D, Densem CG, et al. Association Between IVUS Findings and Adverse Outcomes in Patients With Coronary Artery Disease. JACC: Cardiovascular Imaging. 2011 Aug;4(8):894–901.
- Oemrawsingh RM, Cheng JM, García-García HM, van Geuns R-J, de Boer SPM, Simsek C, et al. Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease. J Am Coll Cardiol. 2014 Dec 16;64(23):2510–8.
- Schuurman A-S, Vroegindewey M, Kardys I, Oemrawsingh RM, Cheng JM, de Boer S, et al. Near-infrared spectroscopy-derived lipid core burden index predicts adverse cardiovascular outcome in patients with coronary artery disease during long-term follow-up. European Heart Journal. 2018 Jan 21;39(4):295–302.
- Madder RD, Husaini M, Davis AT, VanOosterhout S, Khan M, Wohns D, et al. Large lipid-rich coronary plaques detected by near-infrared spectroscopy at non-stented sites in the target artery identify patients likely to experience future major adverse cardiovascular events. Eur Heart J Cardiovasc Imaging. 2016 Apr;17(4):393–9.
- Danek BA, Karatasakis A, Karacsonyi J, Alame A, Resendes E, Kalsaria P, et al. Long-term follow-up after near-infrared spectroscopy coronary imaging: Insights from the lipid cORe plaque association with CLinical events (ORACLE-NIRS) registry. Cardiovascular Revascularization Medicine. 2017 Apr;18(3):177–81.
- Waksman R, Di Mario C, Torguson R, Ali ZA, Singh V, Skinner WH, et al. Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study. Lancet. 2019 02;394(10209):1629–37.
- Wykrzykowska JJ, Diletti R, Gutierrez-Chico JL, van Geuns RJ, van der Giessen WJ, Ramcharitar S, et al. Plaque sealing and passivation with a mechanical self-expanding low outward force nitinol vShield device for the treatment of IVUS and OCT-derived thin cap fibroatheromas (TCFAs) in native coronary arteries: report of the pilot study vShield Evaluated at Cardiac hospital in Rotterdam for Investigation and Treatment of TCFA (SECRITT). EuroIntervention. 2012 Dec;8(8):945–54.
- Brugaletta S, Radu MD, Garcia-Garcia HM, Heo JH, Farooq V, Girasis C, et al. Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: Can the scaffold cap the plaque? Atherosclerosis. 2012 Mar;221(1):106–12.
- Ahmadi Amir, Stone Gregg W., Leipsic Jonathon, Shaw Leslee J., Villines Todd C., Kern Morton J., et al. Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease. Circulation Research. 2016 Jul 8;119(2):317–29.
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