Introduction

Previous studies have indicated that factors such as diabetes duration, HbA1c levels, and type of antihyperglycemic treatment can impact cardiovascular events in patients with type 2 diabetes mellitus (T2DM).^1,2 Aspirin use is recommended in recent guidelines for cardiovascular secondary prevention in order to lower cardiovascular events in individuals with T2DM.^3-5

The CHARISMA study and other cohort trials suggested that DAPT (Dual antiplatelets therapy) would offer protection above and beyond what aspirin offers.^6-8 The use of potent P2Y12 receptor inhibitors is recommended for treatment and secondary prevention,^9,10 such as prasugrel¹¹ and ticagrelor,^8,12 for patients with diabetes mellitus (DM) and coronary artery syndromes due to their greater reduction in mortality and ischemic event recurrences, albeit at the cost of more bleeding. Both ticagrelor and prasugrel can safely be used in patients with T2DM following coronary intervention since they did not show any significant differences in poor clinical outcomes or bleeding events.¹³ While ticagrelor provides similar or greater inhibition of ADP-induced platelet reactivity compared to prasugrel, the 2 agents did not show a significant difference in inhibiting non-ADP-induced platelet reactivity.¹⁴

Extra consideration needs to be given to diabetic patients after small diameter stents implantations, which accounts for 30%-70% of patients undergoing percutaneous coronary intervention (PCI)¹⁵ due to increased risk of restenosis and the requirement for revascularization and potential procedure-related complications.¹⁶ Small caliber vessel lesions tend to be very complicated, involving multiple vessels, distal locations, and type C lesion characteristics. The limited margin of error in stent expansion and sizing associated with small lumen size is a challenge to current therapeutic approaches. The aim of this study was to compare clinical outcomes between clopidogrel and ticagrelor in type 2 diabetic patients after implantation of small diameter stents at 1 year.

Study Population

Proactive, open-label, controlled registry trial in a single center. During the period of October 2021-November 2023, we included and monitored 332 patients with a history of coronary artery diseae and type 2 diabetes who were admitted to our hospital and were older than 18 but younger than 70 years. Our enrolled patients underwent PCI with implantation of small-diameter stents (SDS), that are equal to or less than 2.5 mm in diameter. Diabetes was defined as individuals with fasting blood glucose ≥126 mg/dL (7.0 mmol/L) or random blood glucose ≥200 mg/dL (11.1 mmol/L) or patients with a known history of ongoing hypoglycemic therapy. Pregnancy, any antiplatelet medication contraindications,¹⁷ the requirement for oral anticoagulation therapy, the concurrent use of strong cytochrome P450 3A inducers or inhibitors, the combination of chronic infections, malignant tumors, end-stage liver diseases, and life expectancy less than a year were the main exclusion criteria. The supplementary material provides information on the study’s inclusion and exclusion criteria.

Study Design

The study compared clinical outcomes between clopidogrel and ticagrelor in type 2 diabetic patients after implantation of SDS at 1 year. The choice of clopidogrel or ticagrelor, emergent or early invasive treatment strategies, stent type, pre-dilatation or post-dilatation, use of post-procedural glycoprotein IIb/IIIa inhibitors, and antithrombotic medication were established in accordance with the Patent’s clinical status and according to the clinical decision of operators under relevant guidelines and recommendations. A procedure was deemed successful if the target vessel had no residual stenosis following stenting, had a final TIMI flow grade of 3, and no major side branch occlusion or flow-limiting dissection following the procedure. Two groups of patients were identified: group 1 underwent DAPT with clopidogrel, and group 2 underwent DAPT with ticagrelor. The recommended loading and maintenance doses of aspirin, ticagrelor, and clopidogrel were given.^10,18 Guideline-directed medical therapy for other medical treatments was encouraged (e.g., optimal pharmacologic treatment for heart failure, control of hypertension or diabetes mellitus, and prescription of high-intensity statin). Every patient had a P2Y12 inhibitor for a year in addition to oral aspirin at a dose of 100 mg once daily for the duration of the study.

Artificial Intelligence Disclosure

We disclose that we did not use artificial intelligence (AI)-assisted technologies (such as Large Language Models [LLMs], chatbots, or image creators) in the production of this submitted work.

Follow-Up and Endpoints

Data have been collected about the patients' pre-existing conditions, medical background, risk factors, clinical diagnosis, medications used both upon admission and after discharge, results of in-hospital lab tests, and coronary procedures. Following PCI, each participant's general health condition, current medication, and end point-related events were recorded. This was done at follow-up appointments at the outpatient clinic or, if that was not feasible, over the phone at baseline and then again at 3, 6, 9, and 12 months.

The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) at 1 year, including composite (cardiac death, MI, stroke, and target vessel revascularization [TVR]), cardiac death, non-fatal MI, stroke, or TVR. As a secondary endpoint, the incidence of stent thrombosis, non-TVR, and bleeding (Bleeding Academic Research Consortium [BARC] 2, 3, or 5) was also examined. The fourth universal definition of MI was used to define it.¹⁹ Angiographic restenosis was defined as a percent diameter stenosis of 50% inside and just adjacent to the proximal and distal end of the stent. Target vessel revascularization was defined as repeat angioplasty or coronary bypass surgery performed because of restenosis for the target lesion or any segment of the artery containing the target lesion during follow-up. Death was classified as cardiac in origin unless clear non-cardiac causes could be identified.^20,21 Bleeding complications were defined based on the criteria of the BARC definition.²² Only events associated with the vessel with ≤2.5 mm were included.

Statistical Analysis

Continuous variables were expressed as mean ± SD or median and interquartile range, and categorical variables are represented by n (%). To check for normal distribution, either the Kolmogorov–Smirnov test was used.As appropriate, independent t-test or the Mann–Whitney U test, Pearson chi-square, or Fisher exact tests between the 2 groups were used after evaluation of normal distribution to compare the differences between the clopidogrel group and ticagrelor group. In order to reduce study selection bias, propensity score matching (PSM) was performed with a caliber width of 0.2 of the SD. The baseline characteristics, procedural variables, and outcomes of the clopidogrel and ticagrelor groups were compared once more, controlling for adjustments with PSM. Using multiple binary logistic regression models, the independent risk variables were identified. In the multiple model, only variables that had a P-value < .05 in the univariate analysis were included. Cox proportional hazards regression analysis was used to explore the correlation between the different antiplatelet strategies and clinical endpoints. A P-value < .05 was considered statistically significant. All the statistical analyses were performed using SPSS (Statistical Package for Social Science, SPSS Inc, Chicago, IL, USA) for Windows, Version 27.0.

Results

The study included 332 patients, of whom 197 patients were on clopidogrel and 135 on ticagrelor, as shown in the patient recruitment pathway in Figure 1. Males made up around 68% of the subjects. Following matching, patients in the ticagrelor group had greater rates of obesity, ischemic heart disease, hypertension, hyperlipidemia, and chronic kidney disease (CKD) compared to the clopidogrel group; however, the effect was only statistically significant for hyperlipidemia. Differences in baseline characteristics, medical history, and medications between both groups before and after propensity score matching are shown in Table 1.

It should be noted that left anterior descending coronary artery was the culprit vessel in 79 (23.7%) vs. 54 (16.2%) patients in the clopidogrel and ticagrelor groups, respectively. In the study, anterior wall MI accounted for 50.5% of all ST-segment myocardial infarction (STEMI) cases, with clopidogrel patients having higher rates of STEMI. The presentations and procedural outcomes among the clopidogrel and ticagrelor groups were comparable in Table 2. Second-generation Drug eluting stent, everolimus-eluting coronary stent, Xience (Abbott Vascular, Santa Clara, CA, USA) or Synergy (Boston Scientific), and zotarolimus eluting coronary stents: Resolute Onyx and Onyx Frontier (Medtronic, Santa Rosa, CA, USA) were used. Prior to stenting, nearly all patients (97.3%) underwent predilation balloon angioplasty. With respect to ischemic events, there was no significant interaction in the total trial group based on insulin treatment or baseline HbA1c levels. No cardiovascular death, myocardial infarction, or ischemic stroke were recorded in either group during the 30-day treatment period.

Analysis of Risk Factors of Outcomes

Logistic regression analysis of clinical characteristics, medical history, medications, laboratory biomarkers, and coronary angiography outcomes showed that male gender, history of ischemic heart disease, EF, coronary lesion type and presence of CKD were found to be potential predictors for the composite of CD, MI, stroke, TVR endpoint (Table 3).

Clinical Outcomes and Survival Analysis

Univariate and multiple Cox proportional hazards regression were used to identify the factors affecting the survival outcome of primary and secondary endpoints, including the predictors from logistic regression analysis (Table 4). The 12-month analysis showed a higher incidence of composite of CD, MI, stroke, and TVR in clopidogrel group (21.6% vs. 15.5%) than in the ticagrelor group. However, based on the Cox survival regression analysis, the results showed no significant difference in the primary endpoint between the 2 groups in the crude analysis (HR = 1.25, 95% CI: 0.70-2.22, P = .437) and in the propensity score matched analysis (HR = 1.39, 95% CI: 0.751-2.573, P = .295) (Figure 2). Compared with the patients who received clopidogrel, those who received ticagrelor had lower incidences of cardiac death after 12 months follow-up.

For the secondary endpoints, the total number of bleeding events defined by BARC 2, 3, or 5 did not reach significant statistical difference in crude analysis (HR = 1.315, 95% CI: 0.588-2.941, P = .505) and in propensity score matched analysis (HR = 1.095, 95% CI: 0.478-2.511, P = .829) (Figure 3).

Sub analysis of CKD patients, the 12-month rates of the composite of CD, MI, stroke, and TVR were lower in the ticagrelor group than in the clopidogrel group in propensity-matched patients (HR = 1.41, 95% CI: 0.619-3.558, P = .024). However, ticagrelor group was associated with a higher rate of bleeding than clopidogrel group (20% vs. 9%) (HR = 1.190, 95% CI: 0.580-4.059, P = 0.041). In ACS patients, the overall incidences of ischemic (HR = 1.300, 95% CI: 0.692-2.444, P = .414) and bleeding (HR = 1.282, 95% CI: 0.553-2.973, P = .562) events during the 12-month follow-up period did not differ between treatment groups.

Discussion

Patients with DM have a higher incidence of cardiovascular events compared with nondiabetic patients, as a result of increased adhesion, chronic proinflammatory and prothrombotic environments that promote platelet activation.^23,24 In managing a certain subset of diabetic patients with atherosclerotic small diameter vessels, it is necessary to optimize the antiplatelet strategy and further pay attention to the anatomical and technical complexities. Consideration should be given to the distal location, calcifications, vessel tortuosity, malposition, stent under-expansion, and difficulty in achieving adequate preparation prior to stenting small diameter vessels, which might lead to uncertain outcomes.^25-28

While ticagrelor offers quicker and more favorable antiplatelet results, clopidogrel is the antithrombotic adjunct to aspirin that is most frequently administered.^29,30 In fact, head-to-head assessments have shown that ticagrelor provides better advantages than clopidogrel in the treatment of acute coronary syndrome.⁸ Furthermore, ticagrelor may be favorable in diabetes mellitus, where platelet turnover rates are high.⁹ One possible explanation for the advantages of ticagrelor over clopidogrel in people with type 2 diabetes mellitus is impaired clopidogrel metabolism resulting in less exposure to the active clopidogrel metabolite.³¹ Notably, no differences in clopidogrel- or ticagrelor-mediated platelet inhibition were found when comparing patients with or without insulin therapy. The antiplatelet impact of ticagrelor, however, is more potent than clopidogrel after the loading dose and during the maintenance phase of therapy.³²

Our study compared clinical outcomes between the clopidogrel and ticagrelor groups in patients with diabetes after stenting with small diameter stents. The rates of MACEs, bleeding, and net adverse clinical events did not significantly differ between individuals treated with ticagrelor or clopidogrel during a 12-month follow-up. These outcomes were comparable to those of earlier research projects including individuals with diabetes. According to research by Ahn et al, prasugrel/ticagrelor (n = 1000) significantly increased the number of major bleeding events compared to clopidogrel treatment (n = 2985) but did not improve the composite of cardiac mortality, recurrent MI, or stroke in MI patients with diabetes having PCI.³³ In addition, Goto et al³⁴ and Park et al³⁵ discovered a minor rise in the number of major bleeding incidents in the ticagrelor treatment group. However, among Asian patients, there was no appreciable difference in the risk of ischemia between the ticagrelor and clopidogrel groups.^33-35 It should be noted that part of this study population is Asian and this may contribute to our results; hence, a racially differentiated antiplatelet strategy might be needed in future studies. Additionally, small diameter coronary artery intervention still has a technical challenge with uncertain outcomes.^25-28

In the current study, male gender, history of ischemic heart disease, EF, coronary lesion type and presence of CKD were found to be potential predictors for the composite of CD, MI, stroke, TVR endpoint in univariate logistic regression model analysis. Further research is required on this. Without doubt, both DM and CKD are independently linked to a higher risk of cardiovascular ischemic events; moreover, these 2 conditions might compound the hazards when they co-exist.^9,36 The combination of DM and CKD had a 2-3 folds increase in the risk of mortality.^37,38 Despite the continuous improvements in stent design and preventive therapies, diabetic patients with CKD still had a 1.6-fold greater risk of repeat revascularization and 1.6-fold higher risk of BARC 3 or 5 bleeding, compared with patients without these risk factors.³⁸

The advantage of ticagrelor was seen in a subgroup analysis of the PLATO research, with patients with CKD (eGFR of <60 mL/min) seeing a higher absolute reduction in ischemia risk than those with normal renal function; however, the associated risk of bleeding increased with CKD stage.³⁹ In our analysis, we found that 20%-25% of diabetic patients had CKD. This proportion is consistent with previous cardiovascular RCTs.⁸ Sub analysis of CKD patients in the present study demonstrated similar results at a 12-month follow-up, as rate of composite of CD, MI, stroke, and TVR was lower in the ticagrelor group than in the clopidogrel group in propensity-matched patients (HR = 1.41, 95% CI: 0.619-3.558, P = .024). However, ticagrelor group was associated with a higher rate of bleeding than clopidogrel group (20% vs. 9%), (HR = 1.190, 95% CI: 0.580-4.059, P = .024). SWEDEHEART database sub-analysis of patients with ACS and CKD showed that patients with CKD stage 3 treated with ticagrelor had a lower mortality rate, MI, and stroke at 12 months than the clopidogrel group; however, no definite benefit was observed for patients with advanced CKD and End stage renal disease (ESRD). Meanwhile, for patients with CKD stage 3, bleeding rates were comparable between both treatment groups; however, a tendency toward higher bleeding rates was recorded in patients with advanced CKD, including those with ESRD.⁴⁰ Anyhow, long-term randomized clinical trials including mortality are needed to verify this patient cohort.

Study Limitations

There are various constraints to consider when interpreting the results of this study. First, residual confounding, a known potential source of error in registry research, is made possible by the observational study design. Secondly, the absolute risk of bleeding is lower in the registry than the risk seen in clinical trials. It is conceivable that this relates to underreporting of bleeding events in the registry. However, this should impact the absolute number of bleeds and not the relative risk with ticagrelor. Third, intravascular imaging-guided stent deployment was not used in this study in demonstrating that coronary stenting is effective in establishing and maintaining small coronary artery patency without complications. Finally, a larger number of patients would increase the study’s power, resulting in more precise estimates. Further prospective multicenter trials enrolling larger patient numbers with diabetes, different risk factors, and ESRD are recommended to evaluate the outcomes in the Middle East population.

Conclusion

In conclusion, our study shows that ticagrelor did not improve the composite of cardiac death, MI, stroke, target vessel revascularization, or the risk of bleeding events defined by the BARC criteria in patients with diabetes and small diameter stents compared with clopidogrel emphasizing the importance of individualized treatment decisions based on patient characteristics and preferences. However, the results may not be representative of the entire population. Further research is warranted to validate these findings and explore long-term outcomes.

Footnotes

Ethics Committee Approval: The study was approved by the Unit of Biomedical Ethics in King Abdulaziz University Hospital, Chairman of the Research Ethics Committee; Professor Hasan Alzahrani. Research Ethics Committee (REC) NCBE Registration No.: (HA-02-J-008) with Reference No. 307-21.

Informed Consent: Written informed consent was obtained from participants to participate in 1-year follow-up. The study was conducted in accordance with the Helsinki Declaration of 1971, as revised in 1983.

Peer-review: Externally peer-reviewed.

Author Contributions: A.S.A. and M.Q. contributed to conceptualization, methodology, and statistical analysis. R.M.A. and E.M.E. organized and collected database. G.Y.D. and H.H.M. prepared draft preparation. R.H.A., R.S.B., and A.H. contributed to supervision, review, and editing. All authors have read and agreed to the published version of the manuscript.

Declaration of Interests: The authors have no conflict of interests to declare.

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