Our findings revealed that 1) the minimum NIC grade was lower in the patients with DM compared to the non-DM patients at 3-5 months after DES implantation; 2) the dominant NIC grade, maximum NIC grade, yellow color grade, and the incidence of thrombus adhesion were similar between the DM and non-DM groups; 3) DM was an independent factor for predicting the minimum NIC of grade 0, which demonstrates uncoverage; 4) in the DM group, the use of sulfonylurea was an independent predictor of the minimum NIC of grade 0 even after the adjustment for confounding factors. To the best of our knowledge, this is the first report describing the relationship between early-phase arterial healing after DES implantation and DM.
Immediately after stent implantation in coronary arteries, bare stent struts are in direct contact with the vessel wall, and the process of arterial healing begins as follows (16) (17): 1) the first step in arterial healing is the formation of a local thrombus. At the injury site, platelets, fibrin, and red blood cells accumulate and a local thrombus is formed; 2) then, inflammatory cells such as macrophages infiltrate the site; 3) inflammatory cells secrete various growth factors such as platelet-derived growth factor, and smooth muscle cells (SMCs) migrate into the site and begin to proliferate; 4) at 2 weeks after stenting, in addition to the proliferation of SMCs, the extracellular matrix is formed. Neointima formation, that is, neointimal coverage is completed in 12 weeks. The neointima is lined by one layer of endothelial cells which served as an antithrombotic barrier. However, delayed arterial healing sometimes occurs after DES implantation due to the component of DES instead of preventing SMC proliferation, which can lead to in-stent restenosis (18). A pathological study suggested that widely uncovered struts are a risk factor for stent thrombosis (19), and optical coherence tomography (OCT) studies reported that uncoverage was one of the mechanisms of stent thrombosis (20-22). There have been several articles which mentioned the neointimal coverage in relation to DM evaluated by OCT. Briguori C et al elucidated that baseline on-clopidogrel platelet reactivity and complex lesions were independent predictors of uncovered strut rate at 3 months (23). Kubo T et al compared the OCT findings between 1st generation sirolimus-eluting stent and 1st generation paclitaxel-eluting stent, and they demonstrated that 1st generation sirolimus-eluting stent showed stronger prohibition of neointimal hyperplasia compared with 1st generation paclitaxel-eluting stent in DM patients as well as in non-DM patients (24). Kuroda et al reported that large glucose fluctuations were an independent risk factor for impaired uniform vessel healing after second-generation DES (25). However, these articles did not compare the early-phase arterial healing between DM and non-DM patients. In the present study, the CAS evaluation demonstrated that the rate of the minimum NIC of grade 0 was significantly higher in the DM group compared to the non-DM group at 3-5 months after DES implantation, which suggests that arterial healing is more delayed in patients with DM compared to those without it.
There are several reports regarding the relationship between the findings of intravascular imaging devices and DM. Kurihara et al. used angioscopy and observed that compared to non-diabetic patients, in pre-diabetic and diabetic patients the number of yellow plaques was greater and the intensity of yellow was greater (26). They also reported that the number of yellow plaques and the maximum yellow color grade were significantly greater in patients with diabetic retinopathy than in those without it (27). However, in the present study the yellow color grade was similar between the DM and non-DM groups. Kurihara et al. assessed the CAS findings of the native coronary arteries, whereas we evaluated them 3-5 months after DES implantation. Even with the observation in the relatively early phase after the DES implantation, the difference in the timing of the CAS observations would contribute to the difference in the yellow color grade outcome.
An optical coherence tomography study demonstrated that DM patients had a higher prevalence of calcification compared to non-DM patients (28). Malapposition can occur when a stent is implanted in a lesion with severe calcification, because a site of calcification may result in a localized underexpansion of the stent and malapposition at its vicinity due to either insufficient balloon pressure or an inability to overcome the inherent stiffness of the stent structure (29). One of the mechanisms of arterial healing is that the migration and proliferation of SMCs occur longitudinally from the area where the stent struts attach to the vessel wall, and acute malapposition is related to the following insufficiency of the stent coverage (30). Severe calcification can therefore cause incomplete stent apposition after DES implantation, which may result in delayed healing. Although we cannot make a conclusion due to the non-availability of intravascular imaging findings immediately after DES implantation in the present series, we speculate that more severe calcification would contribute to the higher incidence of the minimum NIC of grade 0 3-5 months after DES implantation in DM patients.
Our present analyses revealed that the post-dilatation balloon size and post-dilatation balloon inflation pressure were the negative predictors of the minimum NIC of grade 0. A study of peripheral arteries showed that the oversized stents caused more neointimal proliferation, which was due to the greater injury to the vessel wall (31). In addition, malapposition was related to the subsequent incomplete NIC (27). Adequate strut embedment may cause better neointimal coverage (32, 33). Since a smaller balloon size and lower inflation pressure would result in less injury to the vessel wall, the difficulty of achieving complete apposition to the vessel wall and inadequate strut embedment, the post-dilatation balloon size and post-dilatation balloon inflation pressure were negatively associated with uncoverage in this study.
Although a previous article revealed that the negative prognostic effect of DM following contemporary PCI was heightened in the presence of insulin treatment (34), insulin therapy did not impact on the early-phase arterial healing in the current study. Instead, we observed that the use of sulfonylurea was an independent predictor of the minimum NIC of grade 0 in the DM patients. It is apparent that aggressive glucose-lowering therapy increased the mortality of DM patients (35), and it has been reported that the use of sulfonylurea itself increased the risk of adverse cardiovascular events (36, 37). Although the mechanisms underlying the relationship between the use of sulfonylurea and delayed arterial healing after DES implantation in the early phase are not yet understood, it appears that the delayed healing caused by the usage of sulfonylurea may contribute to patients’ poor clinical outcomes. Our present findings also revealed that the glucose control parameters such as the HbA1c had no association with the NIC, and the aggressive glucose control did not impact on the early-phase arterial healing after DES implantation. Although the precise mechanism remains to be undetermined, sulfonylurea treatment should be avoided to prescribe in patients with DM.
There have been several reports which mentioned the relationship between thrombogenicity and DM. Nusca et al reported that glyco-metabolic state significantly correlated with high platelet reactivity in well-controlled type 2 DM patients on clopidogrel therapy and HbA1c identified patients at higher thrombotic risk but the highest diagnostic accuracy was achieved by combining glycemic variability and HbA1c (38). Lee et al mentioned that impaired glucose metabolism was associated with increased thrombin generation potential in patients undergoing PCI (39). However, the incidence of thrombus adhesion was similar between DM and non-DM patients in the current study. This would be because angioscopic thrombus does not directly mean the thrombogenicity. In other words, angioscopic thrombus adhesion is a benchmark of the completeness of arterial healing because it does not occur where satisfactory arterial healing is achieved (40, 41).
Recent guidelines note that the patient’s bleeding risk and the thrombotic risk should be considered when selecting the duration of DAPT (42-44). The DAPT score is a landmark of the duration of DAPT performed 1 year after stent implantation, and the presence of DM is one of the factors that encourages the longer DAPT (42). The PRESICE DAPT score, which evaluates the duration of DAPT at the time of stent implantation, does not include DM as a factor (43). In the PARIS scoring system, which predicts the risk of thrombotic and bleeding events after discharge based on only the patient’s background, DM is one of the factors that increases the thrombotic risk (44). A recent European Society of Cardiology guideline also suggests that diffuse lesions in an individual with DM is a risk for stent thrombosis (3). A diabetic sub-analysis from the PEGASUS-TIMI 54 scribes this point concluding that prolonged DAPT regimens is beneficial in patients with DM (45). Furthermore, the DAPT score is utilized for prolonged DAPT regimens after one year (42). Numerous recent trials also have investigated the optimal therapy time for DAPT in non-exclusive DM population below one year in which the results leaves room for debate (46-48). The patients with DM were low in these trials and therefore these results should not be applied to diabetic patients. In addition, although some clinical trials revealed that the clinical outcomes with short DAPT were non-inferior to those with long DAPT in DM patients, the duration of short DAPT was around 6 months (49, 50). In the present study, the CAS evaluations demonstrated that the rate of the minimum NIC of grade 0 was significantly higher in the DM group than in the non-DM group 3-5 months after DES implantation, which is consistent with the concept that DM is a factor that increases the thrombotic risk even in the early phase. Clinicians should therefore pay attention to the possibility of switching from DAPT to SAPT in the early phase for patients with DM, and the recent ultra-short DAPT strategy might not be easily applied to DM patients.
Limitations
This study has several limitations. First, it was a non-randomized, retrospective, observational study; however, the multi-center aspect of the study made the sample size relatively large compared to those of previous studies. Second, an angioscopically observed thrombus does not directly indicate the risk of stent thrombosis. Third, although underlying plaque morphology is associated with vessel healing with neointimal formation, we did not evaluate the baseline lesion morphology by fixed intravascular imaging devices. Forth, since there was a possibility of some differences between 3 months and 5 months after stenting in regard to the NIC, more strict selection of the cases regarding the timing of CAS evaluation would be preferable. However, since the sample size was limited in this retrospective analysis, we cannot help including patients with 3-5 months follow-up. In addition, the follow-up duration was not independently associated with minimum NIC of grade 0 as shown in Table 5. Fifth, the CAS devices were not fixed between these facilities, because this was a retrospective study. Sixth, we included the various type of DES, although it would have a great impact on the results. However, since this was a retrospective study and the sample size was limited, we could not help including the various type of stent, and the type of DES was similar between DM and non-DM groups as shown in Table 4. Seventh, the follow-up time in the DM group was shorter than in the non-DM group and it could affect in the endpoints results. However, in terms of the minimum NIC of Grade 0, follow-up duration did not impact on the result as shown in Table 5. Finally, on some occasions the CAS could not completely evaluate the entire stented segment because of the limitations of the CAS visual field, especially in angulated or tortuous lesions.