**2. Vascular abnormalities and atherothrombotic risk in diabetic patients**

DM is linked to an increased atherothrombotic risk. In fact, diabetics with coronary artery disease suffer a higher rate of recurrence following their index MI [18]. Atherothrombotic disease is accelerated in subjects with both type 1 and type 2 diabetes, with diverse underlying mechanisms, despite the common characteristic of hyperglycaemia. The main feature of type 2 DM is insulin resistance, which precedes the development of hyperglycaemia [19]. Contrastingly, in type 1 diabetes, hyperglycaemia is the dominant feature with insulin resistance appearing at later stages, in patients who develop renal disease [20].

#### *Percutaneous Coronary Intervention in Diabetic Patients DOI: http://dx.doi.org/10.5772/intechopen.94533*

One of the main contributors to the increased atherothrombotic risk in DM patients relates to their pro- inflammatory and prothrombotic status that involves abnormalities in endothelial and vascular smooth muscle cells, in platelet function and the coagulation cascade. Endothelial dysfunction in diabetics is characterised by a decrease in nitric oxide (NO), and also by an increase in the synthesis of vasoconstrictor prostanoids and endothelin [21]. Hyperglycaemia decreases endothelium-derived NO via multiple mechanisms, including the intracellular production of advanced glycation end-products (AGEs) and free radical formation [22, 23]. Furthermore, hyperglycaemia also produces an increase in the concentration in plasma of vasoconstrictors, such as endothelin, which is related to both the incidence of inflammation and smooth-muscle contraction and growth. Other metabolic disorders known to occur in diabetes including an increase in the circulating levels of free fatty acid, an increase in the production of free radicals or an exacerbation of dyslipidaemia, may also impair the endothelial function [24–26]. On the other hand, hyperinsulinemia [ 27] also plays an important role in the pathophysiological mechanisms that may contribute towards vascular disease in diabetic patients. The concentration in plasma of vasoconstrictors, such as endothelin, increases after administration of insulin to healthy subjects and patients with type 2 diabetes [28–31]. This phenomenon may be related to both the incidence of inflammation and smooth-muscle contraction and growth. In addition, hyperinsulinemia is a potent mitogen for restenosis, as it stimulates the proliferation and migration of smooth cells [32]. Previous studies have demonstrated that hyperinsulinaemia enhances the secretion of insulin during the oral glucose tolerance test, and is a predictor of restenosis after balloon angioplasty and stent implantation [33–35].

Platelets are also affected in diabetic patients. Both insulin resistance and hyperglycaemia contribute to a prothrombotic state by exerting several salient effects on both coagulation and platelet function. The effects of insulin resistance on platelet function is related to intra-cytosolic calcium levels, a mediator of platelet activation. Whilst insulin decreases the intra-cellular concentration of calcium in platelets from insulin-sensitive subjects *in vivo* and *in vitro*, it appears to increase the intraplatelet calcium concentrations in the insulin-resistant state, promoting platelet aggregation and activation [36]. Platelets obtained from diabetic subjects showed both increased adhesiveness and an exaggerated aggregation following activation [24]. In addition, reduced responsiveness of diabetic patients to antiplatelet therapy has been documented [14]. The overall picture of platelet abnormalities in DM results in the hypersensitivity of diabetic platelets to agonists. In fact, platelets in diabetic subjects appear to be in an activated state even in the absence of vascular injury, and they respond more frequently even to sub threshold stimuli. It has been shown that there is greater expression of the fibrinogen-binding glycoprotein IIb/ IIIa receptor, which constitutes the final common pathway of platelet activation and allows for cross-linking of individual platelets by fibrinogen molecules and formation of thrombus [15]. Finally, there is also impairment of the coagulation cascade. Insulin resistance gives rise to increased levels of the fibrinolytic inhibitor Plasminogen Activator Inhibitor-1 (PAI-1), and hyperglycaemia induces the enhancement of thromboxane A2 production and an increase in factor VII and anti-thrombin III production [24–26].

The alteration in platelet function is especially relevant in diabetics patients treated percutaneously, as it may affect the response to antiplatelet treatment. Although, clopidogrel response variability is a multifactorial process, the mechanisms above explain why dual antiplatelet regimen with ASA and clopidogrel presents important limitations in diabetic patients. The main mechanisms in this patient cohort that explain poor response to dual antiplatelet therapy in diabetes

mellitus are antiplatelet resistance and clopidogrel response variability. Variability in antiplatelet effects following clopidogrel therapy is present in both the acute and the chronic phases of therapy [37]. Of note, diabetics requiring insulin are those who persist with the highest platelet reactivity, despite dual antiplatelet therapy [37]. This antiplatelet variability has clinical implications, such as increased rates of coronary stent thrombosis and recurrent ischaemic events after PCI in poor clopidogrel responders. Among the clinical factors involved in clopidogrel variability, diabetes mellitus has been associated with a greater prevalence of poor responsiveness [38]. Overall, the persistence of elevated platelet reactivity and reduced response to aspirin and clopidogrel therapy enhances the atherothrombotic risk of DM patients. Multiple causes have been implicated in these observations. Poor glycaemic control is an important cause of increased platelet reactivity. Hyperglycaemia leads to non-enzymatic glycation of platelet glycoproteins, causing changes in their structure and conformation, as well as alterations of membrane lipid dynamics. This may explain why platelet reactivity can be reduced with tight control of glucose levels [39].

The introduction of new regimens and antiplatelet agents may improve and overcome the variability in the response to clopidogrel. The P2Y12 inhibitors, with a more uniform and potent effect, have recently been evaluated. Prasugrel is a P2Y12 inhibitor of the third generation, with more potent and less variable antiplatelet effects compared to clopidogrel [ 40]. The TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet InhibitioN with Prasugrel-Thrombolysis in Myocardial Infarction) trial showed significantly reduced rates of ischaemic events, including stent thrombosis, in patients presenting with acute coronary syndromes undergoing PCI treated with prasugrel compared to clopidogrel [ 41]. In the subgroup analyses of diabetes population (n = 3146) the greatest risk reduction (rate of primary endpoint, defined as death from cardiovascular causes, non-fatal MI or non-fatal stroke) was observed in 12.2% of the diabetics treated with prasugrel vs. 17.0% in diabetic patients on clopidogrel with 30% relative risk reduction. Importantly, prasugrel was not associated with an increased risk of major bleedings compared to clopidogrel in these patients [42]. The functional impact of prasugrel versus clopidogrel, specifically in diabetic patients, was evaluated in the OPTIMUS-3 study. In this prospective, randomised, double-blind, crossover study, the standard-dose prasugrel was associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods, when compared with double-dose clopidogrel [43].

On the other hand, ticagrelor, has a faster onset and offset of action and achieves higher inhibition of platelet aggregation compared to clopidogrel. In the RESPOND trial [44] Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and non-responders. The phase III Study of Platelet Inhibition and Patient Outcomes (PLATO) trial randomised acute coronary syndrome patients (n = 18,624) to receive either ticagrelor (180 mg loading dose followed by 90 mg twice daily) or clopidogrel (300–600 mg loading dose followed by 75 mg daily). In a predefined subgroup analysis of diabetic patients (n = 4662) there was a non-significant reduction of the primary endpoint [14.1% vs. 16.2%; HR 0.88 (0.76–1.03)], while no difference in major bleeding rates was found [14.1% vs. 14.8%; HR = 0.95 (0.81–1.12)] [45]. The recommendations from the recent ESC guidelines for the selection of antithrombotic therapy in diabetic patients with an acute coronary syndromes in patients presenting without persistent ST-segment elevation, state that the therapy should not differ from those without diabetes [46].

Phase III trial data on the use of factor-Xa inhibition direct oral anticoagulants for treatment of ACS has emerged. The APPRAISE-2 (Apixaban for Prevention of *Percutaneous Coronary Intervention in Diabetic Patients DOI: http://dx.doi.org/10.5772/intechopen.94533*

Acute Ischemic Events) resulted in early termination of the study, due to an increase in Thrombolysis in Myocardial Infarction (TIMI) major bleeding in apixaban 5 mg bid (1.3%) compared with placebo (0.5%). There was no improvement in the composite of cardiovascular death, MI, or ischemic stroke with apixaban compared with placebo. Similarly, the ATLAS ACS 2-TIMI 51 (Anti Xa Therapy to Lower Cardiovascular Events in Addition to ASA with or without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction) study had a significant increase in major bleeding with their respective Factor Xa inhibitors compared with dual antiplatelet therapy. It was noted however, in the primary analysis of the combined dosing arms, rivaroxaban (combined dose arms) reduced the composite of cardiovascular death, MI, or stroke compared with placebo (8.9% versus 10.7%, respectively). In a secondary analysis of the efficacy and safety of rivaroxaban (2.5 or 5 mg bid) compared with placebo in a pooled subset of ACS patients from the ATLAS ACS-TIMI 46 (phase II) and ATLAS ACS 2-TIMI 51 (phase III) trials [47] showed that the addition of rivaroxaban to aspirin reduced a composite of cardiovascular death, myocardial infarction, and stroke versus aspirin alone, primarily by a reduction in the risk of myocardial infarction. However, the combined rivaroxaban dose groups were associated with higher rates of non-CABG TIMI major bleeding. The use of these strategies specifically in diabetic patients remains under investigation. In the stable cardiovascular disease setting, the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial [48] investigated very low-dose rivaroxaban (2.5 mg b.i.d.) in combination with aspirin vs. aspirin alone or rivaroxaban 5 mg b.i.d. alone. Those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Greater absolute risk reductions were seen in high-risk patients, including those with diabetes.

### **3. Percutaneous revascularisation in diabetic patients**

Since its inception, the use of percutaneous transluminal balloon angioplasty (BA) to treat coronary stenosis, diabetics have shown less favourable long-term clinical outcomes, compared to non-diabetics. Diabetes mellitus has been identified as an independent predictor of restenosis. In fact, the restenosis rate following BA in diabetics ranges between 35% and 71%, which is much higher than seen in the general population (30–35%) [49]. In addition, the pattern of restenosis is more severe, as these patients typically show more proliferative and occlusive types of restenosis. The main contributor to the restenosis process following plain BA is negative remodelling (i.e., vessel shrinkage) [50] that accounts for 73% of lumen reduction after balloon angioplasty, while plaque burden contributes 27% [51].

Coronary stenting was able to reduce the occurrence of restenosis, not only in general population but also in diabetic patients [52]. Two pivotal randomised controlled trials demonstrated the beneficial effects of stenting as compared to BA, the STRESS and the BENESTENT trials [53, 54]. The analysis of diabetic patients in these two trials revealed a significant reduction in restenosis rate (STRESS: stent 32%, balloon 42%; p = 0.046; BENESTENT: stent 22%, balloon 42%; p = 0.02) and clinical outcomes improvement at 6 months and at 4 years follow-up (including cardiac death, non-fatal MI and the need for repeat revascularization) [55]. Despite these results, restenosis rate remained higher in diabetics compared to non-diabetics. In a meta-analysis [56] of 16 studies, after stent implantation angiographic restenosis (defined as ≥50% diameter stenosis at follow-up) occurred in 550 of 2672 (20.6%) of non-diabetics as compared to 130 of 418 (31.1%) of diabetic patients

(p < 0.001). The authors identified, among other factors, insulin treatment in type 2 diabetes, a marker of disease duration and severity, as an independent predictor of restenosis. The prevailing mechanism of restenosis after stenting is accelerated intimal hyperplasia which is especially exaggerated in diabetic patients [57]. Thus, the development of drug-eluting stent (DES) to tackle this mechanism of restenosis directly was a revolutionary development in this field. In this regard, the subgroup analysis of the two pivotal randomised trial, which evaluated the efficacy of first generation DES (Cypher® stent; Cordis, Johnson & Johnson, Warren, NJ, USA and Taxus® stent; Boston Scientific, Natick, MA, USA) showed positive results in terms of restenosis rates and in MACE [58, 59].

In the SIRIUS trial (Sirolimus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) [60] a total of 1058 patients were randomised to either SES or BMS for the treatment of de novo coronary stenosis. The primary endpoint was target vessel failure (cardiac death, myocardial infarction and target vessel revascularisation [TVR]) at 9-month follow-up. The diabetes subgroup analysis of the SIRIUS trial included 279 patients, 131 receiving SES and 148 receiving BMS [61]. In this subgroup of patients, SES implantation demonstrated favourable results with significant reductions in restenosis rates (in-lesion 50% for BMS vs. 17% for SES), and in MACE (25% for BMS vs. 9.2% for SES). The TAXUS IV trial [62] enrolled 1326 patients that were randomised to PES or BMS for the treatment of de novo coronary stenosis. The primary endpoint was ischaemia driven TVR and the incidence of cardiac death, and MI at one year. Overall, the PES group showed a significant reduction in the occurrence of the primary endpoint (TVR 7.4% vs. 20.9%, p = 0.0008). The study included 155 diabetic patients (32% of the total population) and 33% of the diabetics were insulin-dependent DM. In this subgroup, the use of PES significantly reduced the risk of binary restenosis (70% reduction of in-segment restenosis). This reduction was also observed in insulin-dependent DM subjects (42.9% for BMS vs. 7.7% for PES, p = 0.007).

The DIABETES (Diabetes and Sirolimus-Eluting Stent) trial [63] was the first randomised multicentre controlled trial specifically designed to assess the efficacy of SES vs. BMS in diabetics. This study included 160 diabetic patients, 80 of whom received BMS, while 80 were treated with SES. Late lumen loss assessed by QCA at 9-month follow-up was the primary endpoint. The SES treated group showed a significant reduction of late lumen loss (relative reduction 87%). The study considered a sub-randomisation, according to the type of anti-diabetic treatment and the SES benefit was independent from diabetic status. This benefit was maintained up to 5-year follow-up [64]. Subsequently, 3 other randomised trials also designed for diabetic patients (SCORPIUS [65, 66], DESSERT [67] and DECODE [68]) have corroborated the same positive results of SES in reducing neointimal proliferation to mid and long-term. A meta-analysis of all available data in diabetics treated with PCI [69] demonstrated the benefit of DES in terms of restenosis and target lesion revascularisation.

Finally, other studies compared both DES in terms of efficacy (**Table 1**). The SIRTAX (SIRolimus versus pacliTAXel-eluting stents) trial [70] and the ISAR (In-Stent Angiographic Restenosis)-DIABETES trial [71] showed that SES in diabetics had lower MACE and lower late lumen loss compared with PES. The efficacy of new generation DES has also been evaluated. The everolimus-eluting stent (EES) has been tested against PES in the SPIRIT IV and V trial. In the subgroup analyses of the SPIRIT IV [72] EES compared with PES showed no difference in target lesion failure (6.4% vs. 6.9%, respectively, p = 0.80) or any of its components was present among diabetic patients, regardless of insulin use. In contrast, in the SPIRIT V


*Percutaneous Coronary Intervention in Diabetic Patients DOI: http://dx.doi.org/10.5772/intechopen.94533*

*SES: sirolimus-eluting stent; BMS: bare metal stent; PES: paclitaxel-eluting stent; DM: diabetes mellitus; EES: everolimus-eluting stent; ZES: zotarolimus-eluting stent; BES: biolimus-eluting stent; MACE: major adverse cardiac events; TVF: target vessel failure; TVR: target vessel revascularisation; P: prospective; NI: non-inferiority trial, R: randomised; M: multicenter.*

*\* Composite endpoint of cardiac death, myocardial infarction and clinically-driven target vessel revascularisation at 9 months.*

*# Diabetic subgroup.*

**Table 1.**

*Randomised controlled trials comparing drug-eluting stent vs. drug-eluting stents in diabetic patients.*

Diabetic Study Everolimus-eluting stent was superior to PES for in-stent late loss at 9 months, however, clinical endpoints were similar between the two groups [73]. Interestingly no stent thromboses (Academic Research Consortium definite and probable) were seen at 1 year with EES, compared with 2 of 104 (2%) with PES (P = 0.11). The efficacy of the zotarolimus-eluting stent (ZES) has been assessed in the Endeavour IV trial against PES [74] and the Resolute™ [75] stent a new generation ZES against EES. In these studies, ZES was comparable with PES and non-inferior to EES. Finally, the biolimus-eluting stent (BES) has been compared to SES in the LEADERS all-comer trial. BES appeared to be non-inferior to SES with regard to the primary endpoint in the subgroup of diabetics [76].

The effectiveness of different DES platforms has been addressed in the Swedish Angiography and Angioplasty Registry (SCAAR) [77]. Data on restenosis from 2004 and 2008 was collected. Four DES types qualified for inclusion. In total, 35,478 DES were implanted at 22,962 procedures in 19,004 patients and 1807 restenosis events were reported over a mean 29-month follow-up. In the entire study population, the restenosis rate per stent was 3.5% after 1 year and 4.9% after 2 years. The adjusted risk of restenosis was higher in patients with DM, compared to patients without DM (relative risk [RR]: 1.23, 95% confidence interval [CI]: 1.10 to 1.37). In patients with DM, restenosis was twice as frequent with the ZES stent compared with that in SES and PES types.

Another important aspect in the use of DES is the safety, especially in diabetic patients. Safety of DES mainly refers to the incidence of ST, MI or death during follow-up. Diabetes has been identified as an independent predictor of ST in many registries with the use of first-generation DES (SES and PES) [17, 78]. In a large multicentric registry 66 of more than 15,000 patients treated with SES, the overall incidence of stent thrombosis at 1 year was 0.87% and the most potent independent predictor of thrombosis was the insulin-dependent DM [78]. Diabetic patients, as mentioned previously, exhibit specific pathophysiological factors as well as unfavourable angiographic parameters, which confers an especially high risk of thrombosis.

A Swedish Registry (SCAAR) compared diabetic patients treated with DES to those treated with BMS. The median follow-up was 2.5 years. This study included 4754 patients who received at least one DES and 4956 patients that received only bare metal stents (BMS) at the index procedure. The study showed that restenosis was halved by DES in diabetic patients with stable or unstable coronary disease, compared with BMS [RR, 0.50 (95% CI, 0.35–0.70)] and was associated with a higher adjusted RR of MI, [RR 5.03 (95% CI, 4.25–5.97)] [79]. Similar results were observed in a meta-analysis of individual patient data from four randomised trials reporting on the use of SES in diabetics [80]. This meta-analysis included 583 patients (SES vs. BMS; median follow-up of 4.2 years). There was a significant reduction in the overall hazard of MACE (hazard ratio, [HR] 0.48, 95% confidence interval [CI] 0.36–0.63, P < 0.001) with SES. The overall hazard of death (HR 0.91, 95% CI 0.59–1.41, P = 0.68), as well as death or MI (HR 0.77, 95% CI 0.54–1.09, P = 0.14), was not significantly different between the groups. No significant differences were observed regarding ST (HR 0.50, 95% CI 0.15–1.69, P = 0.26) [80]. Reassuring data also comes from the Massachusetts Data Analysis Registry that included 6008 diabetics treated between April 2003 and September 2004. After propensity score-matched risk analysis, the use of DES was associated with a significantly lower rate of death, MI and TVR [52].

New generation EES stent showed a safety benefit as compared to PES in the Spirit V- diabetic randomised trial at 1 year; the composite of death and MI was reduced by EES (9.6% vs. 3.7%; p = 0.04) as well as the thrombosis rate (1.9% vs. 0%; p = ns) [73].

*Percutaneous Coronary Intervention in Diabetic Patients DOI: http://dx.doi.org/10.5772/intechopen.94533*

Data concerning safety of BES in diabetics comes from a sub-study from the LEADERS trial. Among insulin-dependent diabetics, the rate of all-cause death and cardiac death was 0% after BES implantation, compared to 9.1% and 6.5% respectively, after SES implantation at 12 months follow-up (p < 0.01) [76].

Finally, the Resolute™ stent showed a higher incidence of definite ST at 1-year follow-up, compared to EES (1.2% vs. 0.3%; <0.01) in the all-comer RESOLUTE trial [81].
