Clinical Outcomes after Intravascular Ultrasound Assessment of Coronary Intermediate Lesions

Purpose: Coronary angiography has limitations in the assessment of intermediate coronary lesions (ICL). Intravascular ultrasound (IVUS) can evaluate more accurately the severity of a lesion to guide the therapeutic strategy. This study sought to evaluate long-term clinical outcomes after IVUS-guided coronary revascularization of ICL lesions in patients from the Western Mediterranean region of coastal North Africa (Maghreb) in whom IVUS severity criteria have not been validated. Methods: We conducted a prospective monocentric study including 113 patients with angiographic ICL evaluated by IVUS. Minimal lumen area (MLA) cut-offs value to perform revascularization were 6 mm2 for the left main coronary artery (LMCA) and 4 mm2 for nonLMCA lesions. The primary outcome was defined as a composite of major adverse cardiac events (MACE) including death, myocardial infarction (MI), and target lesion revascularization (TLR) at 12 months. Results: Mean age was 59,5 ± 12,0 years, 79% were men. Multi-vessel disease was present in 65.5% of our patients, of whom 36 patients had LMCA disease. We analysed 146 arteries with 178 lesions. Revascularization was deferred for n=46 (40.7%) patients after IVUS evaluation. After a mean follow-up of 20± 10 months, we observed no significant differences between the revascularized patients and the patients with a deferred revascularization strategy in terms of mortality (1.5% and 2.2% respectively, p=0.7), and a favourable safety trend for 12-month rate of MACE (10.6% and 2.2% respectively, p=0.165), MI (4.5% and 2.2%, p=0.44) and TLR (10.7% and 2.2%, p=0.23). Conclusion: We demonstrate that previously validated IVUS criteria to defer revascularization of angiographically ICL can be safely applied to Maghrebi patients.


Introduction
Clinical decision making and the management of intermediate coronary lesions (ICL) continues to be a therapeutic dilemma for cardiologists. The limitations of coronary angiography for the evaluation of such lesions are well recognized since 20 years [1], and adjunctive diagnostic techniques have been developed. Intravascular ultrasound (IVUS) offers the possibility to base decisions not only on lumeno grams but also on true lumen and vessel size and plaque accumulation in the coronary wall. The IVUS criteria reported in the literature defining a functional significant coronary stenosis have been recently reassessed and compared with the fractional flow reserve (FFR) derived from intracoronary pressure measurements. The princeps criteria of a significant stenosis based on a lumen area less than 4 mm² has However, many of these studies were only reporting a head to head comparison with a FFR cut off of 0.75 or 0.8 without outcome data, while a recent prospective study of nearly 700 patients demonstrated that ICL with a lumen area <4 mm² were associated with three more times major adverse cardiovascular events [17]. The aim of this study was to evaluate long-term clinical outcomes in patients from Western Mediterranean region of coastal North Africa (Maghreb) where IVUS studies so far have not been conducted and reported. In these patients, Percutaneous coronary intervention of angiographically ICL was decided on the basis of the IVUS findings using criteria reported in Western population and Asia but so far not prospectively assess in this region of North Africa characterized by a high incidence of diabetes mellitus and hypertension [18,19].

Methods
Study population: Between October 2010 and December 2013, we conducted a prospective monocentric study including 113 patients with angiographically ICL who underwent IVUS assessment to decide whether to perform or not revascularization. Patients with acute myocardial infarction, significant distal lesions, those in whom the IVUS-imaging catheter failed to cross the lesion due to severe stenosis or tortuosity and small vessels (reference diameter <2.5mm) were excluded. The primary outcome was defined as a composite of major adverse cardiac events (MACE) including death, myocardial infarction (MI), and target lesion revascularization (TLR) at 12 months.
Angiographic analysis: Coronary angiography was performed with GE Innova® 2000 and Innova® 2100 IQ interventional cardiology systems. Visual estimation of lesion severity, length and reference diameter was performed and reported on the CARDIOREPORTTM database by a single operator who proposed an initial therapeutic strategy. All lesions were classified according to the ACC/AHA consensus [20]. All ICL, defined by a diameter stenosis of 30% to 50% for the left main coronary artery (LMCA) and 40% to 70% for non-LMCA lesions, were revaluated on a heart team staff, and IVUS evaluation was decided each time that there was no unanimity on the therapeutic strategy.
IVUS analysis: Intravascular ultrasound guidance was performed using conventional 6-F guiding catheters and a 0.014mm guide wire positioned distally, and 40 MHz IVUS catheters (Boston Scientific®) pulled back automatically at a constant speed of 0.5 mm/s. After imaging acquisition the lumen-intima and media-adventitia interfaces were measured at the target site following the guidelines of the American College of Cardiology MLA cut-offs value to perform revascularization were 6 mm² for the LMCA and 4 mm² for non-LMCA lesions.
Clinical Data, Definitions, and Outcomes: Hospital records of all patients were reviewed to obtain information on clinical demographics and medical history. Follow-up information was obtained through review of hospital charts or telephone interviews. The primary outcome was defined as a composite of major adverse cardiac events (MACE), including death, myocardial infarction (MI), and target lesion revascularization (TLR) at 12 months. Death was defined as cardiac mortality. The diagnosis of myocardial infarction was based on either the development of new pathological Q waves in ≥ 2 contiguous electrocardiogram leads and/or cardiac enzyme level elevation 3 times the upper limit of normal value. TLR included target lesion percutaneous coronary intervention (PCI) and bypass surgery of the target lesion (CABG).
Statistical analysis: Statistical analysis was performed using IBM® SPSS® Statistics version 20 for Windows. Data are expressed as mean ± SD for continuous variables and as percentages for discrete variables. The normal distribution of variables was verified by the Kolmogorov-Smirnov test for normality. Categorical data were compared using chi-square test. Event-free survival curves were established using the Kaplan-Meier estimation. All calculated p values were 2-sided and differences were considered to be statistically significant when the respective p values were < 0.05. A total of 113 consecutive patients were included, 146 arteries and 178 lesions were analysed. Baseline clinical characteristics, angiographic and IVUS finding are summarized in (Table 1). Complete follow-up data were available for 112 patients over a mean follow-up time of 20 ± 10 months. There was no protocol violation and all patients with MLA values below the defined cutoffs underwent either PCI or CABG. Overall revascularization was deferred for 46 patients (40.7%) after IVUS assessment. There were significantly more patients with diabetes mellitus, hypercholesterolemia and complex lesions in the revascularized group (Table 2). Decision making: 31% of the LMCA lesions and 41% of the non-LMCA lesions that were angiographycally estimated more than 50% stenosis were not significant as assessed by IVUS (p<0.01). This discordance resulted in a change in the therapeutic strategy in 49 patients (43.3%) with a significant reduction in the indications of revascularization: 81.6% of the initial PCI or CABG indications in this group were delayed. This was significantly more frequent with lesions involving the LMCA and the proximal left anterior descending artery or when there were 2 or more intermediate lesions to evaluate (Figures 1-4).    Major adverse cardiovascular event at 12 months followup: Overall, 12 patients presented a major cardiac event after a mean follow-up of 20 ± 10 months. In the deferred group, only one cardiac death was reported and one patient presented a MI for which he underwent PCI. There were two cardiac deaths. One patient died after complications of bypass surgery and the second from a NSTEMI complicated by cardiogenic shock, after proximal LAD PCI was not performed in basis of IVUS finding. Three MI occurred: two patients had NSTEMI related to late stent thrombosis, and one patient had anterior STEMI one month after he underwent IVUS assessment for an ICL in the proximal LAD (MLA = 8.61 mm²). During the 12-month follow up period, 10 TLR were performed. Nine patients had PCI; eight with DES and one with BMS. Only one patient had CABG. We observed no Journal of Cardiology & Cardiovascular Therapy significant differences between the revascularized patients and the patients whose revascularization was postponed in terms of mortality (1.5% and 2.2% respectively, p=0.7), 12-month rate of MACE (10.6% and 2.2%, p=0.165), myocardial infarction (4.5% and 2.2%, p=0.44) and 12-month rate of target lesion revascularization (10.7% and 2.2%, p=0.23) (Figures 5 & 6). No cardiac events occurred during the first 12 months follow up for all the patients with LMCA ICL in whom revascularization was deferred. Age and diabetes mellitus were the only significant univariate predictors of, respectively, cardiac death (p<0.01) and TLR (p=0.015). The change of the therapeutic strategy after IVUS evaluation was not correlated with significant change in events rates (Table 3).

Discussion
The present study showed the following: a. There was a poor correlation between visual angiographic estimation and IVUS MLA assessment of a coronary stenosis severity, b. This led to a change of therapeutic strategy in 43.3% of cases, c. The use of a MLA cut-off value of 4 mm² for the non-LMCA stenosis and 6 mm² for the LMCA stenosis, was correlated with favourable outcomes.
The limitations of coronary angiography in assessing lCL severity have been well documented. The inter-observer variability is high and little further information is gleaned from computer-assisted quantitative angiography [1,[22][23][24]. IVUS has been used since the 1990's to assess the severity of intermediate coronary stenosis and several studies proved the good correlation between MLA and the physiological significance of such lesions. Its incremental diagnostic value was proven repeatedly for the most challenging lesions, those of the left main (LM). Sano et al. [25] reported three times more significant lesions by IVUS among 115 consecutive patients with a de novo, angiographically ambiguous, intermediate LM lesions, compared to QCA [25].
Few studies compared IVUS finding with FFR as the "gold standard" for determining the functional significance of LMCA ICL. In an analysis of 55 western patients, Jasti et al. [27] reported that an MLA < 6 mm2 strongly predicted FFR < 0.8 (sensitivity and specificity of 93% and 95%, respectively). Lower MLA cutoff was again reported in Asian population; Kang et al. suggested that 4,8 mm² was the best MLA cutoff correlated to an FFR < 0,8 with 89% sensitivity and 83% specificity.
Care must be taken in the interpretation of these studies conducted in different populations, many in Japan and Korea where there is a large usage of IVUS in the cat lab. There is presently no IVUS report from North Africa / Arabic countries Journal of Cardiology & Cardiovascular Therapy characterized by a higher incidence of smoking, diabetes mellitus, and hypertension.
Different studies had reported that using IVUS to guide decision making induced a significant change in the therapeutic strategy. Mintz et al. [31] reported that pre intervention IVUS imaging performed in 301 patients led to a change on revascularisation therapy in 121 patients (40%). A higher rate of change in clinical decision after IVUS assessment was reported by other authors (60 to 70,6%) [32][33][34]. However there is few clinical trials that established the clinical safety of using IVUS MLA to defer a myocardial revascularization. The chosen MLA cut-off thresholds to defer revascularization in those studies were 4mm² for the non-LMCA ICL [35][36][37] and 6mm² [28,38]or 7.5 mm² [29] for the LMCA ICL (Table 4). In 300 patients with non LMCA ICL, deferring PCI on the basis of an IVUS MLA ≥ 4.0 mm2 was associated with a low rate of events (8% at 12 months) [35]. Clinical safety of this MLA cut off was confirmed by others studies showing even fewer cardiac events [36,37]. Otherwise, compare to FFR based decision making, Hernandez et al. [37] reported that even if IVUS assessment led to more revascularization procedures, there was no significant differences in MACE-free survival (97.7% at one year and 93.1% at two years in the FFR group and 97.7% at one year and 95.6% at two years in the IVUS group; p=0.35) and among those with deferred intervention (97.9% at one year and 94.2% at two years in the FFR group and 96.5% at one year and 93.6% at two years in the IVUS group; p=0.7).
For the LMCA ICL, different studies reported that using the IVUS MLA to defer myocardial revascularisation is also correlated with favourable outcomes [28,29,38]. In the LITRO study [28], which enrolled 354 patients with LMCA ICL, there was no significant difference between the deferred and revascularized groups in terms of cardiac death-free survival (97.7% vs 94.5%, respectively, P = 0.5) and event-free survival (87.3% vs 80.6%, respectively, P = 0.3) after a mean follow up of 24 months. Our study confirmed the high negative predictive value of this MLA cut-off and accordingly the clinical safety of delaying myocardial revascularization of ICL based on IVUS evaluation.
Study limitations: Principal's limitations of the present study are: a. The limited number of included patients due to economic difficulties in an emergent region where IVUS prone are not reimbursed by any insurance funds. We estimate that only one in four patients with ICL underwent IVUS analysis.
b. The MLA cut off value of 4 mm² chose to perform revascularisation on non-LMCA lesions might to appear too high (and well above the ischemic threshold) [12], and c. The lack of clear criteria to make the initial therapeutic decision which was at the operator's discretion.

Conclusion
The use of IVUS in a population from Maghreb to assess angiographically intermediate coronary lesions is correlated with a significant decrease of myocardial revascularization indications and favourable long term outcomes.