In this retrospective cohort study, we enrolled 1029 diabetic patients with stable CTO. Glycemic control was reflected by the HbA1c level detected one year after enrollment. After a long-term follow-up, we observed that: (1) In the overall population, there were no significant difference in the rate of primary endpoint except repeat revascularization. (2) After propensity matched analysis, patients with HbA1c ≥ 7.0 tended to sufferer a higher risk of MACE than those with HbA1c < 7.0, which was mainly attributed to repeat revascularization. And well-controlled glycose (HbA1c < 7.0) resulted in more substantial benefits for CTO-NSR patients in terms of MACE, repeat revascularization and TVR. These benefits were not observed in CTO-SR patients. We think that the differences of the results before and after propensity score matching were the result of strong selection bias, as patients with poorly controlled HbA1c likely had many differences than those with controlled HbA1c as shown in Table 1. This article will focus on the results after propensity score matching and adjustment, because propensity score match (353 pairs) corrected for differences in baseline differences.
Diabetes is considered equivalent to coronary artery disease due to its poor clinical outcomes (17). In the CTO population, the prevalence of diabetes was as high as 34%-40% (18). CTO patients with diabetes suffered poorer clinical outcomes than CTO patients without diabetes (19). A few studies have demonstrated that hyperglycemia can result in an abnormal immune response, vascular inflammation, endothelial dysfunction, thrombosis, myocardial microangiopathy and collateral circulation decreases, and excessive protein glycation end product formation and oxidative stress activation may be two primary mechanisms (6, 11).
However, whether glycemic control benefits diabetic CTO patients is unclear. Indirect evidence could be obtained from previous studies that focused on glycemic control and cardiovascular complications. The VADT (veterans affairs diabetes trial) (20, 21) enrolled 1791 military veterans. After a follow-up of 5.6 years, the study found that intensive glucose control (HbA1c approximately 7.0%) failed to effect the incidence of cardiovascular events, microvascular complications and death. Similar results were also reported by the ACCORD trial and the ADVANCE trial (20, 22, 23). However, the majority of patients enrolled in these three studies were patients without prior cardiovascular events. In the present study, we enrolled only CTO patients, who present with severe atherosclerosis. We demonstrated that patients with HbA1c < 7.0 were superior to patients with HbA1c ≥ 7.0 in terms of MACE, especially in the CTO-NSR subgroup. Our results were consistent with professor Hwang and colleagues (20), who studied 980 diabetic patients undergoing percutaneous coronary intervention and demonstrated that HbA1c < 7.0 (measured two years after PCI) was associated with lower incidence of major adverse cardiac and cerebrovascular events (MACCE). However, the EXAMINE (Examination of Cardiovascular Outcomes: Alogliptin vs. Standard Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) trial (9) reported an opposite outcome. A possible explanation for the different results is the different definitions of the standard of anti-diabetic treatment and the different enrollment criteria or baseline characteristics of the subjects.
Importantly another point that should be emphasized is that vascular complications are not caused by hyperglycemia alone, but hypoglycemia is associated with an increased incidence of cardiovascular events (6, 24). Three studies, including ADVANCE, ACCORD and VADT, showed that hypoglycemia was associated with higher mortality rates than standard glycemic levels (25). Currie et al reported that type 2 diabetes mellitus (DM) patients with hypoglycemia had increased all-cause deaths and cardiac events compared with DM patients with standard glycemic levels (26). These results were the same as those in the study by E. Marchionni, which showed that inappropriate hypoglycemia significantly increased the incidence of cardiovascular death in the intensive treatment group (27, 28). Therefore, determining of the optimal strategy for glycemic control in diabetic CTO patients has important clinical implications.
In our retrospective cohort study, to further examine the relationship between glycemic control and clinical outcomes, we selected HbA1c levels measured 1 year after enrollment, based on which the study population was divided into 2 groups: HbA1c < 7 and HbA1c ≥ 7 groups. Favorable effects were observed in patients with HbA1c < 7, and the incidence of MACE was lower in these patients than in patients with HbA1c ≥ 7; these results were mainly attributed to the decrease in repeat revascularization. In the subgroup analysis, strong benefits were observed in CTO-NSR patients in terms of MACE, repeat revascularization and TVR. Taken together, our results suggest that good glycemic control may improve clinical outcomes in CTO patients with DM, especially CTO-NSR patients. We think that our study provides crucial new information about the target range for glycemic control in diabetic CTO patients.
To date, there have been few studies on the association between CTO in diabetes patients and adverse clinical outcomes. Abdulla et al reported that, for diabetes patients with coronary heart disease, the presence of CTO of coronary arteries increases the risk of death in patients receiving medical therapy alone but may not increase the risk of death in patients treated with revascularization (18). A previous study of CTO PCI in diabetes patients was performed by Bimmer, who reported reduced mortality of diabetes patients after successful CTO PCI (19). However, in the present study, CTO-NSR patients benefited the most from well-controlled glycose (HbA1c < 7.0) in terms of MACE, repeat revascularization and TVR. These benefits were not observed in CTO-SR patients. We think that these results may be explained by well-developed collaterals.
In CTO lesions, the normal coronary blood flow is completely occluded, and the majority of patients develop compensating vascular collateralization to supply ischemic distal tissue (7, 10). Vascular collateralization is a response to slow progressive stenosis; given the prolonged duration of stenosis formation, blood flow is redirected into pre-existing collateral arteries bypassing the occluded artery (9). For CTO-NSR patients, the downstream, postobstruction coronary artery segments depend entirely on collateral blood flow (10). A previous study found that patients with well-developed collaterals have higher rates of survival and lower risk of cardiac death at 5 years than patients with poorly developed collaterals (10). Similarly, some clinical data suggest that collateral blood flow can protect the myocardium of patients with CTO, for example, by reducing transmural myocardial ischemia (29, 30). These results suggested that the degree of vascular collateralization may be significantly related to CTO patient outcomes. However, our study found that CTO-NSR patients benefited the most from well-controlled glycose (HbA1c < 7.0) in terms of MACE, but these benefits were not observed in CTO-SR patients. A possible explanation is that collaterals regress to a greater extent post-SR in CTO-SR patients.
The present study demonstrated a significant reduction in MACE in patients with HbA1c < 7.0, which was mainly attributed to a decrease in repeat revascularization. Although the use of second-generation everolimus-eluting stents (EES) improves treatment efforts of CAD after PCI, patients with diabetes mellitus (DM) have a 2–4 times higher risk compared with patients without DM in terms of rate of in-stent restenosis (2, 3). The available evidence shows that chronic hyperglycemia can lead to vascular endothelial cell damage, with resultant abnormal vasodilation and vasoconstriction functions, excessive extracellular matrix formation, and promoted cellular proliferation, which in turn may lead to restenosis and TVR after PCI (31, 32). DM itself can cause excessive thickening of the vascular intima and is the primary risk factor for higher stent restenosis event rates (33). These findings are supported by some studies by Moussa et al. Jiménez-Quevedo et al. and Nobuyoshi Tanaka et al. These studies show that patients with DM have more frequent stent strut coverage, thicker neointima, and higher neointimal hyperplasia compared with patients without DM after drug-eluting stent implantation (33–35). Therefore, a reduction in repeat revascularization is significantly associated with improved rate of cardiovascular accidents in diabetic patients, and glucose control may be an important factor in determining the appropriate treatment strategy.
In the present study, the benefit of well-controlled glycose (HbA1c < 7.0) was more prominent among patients without chronic heart failure than among patients with chronic heart failure. Therefore, reducing the incidence rates of heart failure or improve cardiac function may play an important role in improving the rate of primary endpoint event in diabetic CTO patients, and reasonable glycemic control may be the main treatment methods in this respect.