More than 170 million people suffer from diabetes mellitus worldwide and their number is growing continuously. About 65% of diabetics die of cardiovascular disease and diabetes accounts for over a quarter of percutaneous coronary interventions (PCIs).
Diabetes mellitus has been consistently shown to be an important predictor of poor outcomes after PCI. Diabetic patients have an increased risk for restenosis and their clinical follow-up is characterised by a higher incidence of death, myocardial infarction and revascularisations. A multitude of unfavourable pathophysiologic factors, more severe atherosclerosis and increased prevalence of co-existent risk factors and co-morbidities in diabetic patients make their treatment a challenging problem in modern interventional cardiology.
In the last five years, drug-eluting stents (DES) were introduced and rapidly adopted into everyday practice including treatment of diabetic patients. The most commonly used DES are sirolimus-eluting and paclitaxel-eluting polymer-based stents. Several trials investigating the outcomes after DES implantation in diabetic patients encourage their preferential use over bare metal stents (BMS). Subset analyses from Randomised Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) and Sirolimus-Eluting Balloon Expandable Stents in the Treatment of Patients with De Novo Coronary Artery Lesions (SIRIUS) trial, as well as the one from Treatment of de novo coronary disease using a single pAclitaXel elUting Stent (TAXUS) II, IV, V and VI trials, together with three-dimensional ultrasound results of the Diabetes and Sirolimus- Eluting Stent (DIABETES) trial, demonstrated the superiority of DES over BMS in reducing the need for target vessel revascularisation by 60-70% in diabetic patients.
Compared with non-diabetics, diabetic patients present more often with multivessel disease and have smaller vessel size, diffuse and longer atherosclerotic lesions and left main coronary artery disease. In particular, the combination of diabetes with small vessel size presents a significant challenge for all revascularisation modalities. Revascularisation by aorto-coronary bypass surgery (CABG) is technically difficult and associated with high failure rates, while revascularisation by plain balloon angioplasty and BMS is associated with poor peri-procedural outcome and complications and high rates of restensosis (up to 50%).
Various studies have reported an inverse relationship between vessel size and restenosis rate, reflecting the limited capacity of small vessels to accommodate for the late lumen loss. This capacity is independent of vessel size. Late lumen loss reflects the degree of neointimal proliferation, which is the principal cause of restenosis after stent implantation. Greater late lumen loss is associated with increasing risk of target vessel revascularisation. Thus, considering the fact that BMS have a late lumen loss of nearly 1mm compared with 0.20-0.65mm with DES, the superiority of DES over BMS in small coronary vessels is not unexpected.
There is ample evidence to support the increased risk of restenosis associated with diabetes and small vessel size; both these factors may serve as a 'stress test' helping to assess the performance of coronary devices including DES. In a randomised trial by Pache et al., the degree of restenosis reduction with DES compared with BMS was dependent on vessel size. Compared with BMS, DES was associated with an 80% restenosis reduction in vessels <2.8mm of size, but only a 14% restenosis reduction in vessels ≥2.8mm of size.
Later randomised trials confirmed that high-risk subsets of patients offer the optimal setting to allow better differentiation of various types of DES in terms of efficacy. In the The Intracoronary Stenting and Angiographic Results: Do Diabetic Patients Derive Similar Benefit from Paclitaxel-Eluting and Sirolimus-Eluting Stents (ISAR-DIABETES) study, which randomised 250 diabetic patients to sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES), the SES significantly decreased late lumen loss and angiographic restenosis compared with PES (6.9% with SES versus 16.5% with PES, p=0.03). The mean vessel size was 2.70mm in the group with SES and 2.75mm in the group with PES. The rate of repeat revascularisation was reduced by nearly 50% with the use of SES compared with PES (6.4% with SES versus 12% with PES, p=0.12). Although the difference in repeat revascularisation was not statistically significant due to the modest number of patients, the impact of this difference in the whole population may be immense considering that, in the US alone, nearly a quarter of the 660,000 PCI procedures per year are performed in diabetic patients.
These findings are supported by the Intracoronary Drug-Eluting Stenting to Abrogate Restenosis in Small Arteries (ISAR-SMART) 3 study, which enrolled 360 patients with small coronary arteries (mean vessel size was 2.40 with SES and 2.44mm with PES). The late lumen loss among patients with SES was 0.25 mm compared with 0.56 mm among patients with PES (P<0.001). These values were similar to those reported in other trials with these stents. The reduction in angiographic restenosis was translated into a decrease of about 50% target lesion revascularisation rates.
Although other studies with relatively selected patients favouring inclusion of low-to-intermediary risk patients, found no significant differences between SES and PES, there were exactly the high risk subsets such as for diabetic patients. These include lesions in small vessels and restenotic lesions, increasing the awareness regarding these differences by showing the superiority of SES over PES. A recent meta-analysis has further strengthened this view.
The lack of restenosis in the studies reportedly correlates with improved long-term survival after stenting. If the same holds true for DES this needs to be has to be investigated in larger and long-term studies. Enthusiasm has somehow abated due to the findings that there is an elevated incidence of late stent thrombosis when using DES. Moreover, there is relevant data from pathology studies showing that first-generation polymer-based DES represents a durable stimulus for thrombosis, even long after DES implantation.
These concerns are stimulated by recently published data showing that PES, and especially SES, are associated with higher risk of late mortality and myocardial infarction (MI). The authors of this paper did not utilise patient-level data from the original datasets and, as such, their findings were refuted at the Transcather Cardiovascular Therapeutics (TCT) 2006 meeting in Washington.
Data from two separate presentations revealed a small but significant increase in the rate of late stent thrombosis for both sirolimus- and paclitxel-eluting stents (when compared with bare metal stent controls) at one-year follow-up. This increased rate of DES thrombosis was not associated with an increased risk of death or MI in their analyeses. Additional data from an integrated analysis performed on 1,748 patients enrolled in four prospective double-blind trials, which randomly assigned patients to receive either a SES or BMS for the treatment of a single de novo coronary stenosis, found no significant differences in either frequency or cause of death with implantation of either sirolimus-eluting or BMS.
However, from the beginning of DES era, interventional cardiologists recommended a longer dual antiplatelet therapy in all patients receiving DES despite insufficient clinical evidence. Despite these concerns, before restrictive changes are to be introduced into clinical practice, the recent data should be confirmed by a more rigorous systematic review of the available studies. This should include more complete and sufficiently long follow-up with well-defined end-points accurately reflecting the potential late risk. There are more than 5,000 patients currently enrolled in randomised, head-to-head comparative trials of SES and PES; an updated and extended follow-up of these trials will give invaluable information on their late efficacy.
Multiple factors lead to diabetic patients having an impaired endothelial function. These include hyperglycaemia, excess of free fatty acids and insulin resistance. The increased production of tissue factor and plasminogen activator inhibitor-1 create a prothrombotic environment that, together with the increased ability of platelets to aggregate, leads to an increased propensity for thrombotic complications in diabetic patients. Thus, it is not unexpected that diabetes mellitus in combination with premature discontinuation of antiplatelet therapy, bifurcation lesions, low ejection fraction and renal failure has been identified as an independent predictor of late thrombotic events after DES implantation.
Consequently, an optimised adjunct antiplatelet therapy may be crucial in patients with diabetes. There is strong evidence that timely applied pre-treatment with 600mg clopidogrel in low-to-intermediary risk patients undergoing PCI reduces the need for glycoprotein IIb/IIIa receptor inhibitors. However, abciximab has improved outcomes in patients with acute coronary syndromes, particularly when they present with positive cardiac biomarkers. It has also reduced restenosis in diabetic patients receiving BMS but it is still unknown if beneficial effect is also present in diabetic patients receiving DES.
Diabetes is a systemic disease that affects the entire vascular system and no long-term outcome could be determined solely by the reduction of restenosis with DES. Apart from restenosis, non-culprit lesion progression is another important factor dictating the need for revascularisation. More than one-third of diabetic patients experience the formation of a new lesion less than one year after coronary intervention. Increased blood glucose accounts for 21% of death from ischaemic heart disease and for 13% of deaths from stroke worldwide, while a glucosylated haemoglobin (HbA1c) level less than 7% is shown to abolish differences in revascularisation rates between diabetics and non-diabetics.
The use of thiazolidinediones, a new class of insulin sensitisers, has shown promising results in reducing intimal thickness independent of glycaemic control. They also have multiple beneficial effects on vascular cells such as inhibition of smooth-cell growth and migration or production of proinflammatory cytokines. In addition, intensive management of all other risk factors, including dyslipidaemia, hypertension, smoking and obesity, is required to treat diabetic patients suffering from coronary artery disease.
The quality of glycemic control and the therapeutic options needed to achieve it are being tested as a standalone strategy or in combination with revascularisation procedures (PCI or CABG) in a large randomised clinical trial, including diabetic patients with coronary artery disease.