Percutaneous Coronary Interventions with Sirolimus-Eluting Alex Plus Stents in Patients with or without Diabetes: 4-Year Results

We characterized the performance, as well as the safety, of a second-generation thin-strut sirolimus-eluting stent with a biodegradable polymer, Alex Plus (Balton, Poland), implanted in patients with type 2 diabetes (DM) with a 4-year follow-up. We defined the primary endpoint as the 48-month rate of major cardiovascular adverse events (MACE), including cardiac death, myocardial infarction (MI), or target lesion revascularization (TLR). The secondary endpoints were all-cause death, cardiac death, MI, and TLR rates at 12, 24, 36, and 48 months. We enrolled 232 patients in whom 282 stents were implanted, including 97 DM and 135 non-DM patients. The mean age of the DM patients was 69.5 ± 10.1 years and females accounted for 30% of the patients. DM patients had higher rates of arterial hypertension (97% vs. 88%, p = 0.016), dyslipidemia (86% vs. 70%, p = 0.005), prior MI (61% vs. 40%, p = 0.002), prior PCI (65% vs. 50%, p = 0.020), and prior CABG (14% vs. 5.9%, p = 0.029). We recorded statistically significant differences for MACE (HR 1.85, 95% CI 1.01–3.41, p = 0.046), cardiac death (HR 4.46, 95% CI 1.44–13.8, p = 0.010), and MI (HR 3.17, 95% CI 1.10–9.12, p = 0.033), but not for TLR, between DM and non-DM patients in terms of the analyzed endpoints at 4 years. Our study showed that Alex Plus was efficient and safe in a contemporary cohort of real-world DM patients undergoing percutaneous revascularization.


Introduction
Percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) presents unique challenges and considerations due to the heightened cardiovascular risk associated with this condition.Diabetes is a significant risk factor for the development and progression of coronary artery disease (CAD), leading to an increased prevalence of complex lesions and a higher likelihood of adverse cardiovascular events.Therefore, managing CAD in DM patients often necessitates more aggressive treatment strategies, including PCI or coronary artery bypass grafting (CABG) [1,2].
One of the key concerns regarding PCI for DM patients is the increased risk of restenosis and stent thrombosis compared to non-DM patients [3].This heightened risk is attributed to factors such as endothelial dysfunction, accelerated atherosclerosis, and impaired vascular healing processes observed in diabetic patients [4,5].To mitigate these risks, meticulous attention is paid to the selection of stent types, antiplatelet therapy, and procedural techniques.Drug-eluting stents (DES) are preferred over bare-metal stents (BMS) due to their superior efficacy in reducing restenosis rates [6][7][8].Moreover, the duration of dual antiplatelet therapy (DAPT) may be extended in DM patients to minimize the risk of stent thrombosis, or more potent antiplatelet drugs might be used, such as ticagrelor [9].Furthermore, managing DM patients undergoing PCI involves a multidisciplinary approach, with close collaboration between cardiologists, endocrinologists, and other healthcare providers [10].Optimal glycemic control, along with aggressive management of other cardiovascular risk factors such as hypertension and dyslipidemia, plays a crucial role in improving outcomes post-PCI [6,11].Additionally, careful patient selection, thorough pre-procedural evaluation, and personalized treatment plans are essential for optimizing PCI outcomes and reducing the risk of complications in DM patients with CAD [12].Current guidelines recommend CABG for patients with diabetes; however, the diffuse atherosclerotic process in DM patients makes PCI a cornerstone of treatment for DM patients with CAD [13,14].
We characterized the performance and safety of PCI with a second-generation, thinstrut sirolimus-eluting stent (SES) implanted in DM patients, with a 4-year follow-up.

Study Design and Study Population
We retrospectively collected data from the hospital records.We considered all consecutive patients who were subject to PCI with the sirolimus-eluting coronary stent Alex Plus (Balton, Poland) between July 2015 and March 2016, as described previously [15,16].
We analyzed baseline demographics, clinical and laboratory data, and clinical outcomes at a 48-month follow-up between DM and non-DM patients.
Echocardiographic parameters (left ventricular ejection fraction [LVEF], left ventricular end-diastolic diameter, posterior wall diameter, intraventricular septal diameter, tricuspid annular plane systolic excursion, left atrial diameter) were measured with a commercially available diagnostic ultrasound device (iE 33, Philips Medical System, Amsterdam, The Netherlands).Experienced cardiologists measured the values according to the European Association of Cardiovascular Imaging guidelines [21].

Study Endpoints
The primary endpoint of our study was the occurrence rate of major cardiovascular adverse events (MACE) over 48 months, encompassing cardiac death, myocardial infarction (MI), or target lesion revascularization (TLR).Secondary endpoints included rates of allcause death, cardiac death, MI, and TLR at 12, 24, 36, and 48 months.

Statistical Methods
Descriptive statistics are shown as mean values with standard deviation, minimum values, median values with interquartile range, and maximum values for continuous variables, and categorical variables are presented as counts and percentages.Pearson's chisquared test or Fisher's exact test were employed to compare categorical variables between two subgroups (DM vs. non-DM patients).Fisher's exact test was used when at least one subgroup had a count of zero.Continuous variables between the two subgroups were compared using the Wilcoxon rank-sum test.A p-value < 0.05 was considered statistically significant.
Propensity score matching with the nearest neighbor method was used to adjust for baseline differences.The validity of logistic regression was assessed using the Hosmer-Lemeshow goodness-of-fit test.The model was well calibrated (χ 2 = 4.33; p = 0.84).The propensity model yielded a concordance index 0.76 (95% confidence interval [CI]: 0.69-0.82).
We utilized Kaplan-Meier estimators with 95% CI to compare 48-month survival curves for different endpoints between two subgroups (DM vs. non-DM patients).In cases where a specific endpoint recurred within a patient during the 48-month follow-up, the survival time was recorded as the duration until the first occurrence of that event.It should be noted that when analyzing MACE-a composite endpoint-the survival time was defined as the period leading up to the occurrence of the first event among cardiac death, MI, or TLR.
We performed univariable and multivariable Cox regression analyses, employing the Cox proportional hazards model, to evaluate disparities in survival rates among the groups.The multivariable Cox regression model was chosen using stepwise selection, applying a backward elimination algorithm with a significance threshold of 0.1.Subsequently, we reported the outcomes, including the Hazard Ratio (HR) and the corresponding 95% confidence intervals for HR.
Table 4 provides the drugs administered at discharge.All patients received acetylsalicylic acid and P2Y12 inhibitors.Patients with DM more frequently received Ca-blockers, diuretics, and nitrates.

4-Year Outcomes in Propensity Score Matching
Propensity score matching yielded 69 well-matched pairs of patients with DM or without DM.Baseline clinical and procedural differences were balanced (Tables 1-4).

Discussion
Our study demonstrated that Alex Plus stents were effective and safe for a modern group of real-world diabetic patients undergoing percutaneous revascularization.Using Alex Plus for PCI resulted in low rates of periprocedural complications and a high device success rate of nearly 99%.Predictably, diabetic patients experienced higher rates of MACE, cardiac death, and MI over a 4-year period.However, the TLR rates between diabetic and non-diabetic patients did not show a significant statistical difference at the 4-year follow-up.
Diabetes presents unique challenges in the management of coronary artery disease, necessitating tailored approaches to revascularization strategies.Drug-eluting stents (DES) have revolutionized the treatment landscape by significantly reducing restenosis rates and the need for repeat revascularization procedures [23][24][25].Sirolimus-eluting stents (SES) have emerged as a prominent choice for diabetic patients due to their potent antiproliferative properties and favorable outcomes in inhibiting neointimal hyperplasia, a common complication in this population.Studies have consistently shown improved clinical outcomes with SES compared to bare-metal stents (BMS) and first-generation DES, making them a preferred option in diabetic patients undergoing percutaneous coronary intervention (PCI) [26][27][28].
One of the key advantages of sirolimus-eluting stents in diabetic patients lies in their ability to mitigate the heightened risk of restenosis and adverse events associated with coronary interventions in this population [29].Diabetes is characterized by systemic inflammation, endothelial dysfunction, and increased proliferation of smooth muscle cells, all of which contribute to accelerated atherosclerosis and restenosis post-PCI [5,30,31].Sirolimus, a potent immunosuppressant and antiproliferative agent, effectively inhibits smooth muscle cell proliferation and migration, thereby reducing the risk of restenosis.This property is particularly advantageous in diabetic patients, where restenosis rates tend to be higher compared to non-diabetic patients [1,3,32].
Despite the all-comer nature of this research, the incidence of periprocedural complications was low.One potential explanation might be the fact that transradial access was used in over 80% of the patients.Transradial access is acknowledged to be linked with a decreased risk of adverse events compared to femoral access, particularly in high-risk patients [33].
After 12 months, the cardiac death, TLR, MI, and MACE rates for the DM patients were 10.3%, 9.3%, 7.2%, and 17.5%, respectively.These rates increased at 48 months to 12.4%, 12.4%, 10.3%, and 25.6%, respectively.As can be seen, the highest incidence of events was observed in the first 12 months after the index procedure.In our study population, the MACE rate was mainly driven by cardiac death cases associated with heart failure exacerbation.The cardiac death rates in the non-DM patients were markedly lower-0.74% at 12 months, and 2.9% at 48 months.What is somewhat surprising is that the TLR rates were comparable between DM and non-DM patients [34,35].These results are comparable to those reported in the literature.
Olsen et al. analyzed 5-year results of DM patients treated with either zotarolimuseluting stents (ZES) or SES [37].In these DM patients, the MACE rate was higher in patients treated with ZES than those treated with SES (28.4% vs. 18.5%; p = 0.032) due to an increased rate of target vessel revascularization (TVR, 18.9% vs. 8.3%; p = 0.006).Among non-DM patients, ZES and SES characterized similar MACE rates at 5 years; however, SES were linked with a significantly increased risk of definite stent thrombosis (1.0% vs. 2.3%; p = 0.028).
Here, it is also worth referencing the paper by Koch et al., in which 10-year follow-up data are presented [39].This study involved a total of 3002 participants who were randomly allocated to receive either polymer-free (PF)-SES (n = 2002) or durable polymer (DP)-ZES (n = 1000).The DM prevalence was notably high and comparable between the groups, with 575 patients (28.7%) in the PF-SES group and 295 patients (29.5%) in the DP-ZES group (p = 0.66).Over a span of 10 years, the survival rates were 53.5% for the DM patients and 68.5% for the non-DM patients.In terms of MACE, PF-SES demonstrated similar rates as DP-ZES in DM patients (74.8% vs. 79.6%;p = 0.08) as well as in non-DM patients (62.5% vs. 62.2%; p = 0.88).
Finally, we identified predicting factors of MACE and TLR.They are well known, and include higher EuroScores and cardiogenic shock.Nevertheless, postdilatation (destructive) and arterial hypertension (protective) had a strikingly high impact.The reason for this is unclear.One might speculate that patients with arterial hypertension were under strict surveillance, with better risk factor control.Also, clopidogrel use seemed to protect against MACE, but one can presume that ticagrelor or prasugrel were preferentially given to patients with more complex lesions.Nonetheless, overly aggressive postdilatation could potentially lead to higher rates of vessel injury, coronary dissection, and neointima response, which, in consequence, could cause ischemic events in the future.In this context, one study showed that the stent's diameter and length did not impact the outcomes of DM patients [41].

Study Limitations
This research possesses inherent constraints typical of observational studies, wherein treatment selection relied on the operator's discretion.The lack of randomization might introduce selection bias, although consecutive patient enrollment somewhat mitigated this concern.Moreover, the relatively modest size of the study cohort and challenges in gathering follow-up information might have influenced the outcomes.Furthermore, the absence of a formal sample size calculation could have impacted the results.To partially correct this, a propensity score matching analysis was performed.Finally, the low rate of intravascular imaging could also negatively impact the results.

Conclusions
Our study showed that Alex Plus stents were efficient and safe in a contemporary cohort of real-world DM patients undergoing percutaneous revascularization.PCI with Alex Plus was associated with low periprocedural complication rates and high device success (almost 99%).As could be predicted, the rates of MACE, cardiac death, and MI were higher in DM patients at 4 years.However, the TLR rates did not significantly differ statistically between DM and non-DM patients at the 4-year follow-up.

Figure 1 .
Figure 1.The study flow chart.

Figure 1 .
Figure 1.The study flow chart.

Figure 2 .
Figure 2. Kaplan-Meier curves disclosing event-free survival in DM and non-DM subgroups in propensity score-matched population.DM-diabetes; MACE-major adverse cardiovascular events.

Figure 2 .
Figure 2. Kaplan-Meier curves disclosing event-free survival in DM and non-DM subgroups in propensity score-matched population.DM-diabetes; MACE-major adverse cardiovascular events.
* More than one access or catheter was used during the procedure; DM-diabetes; LM-left main; LAD-left anterior descending artery; LCx-left circumflex artery; MI-myocardial infarction; RCA-right coronary artery; VG-vein graft.

Table 4 .
Drugs administered at discharge.

Table 5 .
Study endpoints by year in patients with diabetes and without diabetes.

Table 6 .
Study endpoints by year in patients with diabetes and without diabetes (propensity scorematched population).

Table 7 .
Multivariable Cox analysis: major adverse cardiovascular events.
: Univariable Cox regression for MACE; Supplementary Table S2: Univariable Cox regression for TLR; Supplementary Figure S1: Kaplan-Meier curves disclosing event-free survival in DM and non-DM subgroups in the