ILUMIEN IV: OPTIMAL PCI - Optical Coherence Tomography Guided Coronary Stent Implantation Compared with Angiography: A Multicenter Randomized Trial in Percutaneous Coronary Intervention

Reported from ESC Congress 2023

Why this study? – the rationale/objective

Long-term results of the IVUS-XPL and ULTIMATE trials have indicated that implementing percutaneous coronary intervention (PCI) with intravascular ultrasound (IVUS) reduces the incidence of target lesion failure compared with angiography alone, primarily due to a lower incidence of target lesion revascularization. (1-4) More recently, the RENOVATE-COMPLEX-PCI trial comparing intravascular imaging (73.3% IVUS and 25.5% optical coherence tomography [OCT]) with coronary angiography alone in the guidance of complex PCI showed at a median follow-up of 2.1 years that intravascular imaging was associated with a reduction of target vessel failure. (5).

OCT has gained increasing popularity as a guiding tool for PCI. Compared with IVUS, its higher resolution provides valuable diagnostic information and allows for a more accurate assessment of plaque morphology and luminal characteristics. These valuable properties of OCT make it useful in determining the appropriate stent size, assessing acute PCI outcomes such as dissection and malapposition, and guiding optimal stent expansion following implantation.

However, challenges such as transitioning from IVUS, complex image interpretation, the absence of a standardized algorithm for PCI guidance, and lack of sufficient data from prospective clinical trials have contributed to its modest adoption. Against this background, the ILUMIEN IV trial sought to define in a large number of patients undergoing PCI whether OCT guidance is associated with improved short and long-term outcomes. (6,7)

How was it executed? – the methodology

ILUMIEN IV was a prospective, single-blind, randomized trial conducted at 80 sites in 18 countries in which adult patients with evidence of myocardial ischemia considered to be at high-risk or had high-risk coronary-artery lesions were randomized in a 1:1 ratio to undergo OCT- or angiography-guided PCI.

A high-risk patient was defined as a patient with diabetes mellitus who was treated with medication, whereas a high-risk coronary-artery lesion was defined as a lesion that was considered responsible for a recent myocardial infarction, long or multiple lesions warranting stenting for more than 28 mm, a bifurcation lesion for which treatment would warrant the implantation of two stents, a severely calcified lesion, a chronic total occlusion (randomization permitted only after successful crossing with antegrade wire escalation and predilation), or diffuse or multifocal in-stent restenosis. The main exclusion criteria included an ST-segment elevation myocardial infarction ≤24 hours, creatinine clearance ≤30 mL/min/1.73 m2, hemodynamic instability or cardiogenic shock, heart failure (Killip class ≥2 or New York Heart Association class ≥3), left ventricular ejection fraction ≤30%, and ventricular arrhythmias.

The primary imaging endpoint was the final minimum stent area after PCI as assessed with OCT, while the primary clinical endpoint was target-vessel failure at 2 years, defined as a composite of death from cardiac causes, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization. The major secondary endpoint was target-vessel failure, excluding periprocedural myocardial infarction.

The ILUMIEN IV trial was designed to test the superiority of OCT-guided PCI compared with angiography-guided PCI in terms of primary imaging and clinical endpoints. Estimated sample sizes (1600 and 2490, respectively) would confer a 95% power to detect a minimum stent area greater than 0.4 mm2 for the primary imaging endpoint and a 90% power to detect a 35% relative risk reduction in the primary clinical endpoint, in both cases with a one-sided alpha of 0.025. The two endpoints had to be tested sequentially. The primary endpoint was assessed after the inclusion of 1600 patients to define if trial enrolment had to continue. In the context of an adaptive design, when 50% of the anticipated events of target vessel failure (n=194) had occurred, the data safety monitoring board indicated the need for a sample size increase to a maximum total of 3656 patients.

What is the main result?

A total of 2487 patients were randomized from May 2018 to December 2020 to undergo OCT-guided PCI (1233 patients, 1353 lesions) or angiography-guided PCI (1254 patients, 1409 lesions). Major protocol deviations were identified in 68 patients (5.5%) in the OCT group and 68 patients (5.4%) in the angiography group, the latter including 8 patients (0.6%) in whom additional PCI was performed after OCT imaging.

The patients had a mean age of 65.6 years, the female gender accounted for 22.6%, and the predominant (78.5%) ethnicity was white; 42% of patients were suffering from diabetes, 17.9% had creatinine clearance <60 mL/min, mean left ventricular ejection fraction was 55.2%; 42.5% of patients underwent PCI for silent ischemia or stable angina, 51.8% for unstable angina or non-ST-segment elevation myocardial infarction, and the remaining 5.7% for an ST-segment elevation myocardial infarction >24 hours. Prespecified high-risk lesion characteristics predominantly consisted of a total stent length ≥28 mm (67.6%), followed by culprit for non-ST-segment elevation myocardial infarction (24.1%), severe calcification (11.6%), and in-stent restenosis (10.8%); chronic total occlusions and bifurcations treated with a two-stent strategy accounted for 7.0% and 3.3%, respectively. Maximum stent diameter per lesion (mean difference 0.11 mm, 95% CI 0.07-0.14), total stent length per patient (mean difference 3.8, 95% CI 1.9-5.6), lesion postdilation (rate difference 12.9, 95% CI 10.7-15.2), maximum inflation pressure per lesion (mean difference 1.4 atm, 95% CI 1.2-1.7) were higher in the OCT-guided PCI group compared with the angiography-guided PCI group as well as the duration of fluoroscopy per patient (mean difference 3.6 min, 95% CI 2.6-4.6), radiation dose per patient (mean difference 0.46 Gy, 95% CI 0.32-0.60), and contrast media volume per patient (mean difference 33.7 mL, 95% CI 27.0-40.4).

The primary imaging endpoint of mean minimum stent area after PCI was significantly lower in the OCT-guided PCI group compared with the angiography-guided group (5.72 ± 2.04 mm2 vs 5.36 ± 1.87 mm2, mean difference 0.36 mm2, 95% confidence interval [CI] 0.21–0.51, p<0.001). Among other procedural endpoints, OCT-guided was associated with improved procedural success (rate difference 17.2; 95% CI 13.6– 20.8) and stent expansion compared with angiography-guided PCI (percentage mean stent expansion, mean difference 8.2, 95% CI 6.9-9.5; mean stent expansion ≥90%, rate difference 17.2, 95% CI 13.6–20.8; intrastent area, mean difference 0.34 mm2, 95% CI 0.19–0.49; and total flow area, mean difference 0.31 mm2, 95% CI 0.16– 0.46). OCT-guided PCI was also associated with a significant reduction in major dissection (rate difference -2.2%, 95% CI -3.9– -0.6), major malapposition (rate difference -17.4, 95% CI -20.6– -14.1), major tissue protrusion (rate difference -3.0, 95% CI -4.9– -1.0), and untreated focal reference segment disease (rate difference -2.7, 95% CI -5.1– -0.2) as well as procedure-related thrombosis (2.3% vs 4.1%; rate difference -1.8, 95% CI -3.1− -0.4) compared with angiography-guided PCI. Procedural complications related to OCT imaging were similar among groups, occurring in 1 patient in the OCT-guided and 2 patients in the angiography-guided group, respectively. No information about postprocedural acute kidney injury was provided.

At a median follow-up of 729 days [709-742], the primary clinical endpoint target-vessel failure was not significantly different between OCT- and angiography-guided PCI (7.4% vs 8.2%; hazard ratio [HR] 0.90, 95% CI 0.67–1.19, P=0.45). Consistently, the composite endpoint of target lesion failure was not significantly different between OCT- and angiography-guided PCI (6.4% vs 7.1%; HR 0.89, 95% CI 0.65–1.21). With respect to the individual components of the primary clinical endpoint between OCT- and angiography-guided PCI, cardiac death (0.8% vs 1.3%; HR 0.57, 95% CI 0.25–1.29), target-vessel myocardial infarction (2.5% vs 3.3%; HR: 0.77, 95% CI: 0.48–1.22); and ischemia-driven target-vessel revascularization (5.6% vs 5.6%; HR 0.99, 95% CI 0.71–1.40) were not significantly different. Ischemia-driven target lesion revascularization occurred in 4.5% of patients assigned to OCT-guided PCI and 4.3% of patients assigned to angiography-guided PCI (HR 1.05, 95% CI 0.71-1.54). Definite or probable stent thrombosis occurred in 0.5% of patients assigned to OCT-guided PCI and 1.4% of patients assigned to angiography-guided PCI (HR 1.05, 95% CI 0.71-1.54; P=0.02).

Critical reading and the relevance for clinical practice

The main conclusion derived from the ILUMIEN IV trial is that while OCT-guided PCI is associated with improved angiographic, imaging, and procedural outcomes when compared to angiography-guided PCI, these favourable results do not have a significant impact on long-term clinical outcomes except for definite or probable stent thrombosis.

The results of the ILUMIEN IV trial are difficult to interpret, especially in light of the main conclusions of the OCTIVUS and OCTOBER trials, presented in the same Hot Line session at the ESC Congress 2023. (8,9) Indeed, the OCTIVUS trial enrolling 2008 patients undergoing PCI randomly assigned to OCT or IVUS guidance found that at 1 year OCT was noninferior to IVUS in terms of the primary endpoint of target vessel failure (2.5% vs 3.5%; absolute difference –0.6%, upper boundary of one-sided 97.5% CI 0.97%, Pnoninferiority<0.001; HR 0.80, 95% CI 0.47-1.36) and superior to IVUS in terms of major procedural complications (2.2% vs 3.7%, P=0.047). (8) In addition, the OCTOBER trial enrolling 1201 patients undergoing PCI for bifurcation disease (two-stent strategy adopted in 64.1% patients) randomly assigned to OCT or angiography guidance found that at 2 years OCT was associated with a significant reduction in the rates of major adverse cardiac events (10.1% vs 14.1%; HR 0.70, 95% CI 0.50-0.98, P=0.035). (9)

It should be also acknowledged that the results of the ILUMIEN IV trial come in the context of lower-than-expected rates of target vessel revascularization (7.5% observed vs 12% expected). These considerations not only translate into an insufficient statistical power to detect differences between the two groups, suggesting that either longer follow-up or a higher number of patients would have been necessary to have conclusive results but may also indicate that lesion complexity is inferior to previous trials. However, the main characteristics of lesion complexity such as total stent length per patient, bifurcation disease, chronic total occlusion, and unstable disease are generally in line with previous trials.

Another possible explanation relies on the different familiarity with OCT of operators across the enrolling centres. However, overall, in the ILUMIEN IV trial participating centres and operators were selected based on their technical experience with OCT and the significant angiographic, imaging, and procedural improvements observed in the OCT-guided PCI group compared with the angiographic-guided PCI group indicate an appropriate PCI optimization in the OCT group.
Finally, considering the mixed results surrounding the use of OCT to guide PCI while accumulated evidence supporting the use of IVUS to guide PCI is more robust and consistent, it might be argued that OCT is inferior to IVUS. However, this interpretation would not be deemed acceptable, as the existing direct comparisons between OCT and IVUS have not yielded such findings. Moreover, the substantial amount of valuable information offered by OCT is evident to operators who possess familiarity with the technique.

References

1. Hong SJ, Kim BK, Shin DH, et al. Effect of intravascular ultrasound-guided vs angiography-guided everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial. JAMA 2015;314:2155-2163. doi:10.1001/jama.2015.15454.
2. Hong SJ, Mintz GS, Ahn CM, et al. Effect of intravascular ultrasound-guided drug-eluting stent implantation: 5-year follow-up of the IVUS-XPL randomized trial. JACC Interv 2020; 62-71. doi: 10.1016/j.jcin.2019.09.033.
3. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE trial. J Am Coll Cardiol 2018;72:3126-3137. doi: 10.1016/j.jacc.2018.09.013
4. Gao XF, Ge Z, Kong XQ, et al. 3-Year Outcomes of the ULTIMATE Trial Comparing Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation. JACC Cardiovasc Interv 2021;14:247-257. doi:10.1016/j.jcin.2020.10.001.
5. Lee JM, Choi KH, Song YB, et al. Intravascular Imaging-Guided or Angiography-Guided Complex PCI. N Engl J Med 2023;388:1668-1679. doi:10.1056/NEJMoa2216607.
6. Ali ZA, Landmesser U, Galougahi KK, et al. Optical coherence tomography-guided coronary stent implantation compared to angiography: a multicentre randomised trial in PCI – design and rationale of ILUMIEN IV: OPTIMAL PCI. EuroInterv 2021;16:1092-1099.
7. Ali ZA, Landmesser U, Maehara A, et al. Optical Coherence-Tomography-Guided versus Angiography-Guided PCI. N Engl J Med 2023 (Ahead of print). doi:10.1056/NEJMoa2305861
8. Kang DY, Ahn JM, Yun SC, et al. Optical Coherence Tomography-Guided or Intravascular Ultrasound Guided Percutaneous Coronary Intervention: The OCTIVUS Randomized Clinical Trial. Circulation 2023 (Ahead of print). doi:10.1161/CIRCULATIONAHA.123.066429
9. Holm NR, Andreasen LN, Neghabat O, et al. OCT or Angiography Guidance for PCI in Complex Bifurcation Lesion. N Engl J Med 2023 (Ahead of print). doi:10.1056/NEJMoa2307770

 

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