Over-expansion of drug-eluting stents in patients with left main coronary artery disease: An in vivo study.

Objective We aimed to determine the capacity of drug-eluting stent (DES) over-expansion in left main coronary artery disease. Methods Left main interventions with the largest available DES platforms (4.0 mm) and post-dilation performed with large non-compliant balloons (≥ 4.5 mm) were included. Maximal stent diameter (mm) and area (mm2) were measured using post-intervention intravascular ultrasound (IVUS). Stent diameter and area were calculated with the balloon diameter and inflation pressure. The diameter and area expansion indices were defined as follows: maximal/calculated stent diameter and maximal/calculated stent area, respectively. Results Twenty-three consecutive patients were included. The maximal stent diameter was 4.40 mm (4.30-4.80 mm), and 22 of 23 patients showed a diameter expansion index greater than 0.90. The area expansion index was 0.862. The expansion index < 0.85 group had a significantly higher percentage of calcification ≥ 90° on IVUS than did the expansion index ≥ 0.85 group (72.7% versus 16.7%, P = 0.007). One stent fracture occurred during over-expansion and one ischemic event occurred during follow-up. Conclusions DESs with a nominal diameter of 4.0 mm can be effectively over-expanded in left main coronary artery disease. Achievement of predicted stent area can be affected by calcification.

Introduction

The left main coronary artery (LMCA) is the initial portion of the left coronary artery circulation, which supplies the majority of the left ventricle. Significant LMCA disease, which is commonly defined as narrowing of the luminal diameter of greater than 50%, is considered the highest risk coronary artery disease subtype and is associated with a poorer prognosis than non-LMCA disease.[1] Before the era of drug-eluting stents (DESs), percutaneous interventions involving the LMCA were associated with considerable risks of acute complications and early mortality,[2,3] as well as long-term restenosis.[4] Therefore, for the last several decades, coronary artery bypass grafting (CABG) has been the standard revascularization treatment for LMCA lesions.

The results of recent, randomized, controlled, trials have shown that the performance of PCI with DESs has comparable cardiac adverse event rates with those of CABG in patients with LMCA disease, especially in patients with less anatomically complex lesions.[5-9] On the basis of these favourable findings, the current guidelines recommend performing PCI as an alternative revascularization strategy for treatment of LMCA lesions with low or intermediate anatomic complexity (Class II).[10,11]

One of the major issues associated with LMCA PCI procedures is the large reference diameter of the left main stem. Several intravascular ultrasound (IVUS) studies have shown that the maximal LMCA diameter can be up to 4.8–5.5 mm,[12,13] while the maximal diameter of most commercially available DESs is 4.0 mm. Stent over-expansion with larger post-dilation balloons may be the only method of reducing the risk of incomplete stent apposition. The over-expansion capacity of contemporary DES platforms has been thoroughly investigated in several in vitro studies,[14-16] while in vivo data regarding this phenomenon are still limited. Therefore, we aimed to determine the efficacy and safety of over-expansion of the current commercially available DESs (4.0 mm) in patients with LMCA disease.

Materials and methods

This was a single-centre, retrospective study. All PCIs performed between January 2013 and June 2016 were retrospectively reviewed to identify the LM interventions that met the following inclusion criteria: (1) interventions performed on de novo LMCA lesions, (2) interventions performed using DESs with a nominal diameter of 4.0 mm, (3) interventions involving post-dilation using non-compliant balloons with a nominal diameter of no less than 4.5 mm, (4) and interventions in which IVUS measurements were performed before stent deployment and after the final post-dilation. The following interventions were excluded from the study: (1) interventions involving use of the two-stent technique for LM bifurcations and (2) interventions in which post-dilation was performed with the kissing balloon technique. The appropriate institutional review board approved the study and informed consent was obtained from each patient.

IVUS measurement protocol

All IVUS images were independently reviewed and analysed by a skilled interventional cardiologist who was blinded to the nominal diameters and inflation pressure of the post-dilation balloons. An Eagle Eye® catheter (Volcano Europe BVBA, Brussels, Belgium) was used for pre- and post-interventional IVUS measurements. A total of 100 µg of intracoronary nitroglycerin was injected before each measurement. The ultrasound images were recorded from the left anterior descending or left circumflex artery to the left main ostium. A validated computer-based contour detection program allowed semi-automatic detection of the lumen, stent, and vessel boundaries in longitudinally reconstructed views of the region of interest.

IVUS data analysis

Quantitative analysis was performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies.[17] For the pre-interventional IVUS measurements, the left main lesion segment with the smallest luminal cross-sectional area was selected, and the following parameters were measured: (1) minimal lumen diameter (mm), (2) minimal lumen area (mm2), and (3) plaque burden. For the post-interventional IVUS measurements, the left main in-stent segment with the largest in-stent area was selected, and the following parameters were measured: (1) maximal stent diameter (mm) and (2) maximal stent area (mm2). Additionally, the left main in-stent segment with the smallest in-stent area was selected for measuring the minimum stent area (mm2). We used the maximal stent diameter/area mainly because it is more likely to be affected by the plaque burden and plaque components than by stent over-expansion capability. Calcification was measured in degrees using the semi-quantitative grading method in the location of maximal stent area measurement.[17] Calcification was divided into two categories: (1) < 90°, less than one quadrant; and (2) ≥ 90°, no less than one quadrant.

The predicted stent diameter (mm) was calculated using the balloon diameter and inflation pressure of the final post-dilation based on the data provided by the manufacturers. The predicted stent area (mm2) was defined as follows: π × (predicted stent diameter/2)2. The diameter expansion index was defined as the ratio of the maximal stent diameter to the predicted stent diameter after post-dilation. The area expansion index was defined as the ratio of the maximal stent area to the predicted stent area after post-dilation.

Statistical analyses

Categorical variables are shown as numbers (percentages). Continuous data are shown as medians (interquartile ranges). Spearman correlation analysis was used to determine the correlation between the maximal stent diameter and predicted stent diameter, as well as the correlation between the maximal/minimal stent area and predicted stent area. The Mann–Whitney U test and chi-square test were used for intergroup comparison of continuous and categorical variables, respectively. The multiple regression model was used to further determine the potential factors associated with stent expansion. Statistical analyses were performed with the SPSS statistical software package (version 20.0, IBM Corp., Armonk, NY, USA) and GraphPad Prism (version 5.0, GraphPad Software Inc., San Diego, CA, USA).

Results

A total of 23 consecutive patients were eligible for inclusion in this study. Most of the patients were men and the median age of the study population was 66 years. Acute coronary syndrome was the major indication for PCI (87.0%) and most of the lesions featured bifurcations (78.3%). The baseline and angiographic characteristics of the study population are summarized in Table 1. Four commercially available DESs with the largest stent platform were analysed, including the PROMUS Element™ (N = 5), XIENCE Xpedition™ (N = 8), Resolute Endeavor™ (N = 7), and Partner™ (N = 3) stents. The designs of these four DESs are shown in Table 2.

Table 1.

Baseline and angiographic characteristics of the study population.

Variables	N = 23
Male, n (%)	20 (87.0%)
Age, years*	66 (56-68)
Hypertension, n (%)	13 (56.5%)
Diabetes, n (%)	6 (26.1%)
Current smoker, n (%)	15 (65.2%)
Family history of coronary artery disease, n (%)	4 (17.4%)
Dyslipidemia, n (%)	16 (36.6%)
Previous revascularization
PCI, n (%)	3 (13.0%)
CABG, n (%)	0 (0%)
Indication for PCI
Acute coronary syndrome, n (%)	20 (87.0%)
Stable angina, n (%)	3 (13.0%)
Left main lesions
Bifurcation, n (%)	18 (78.3%)
Ostium/shaft, n (%)	5 (21.7%)
Left ventricular ejection fraction
>50%, n (%)	20 (87.0%)
30-50%, n (%)	2 (8.7%)
<30%, n (%)	1 (4.3%)
Rotablation, n (%)	1 (4.3%)

PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting.

Data are presented as median (interquartile range).

Table 2.

Design of four different drug-eluting stents.

DES	Largest platform	Metal material	Drug coating	Crown	Connectors	Manufacturers	Maximal diameter recommended by manufacturers
PROMUS Element™	4.0 mm	PtCr	Everolimus	10	2	Boston Scientific, Natick, MA, USA	4.75 mm
XIENCE Xpedition™	4.0 mm	CoCr	Everolimus	9	3	Abbott Vascular, Santa Clara, CA, USA	4.5 mm
Resolute Endeavor™	4.0 mm	CoCr	Zotarolimus	10	2-3	Medtronic, Minneapolis, MN, USA	4.5 mm
Partner™	4.0 mm	Stainless steel	Sirolimus	9	3	Lepu Medical, Beijing,China	4.25 mm

All of the included patients’ IVUS images were suitable for analysis. The maximal stent diameter was 4.40 mm (interquartile range: 4.30–4.80 mm) (Figure 1(a)) and the maximal stent area was 14.0 mm (interquartile range: 13.1–15.6 mm) (Figure 1(b)). The diameter expansion index was 0.968 (interquartile range: 0.940–1.004), and 22 of 23 patients had diameter expansion indices greater than 0.90 (Figure 1(c)). The maximal stent diameter was linearly correlated with the calculated stent diameter, with a correlation coefficient of 0.718 (P < 0.001) (Figure 2). However, the area expansion index was only 0.862 (0.806–0.917). There was also a linear correlation between the maximal stent area and calculated stent area (correlation coefficient: 0.562, P < 0.001) (Figure 2). There was no significant association between the minimal stent area and calculated stent area (correlation coefficient: 0.38, P = 0.073) (Appendix Figure 4)

Figure 1.

Maximal stent diameter (a) and area (b) measured by post-intervention IVUS; diameter and area expansion indices of the included stents (c).

Figure 2.

Relationship between the maximal stent diameter and calculated stent diameter (a); relationship between the maximal stent area and calculated stent area (b).

According to the area expansion indices of the patients, the patients were further divided into the following two groups: the expansion index ≥ 0.85 group (N = 12) and the expansion index < 0.85 group (N = 11). There were no significant differences in LMCA lesion characteristics, minimal lumen diameter/area before PCI, stent length, stent deployment pressure, post-dilation balloon diameter, and post-dilation pressure between the two groups. However, there was a significant difference in IVUS calcification between the two groups. Patients with an expansion index < 0.85 had a significantly higher calcification percentage ≥ 90° on IVUS than did patients with an expansion index ≥ 0.85 (72.7% versus 16.7%, P = 0.007) (Table 3). In the multiple regression model, calcification (≥90°) was still significantly associated with a lower expansion index (< 0.85), even after adjustment for bifurcation lesions, pre-intervention minimal lumen area, plaque burden, post-dilation balloon size, and pressure (B = 4.056, P = 0.046).

Table 3.

Comparison of lesion characteristics, stents, and post-dilation balloon diameters between the expansion index (area) ≥ 0.85 and expansion index (area) < 0.85 groups.

	expansion index ≥0.85 (N = 12)	expansion index <0.85 (N = 11)	P value
Left main bifurcation lesion, n	8 (66.7%)	10 (91.7%)	0.159
Minimal lumen diameter before PCI, mm	2.20 (2.00 - 2.40)	2.20 (2.05-2.53)	0.749
Minimal lumen area before PCI, mm2	6.30 (4.00-7.30)	4.65 (4.35-6.18)	0.378
Maximal plaque burden, %	69.5 (62.9-81.6)	74.1 (71.5-80.5)	0.181
IVUS calcification ≥ 90°, n	2 (16.7%)	8 (72.7%)	0.007
Stent length, mm	18 (15-20)	18 (15-20)	1.000
Stent deployment pressure, atm	14 (10-16)	12 (12-16)	0.950
Post-dilation balloon diameter	/	/	/
4.5 mm	10 (83.3%)	9 (81.8%)	0.924
5.0 mm	2 (16.7%)	2 (18.2%)	/
Post-dilation balloon pressure, atm	15 (12-20)	14 (12-18)	0.385

PCI: percutaneous coronary intervention; IVUS: intravascular ultrasound.

Only one adverse event occurred during the over-expansion process. This event occurred in a 50-year-old patient with isolated stenosis of the LMCA ostium. A PROMUS Element stent (4.0 mm × 16 mm) was deployed at 16 atm after pre-dilation of the lesion (Figure 3(a)). After post-dilation with a Quantum 5.0-mm × 8-mm stent at 16 atm (Figure 3(b)), the distal portion of the stent fractured and the struts fell into the lumen (Figure 3(c)), as confirmed by IVUS (Figure 3(d), supplementary video). Another PROMUS 4.0-mm × 12-mm stent was immediately implanted to cover the fractured segment of the previous stent.

Figure 3.

A case of acute stent fracture during the process of over-expansion.

(a) Image acquired immediately after stent deployment (PROMUS Element 4.0 mm × 16 mm); (b) post-dilation with a Quantum 5.0-mm × 8-mm stent at 16 atm; (c) distal portion of a fractured stent; (d) IVUS shows that the stent had fractured and that the struts had fallen into the lumen.

The medium follow-up duration was 16 months (6–27 months). One patient was admitted for revascularization because of in-stent restenosis of the target lesion.

Discussion

In this study, we attempted to determine the over-expansion capacity of DESs with a nominal diameter of 4.0 mm, as determined by IVUS. Our major finding was that over-expansion of DESs with post-dilation (4.5–5.0-mm post-dilation balloon) could effectively achieve the predicted stent diameter. However, the predicted stent area achievement varied, which could have been due to the presence of calcification.

An in vitro study showed that most of the current DES platforms could be over-expanded above their nominal diameters.[14] For DESs with the largest design (4.0 mm), a maximal stent diameter > 5.5 mm could be achieved using a 6.0-mm semi-compliant balloon at 14 atm.[14] However, the in vivo behaviour of these stents during the over-expansion process may vary considerably. Interactions between stents and plaques/arteries may cause recoil, deformation, and fracture of stents. Previous studies have shown that the magnitude of stent recoil reported in vivo is significantly greater than that reported in bench testing. In an in vivo animal study (Yorkshire pigs), Carrozza et al.[18] found that stent recoil can reach up to 30%, even after oversized post-dilation, in normal and compliant coronary arteries. Bermejo et al.[19] found that elastic recoil was one of the major mechanisms responsible for residual luminal stenosis in patients with coronary artery disease. Additionally, in their study, the luminal dimensions after stenting were only 57% of the maximal achievable luminal dimensions after high-pressure stent deployment, which was confirmed by subsequent studies.[20,21] Therefore, unlike previous in vitro studies,[14,16] our study provided direct in vivo evidence regarding over-expansion in patients with LMCA disease.

Notably, one adverse event involving an acute severe stent fracture, which is a rare complication of stent deployment, occurred during over-expansion in our study. PROMOUS Element stents use a helical two-connector design to achieve maximal flexibility. However, this design may jeopardize the stability of the platform while the stent is over-expanded. Therefore, the number of connectors in PROMOUS Premier™ stents has been increased to five (4.0 mm platform) in the proximal stent segment to enhance radial strength. Although the findings of the current in vitro study showed that current DES platforms could be over-expanded to achieve a maximal stent diameter > 5.5 mm,[14] the following two points must be taken into consideration. The first point is regarding sample size. Only one stent for each platform is usually tested. The second point is regarding stent-plaque interactions. Plaque distribution and components can lead to variations in radial force in different parts of the stent during over-expansion. Moreover, significant crown deformation has been observed in most of the platforms when a maximal stent diameter >5.5 mm was achieved in vitro.[14] Therefore, DES over-expansion in vivo should be applied with caution, especially when using stents with a predicted diameter> 5.0 mm.

The long-term outcome of DES over-expansion in this population is still unknown. Kuriyama et al.[22] reported that bare metal stent over-dilation resulted in a larger intimal-luminal dimension and provided a larger follow-up lumen. Unfortunately, follow-up IVUS data were not available in our study. Therefore, we were unable to assess the effect of over-expansion on intimal hyperplasia.

Our study has several limitations. First, because of the small sample size of the study, it may have been underpowered for detecting other potential differences between two groups. Second, as we mentioned above, follow-up IVUS results were not available for the patients who were included in this study. Third, we could not assess the effect of over-expansion on other DES parameters, such as drug coating and delivery. Finally, different stent types, and differences in lesion location and preparation may also have affected the final results of stent expansion.

Conclusion

The findings of our in vivo study indicate that DESs with a nominal diameter of 4.0 mm can be over-expanded in patients with LMCA disease. Achievement of the predicted stent area can be affected by the percentage of calcification. Stent fracture is a potential complication of over-expansion of stents in vivo.