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Role of Percutaneous Coronary Intervention in Patients with Diabetes
Diabetes mellitus is a major risk factor for cardiovascular disease affecting multiple vascular territories. At the cardiac level, it is associated with a risk of coronary artery disease (CAD) equivalent to 15 years of ageing. Although coronary revascularization has definitively shown a benefit in terms of major cardiovascular event (MACE) reduction, especially in acute coronary syndromes (ACSs), several studies have reported worse outcomes associated with revascularization in diabetic patients than in those without diabetes.
The aims of coronary revascularization in stable CAD are to improve prognosis and symptoms. The importance of optimal medical treatment—independent of the revascularization modality—is especially true for the diabetic patient population. In the current context of an increasing prevalence of diabetes, particular attention is needed in the development of new strategies in the field of adjuvant pharmacologic therapies and new generations of drug-eluting stents (DESs). Despite all the advances in the field, patients with diabetes undergoing revascularization—both surgical and through percutaneous coronary intervention (PCI)—continue to have worse outcomes compared with nondiabetic counterparts.
For patients with diabetes, assessment of several clinical parameters, such as coronary anatomy, complexity of lesions, clinical presentation, left ventricular function, comorbidities, and patient preference, may help to determine the best revascularization option ( Fig. 17-1 ). The European myocardial revascularization guidelines recommend revascularization in all stable patients with diabetes and extensive CAD (Class I, level of evidence A). The type of revascularization is discussed in this section, mainly for patients with stable CAD; revascularization for patients with diabetes in the setting of ACS is covered in Chapter 22 .
Studies have demonstrated the incremental independent risk associated with diabetes mellitus (DM) and insulin-requiring diabetes mellitus (IRDM) for stent thrombosis among patients treated with percutaneous coronary intervention using drug-eluting stents. Results are reported with the hazard ratio or odds ratio of multivariable analyses.
(Modified from Roffi M, Angiolillo DJ, Kappetein AP: Current concepts on coronary revascularization in diabetic patients, Eur Heart J 32:2748-2757, 2011.)
Specific Characteristics of Diabetes-Associated Atherothrombosis
Diabetic patients constitute a subgroup of patients at increased risk of unfavorable outcomes after PCI as a result of more severe and extensive CAD, as well as a higher rate of restenosis. , , In addition, diabetic patients are characterized by prothrombotic and proinflammatory states induced by a variety of metabolic disturbances that may lead, among other complications, to increased plaque vulnerability, platelet reactivity, and thrombotic complications after PCI. The EVASTENT registry, with 1731 patients treated with DESs, reported that patients with diabetes and multivessel CAD had the highest risk of stent thrombosis (ST)—4.3% at 1 year.
Hyperglycemia, insulin resistance, and oxidative stress are the major abnormalities of regulatory mechanisms that contribute to the dysfunction of extracellular and intracellular molecular pathways of endothelial cells, platelets, and blood coagulant factors (for details, see Chapters 9 and 10 ). , In the bare-metal stent (BMS) era, the most evident adverse effect of diabetes after PCI was the increased prevalence of restenosis , with DESs—at least, first-generation DESs. Although diabetes remains a risk factor for increased risk of restenosis, an increased risk of ST has become a greater consideration in the context of diabetes. Accordingly, diabetes has been identified as an independent predictor of ST in a variety of studies addressing the use of first-generation DESs ( Fig. 17-2 ).
Methodologic Considerations Related to Percutaneous Coronary Intervention Trials in Diabetes
A large number of PCI trials have been performed, enrolling nondiabetic and diabetic patients and using composite endpoints, such as death, myocardial infarction (MI), stroke, target vessel MI, repeat revascularization, target vessel revascularization (TVR), target lesion revascularization (TLR), stent restenosis, in-stent late lumen loss, and ST. The angiographic intermediate endpoints, such as late lumen loss and percent diameter stenosis, both in-stent and in-segment, have been well accepted as primary endpoints for the design of stent trials. Composite endpoints are widely used by investigators to decrease the needed sample size and the duration of follow-up and are justified with the rationale that treatment would have comparable directional impact across the spectrum of components incorporated into the key composite endpoints. The interpretation of comparative treatment effects on composite endpoints might be challenging to clinicians attempting to define the best strategy for clinical application. Three questions have been suggested to help clinicians in decision making with their patients while interpreting results of clinical trials: (1) Are the components of the composite endpoint of similar importance to patients? (2) Did each component of the composite endpoint occur with similar frequencies? (3) Can one be confident that the component endpoints share similar relative risk reductions? If the answers to all these questions are “yes,” clinicians might use with confidence the composite endpoints as the primary basis for decision making. If not, the individual component endpoints should be used as the basis for decision making.
Similarly to the increased numbers of randomized controlled trials (RCTs) that have been performed over the past few decades, new meta-analysis designs have been developed, such as direct (head-to-head) RCT comparison and indirect RCT combination. Considering the methodologies described here, readers should be aware of potential controversies and biases among published studies of trials assessing the efficacy or safety of different revascularization options in subgroups of patients such as those with diabetes.
Conservative Strategy
Few studies have compared conservative strategy versus revascularization procedures in patients with CAD. The Medicine, Angioplasty, or Surgery Study (MASS II) RCT compared in 611 patients—among them 190 patients with diabetes—three therapeutic options (medical management, angioplasty, and coronary artery bypass grafting [CABG]) with a follow-up of 5 years. Among diabetic patients, those treated with angioplasty or surgery had a lower mortality of 2 to 5 years compared with those who received medical treatment alone ( P = 0.039). The only trial focusing specifically on diabetic patients was the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, which enrolled 2368 individuals with type 2 diabetes and stable CAD confirmed by angiography (stenosis ≥ 50% with positive stress test or ≥ 70% with classic symptoms). Patients with unstable symptoms, left main coronary disease, creatinine level of more than 2.0 mg/dL (177 μmol/L), a glycated hemoglobin level of more than 13.0%, class III or IV heart failure, or PCI or CABG within the previous 12 months were excluded. Patients were randomized to treatment with optimal medical therapy plus immediate revascularization versus optimal medical therapy alone, with the mode of revascularization (PCI or CABG) selected before randomization. The revascularization group included patients treated with PCI (n = 765) and with CABG (n = 347). This trial showed that intensive medical therapy alone was not significantly different from immediate revascularization plus intensive medical therapy in terms of MACEs (death, MI, and stroke) after 5 years of follow-up (77.2% for the revascularization group versus 75.9% for the medical group, P = 0.70). The corresponding survival rates were 88.3% and 87.8%, respectively. A secondary analysis showed that patients selected to undergo CABG—that is, those with more advanced disease—derived a benefit from revascularization in terms of MACEs (22.5% CABG versus 30.4% medical therapy, P = 0.01). In those chosen to undergo PCI, medical treatment seemed to be an appropriate first-line strategy, particularly in those with less severe CAD. Of note, 23% of those initially allocated to medical therapy underwent revascularization within the 5 years. The intervention strategy reduced the occurrence of symptoms and revascularization at 3 years—lower rates of worsening angina (8% versus 13%, P < 0.001), new angina (37% versus 51%, P = 0.001), and coronary revascularization (18% versus 33%, P < 0.001), and higher rate of angina-free status (66% versus 58%, P = 0.003). However, the results of BARI 2D may be difficult to reproduce in clinical practice because the patients were highly adherent to medical treatment, with the majority achieving all secondary prevention therapeutic goals. A secondary analysis of BARI 2D showed that, independent of the revascularization type, complete revascularization was associated with lower MACE rates.
In conclusion, in low-risk diabetic patients (e.g., moderate CAD on coronary angiogram, stable symptoms, normal left ventricular and renal function) with excellent compliance with medical therapy, an initially conservative strategy is a valuable option. However, the results of the RCT cannot be extrapolated to higher-risk patients, to those with ACS, or to patients with unknown coronary anatomy. Independent of the revascularization strategy, optimal medical management, as described in Chapter 12, Chapter 16 , remains the cornerstone of treatment.
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