Effectiveness and Safety of Sirolimus-eluting Stents in Patients with Diabetes

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Citation
ICR - Volume 3 Issue 1;2008:3(1):52-54
DOI
http://dx.doi.org/10.15420/icr.2008.3.1.52

Cardiovascular disease is a major consequence of diabetes and is associated with peculiar features in this subgroup of patients, representing roughly 25% of the total population treated with percutaneous coronary interventions (PCIs). A consistent proportion of these patients have asymptomatic myocardial ischaemia, which is a more extensive and diffuse atherosclerotic disease with more prevalent multivessel disease. The diabetic milieu (hyperglycaemia and increased oxidative stress) favours plaque instability.1 Coronary revascularisation – using PCIs and/or coronary artery bypass grafts (CABGs) – has a worse prognosis in terms of repeat interventions and mortality in diabetics compared with the non-diabetic population.2,3 In particular, higher rates of repeat revascularisation due to restenosis have been seen after balloon and stent PCI. In the biochemical cascade responsible for neointimal hyperplasia, a near-normal glucose level seems to have a protective effect before and after revascularisation.4
Drug-eluting stent (DES) use has produced a dramatic reduction of restenosis and repeat revascularisation compared with bare-metal stents (BMS). However, data regarding diabetic patients are disconcordant and indicate a more limited effect of DES. This article will analyse data from the literature relative to sirolimus-eluting stent (SES) efficacy and safety in diabetics, focusing on acquired knowledge and remaining uncertainties. Data from diabetic subgroups in randomised controlled trials show that the beneficial effect of DES could be attenuated in diabetic patients compared with that observed in non-diabetic patients. In particular, the diabetic subgroup analysis from the Sirolimus-coated Bx Velocity Balloon- Expandable Stent in the Treatment of Patients with de Novo Coronary Artery Lesions (SIRIUS) trial5 (131 patients in the Cypher® group and 148 in the control group) showed higher absolute value for restenosis and target lesion revascularisation (TLR) for both groups of diabetic patients compared with the total population, with a relatively high in-stent restenosis rate of 17.6% in the diabetic SES group and a smaller relative reduction than that seen in the total series (83% relative reduction of in-stent restenosis in diabetic patients versus 91% in the total population; 65% reduction of in-lesion restenosis versus 75%). At nine months, TLR was reduced in diabetics from 22.3% with BMS to 6.9% with SES and in non-diabetic patients from 14.1 to 2.99%, while major adverse cardiac events (MACEs) were reduced from 25 to 9.2% in diabetics and from 16.5 to 6.5% in non-diabetic patients with BMS and SES, respectively. The higher frequency of in-lesion restenosis and repeat intervention in diabetic patients were particularly evident in the insulin-requiring patients, whereas SES did not show a statistically significant effect compared with BMS.

Meta-analyses6,7 of randomised clinical trials (RCTs) of DES versus BMS confirmed that DES are associated with a remarkable 80% relative risk reduction of restenosis during the first year of follow-up in diabetics. However, despite the use of DES, diabetes remains an independent risk factor for restenosis, need for revascularisation and MACE. Moreover, in a pooled analysis of SES versus BMS Spaulding et al.8 found a significant increase of four-year total mortality in the SES diabetic group in comparison with diabetic patients treated with BMS (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.38–6.10; p=0.008).
The trend towards an absolute reduced effectiveness of DES in diabetic versus non-diabetic patients was more evident in data from a registry study due to increased lesion complexity of the unselected cohorts of diabetics undergoing PCI in the ‘real world’ and the lack of routine angiographic follow-up with a clinically driven re-intervention, which, despite a higher prevalence of asymptomatic restenosis in diabetics, was under-represented. The Rapamicin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry9 reported the benefit of using SES in diabetics, but did not reach statistical significance, and diabetes remained an independent predictor of events and also clinically driven target vessel revascularisation (TVR) in SES-treated patients. In another large Italian multicentre registry10 comprising 1,648 diabetics, the use of DES (71% SES) was associated with an absolute (3%) and a relative (34%) reduction of two-year TVR; again, this benefit was limited to non-insulin-dependent diabetics.
A direct comparison of SES and BMS was performed in a few randomised trials11–14 featuring evaluation of clinical and angiographic end-points. In all of these small studies, in selected anatomical and clinical conditions SES significantly reduced angiographic late loss, binary restenosis, TVR and MACE at the same extent observed in previous large randomised trials not devoted to diabetic patients.
In the recently published Drug Eluting Stents Evaluation; a Randomized Trial (DESsERT),14 75 diabetic patients were treated with SES on 109 lesions and 75 with BMS on 109 lesions. In each patient, the PCI procedure was performed on top of a glycoprotein (GP) IIa/IIIb inhibitor. An eight-month angiographic and a 12-month clinical follow-up were performed. In-stent lumen late loss decreased from 0.96mm for BMS to 0.14mm for SES (p<0.001) and in-segment binary restenosis resulted in 38.8 versus 3.6%, respectively (p<0.001).

At 12 months, MACE were 40 versus 22.1% (p=0.023) and TLR 30 versus 5.9% (p<0.001) in the two groups, respectively. The beneficial effect on binary restenosis of SES regarding BMS was present in each subgroup analysed, irrespective of the vessel diameter, lesion length and insulin use; however, MACE reduction was marginal and no more statistically significant for women and previous insulin use.
Besides routine use of GPIIb/IIIa inhibitors as the standard optimal therapy for PCI in diabetic patients,15–17 for the first time a metabolic control parameter as expressed by glycated haemoglobin (HbA1c) levels was determined in DESsERT at baseline and after 30 days. An uncontrolled metabolic situation with HbA1c >7% decreased from 63% at the time of enrolment to 54% at 30 days and insulin-treated patients increased from 25 to 36%. Of note, HbA1c together with stent type was the only independent predictor of 12- month target vessel failure – composite end-point of death, target-vessel-related myocardial infarction and TVR – at multivariate analysis (p=0.024). Only one case of angiographic stent thrombosis in each group was documented within the per protocol six-month double antiplatelet regimen prescribed to SES-treated patients without events after discontinuation of clopidogrel. If sudden deaths are taken into account (one in each group), the total incidence of definite plus possible stent thrombosis as defined by the Academic Research Consortium (ARC)18 reached 2.6% in both groups, but was not related to stent type.

Safety

Diabetes has been observed to be an independent predictor of stent thrombosis in patients treated with DES,19–22 concomitant with premature antiplatelet therapy discontinuation, renal function impairment, bifurcation lesion and low left ventricular ejection fraction. The inflammatory and prothrombotic milieu favoured by diabetes associated with delayed re-endothelisation of the vessel wall determined by DES are responsible for this increased risk. Registry studies23 report a two-year incidence of angiographic thrombosis of 4.4% for SES and 2.4% for paclitaxel-eluting stents (PES). In the largest registry of PCI in diabetic patients,10 there was a two-fold increase in the incidence of angiographically proven stent thrombosis at two years in DES compared with the BMS group (1.5 versus 0.7%; p=0.48), with a typical trend after the first six months towards a disappearance of the event in BMS together with a constant incidence in DES-treated patients.

This observation has been confirmed by several experiences and makes prudent the prolonging of double antiplatelet therapy until one year or more in diabetics,22 and also questions the long-term efficacy and safety of treatment with numerous DES for extended periods in diffuse multivessel coronary artery disease of diabetic patients.

Sirolimus- versus Paclitaxel-eluting Stents in Diabetics

The components – i.e. stent platform, polymer and drug, the immunosuppressive sirolimus and the antineoplastic paclitaxel – of the two most widely used DES are as different as the results of their use. The indirect comparison between the two DES in the meta-analysis of the RCTs of DES versus BMS24 show not only a significant reduction of MACE with DES but also a significant heterogeneity between subgroups according to the type of DES (p<0.001), with a major reduction of MACE in the sirolimus compared with the paclitaxel group (odds ratio [OR] 0.28, 95% CI 0.25–0.35 for SES; OR 0.62, 95% CI 0.53–0.73 for PES). In a recent meta-analysis of head-to-head trials, Kastrati25 reported a similar difference in favour of SES, although the risk of death or myocardial infarction was not different between the two DES.
Only one study, the Innovative Stratification of Arrhythmic Risk (ISAR): Diabetes study26 enrolled 250 diabetic patients in a direct non-inferiority trial that compared the sirolimus and the paclitaxel stents. The primary end-point was in-segment late luminal loss, which was lower with sirolimus (0.43mm) than with paclitaxel (0.67mm) DES, but the study was not sufficiently powered to assess differences in terms of TVR or MACE. The analysis of the diabetic subgroup (378 patients) of the Reproductive Hormones And Pre-Clinical CVD In Women (REALITY) study27 showed a greater late loss in the paclitaxel than in the sirolimus group, but this loss was not associated with a higher rate of TLR.
Stettler et al.28 conducted an indirect meta-analysis of six trials with SES (SIRIUS, E-SIRIUS, C-SIRIUS, DIABETES, the Randomized, Double-blind Study with the Sirolimus-eluting Bx-Velocity Balloon Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions [RAVEL], SES-Smart)29–33 and four trials with PES (TAXUS I, II, IV, VI)34–37 in patients with and without diabetes. Although sirolimus was superior to paclitaxel DES in patients without diabetes, in those with diabetes the two DES did not differ significantly in any angiographic or clinical end-points. The relative incidence rate ratios for SES versus PES were 0.82 (0.31–2.18; p= 0.694) for in-stent restenosis, 1.51 (0.68–3.33; p=0.312) for in-segment restenosis, 0.86 (0.4–1.86; p=0.703) for TLR and 0.6 (0.21–1.71; p=0.336) for MACE.

Furthermore, in the Taxus Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) and RESEARCH registries,38 there was no difference in diabetic patients in unadjusted one-year outcome by stent type (MACE 20.4% for SES and 15.6% for PES) and after adjustment for multivariate predictors. Furthermore, in a published meta-analysis39 of RCTs, head-to-head trials and registries, including over 11,000 diabetic patients treated with DES, revascularisation and MACE estimates were similar for both PES and SES.

Drug-eluting Stents versus Coronary Artery Bypass Graft in Diabetics

All of the historical RCTs between PCI and CABG in multivessel coronary disease showed a better medium- to long-term prognosis in the surgical arm of diabetics for both the incidence of new revascularisations and death. Conflicting results are reported in the treatment of multivessel diabetic patients with DES. Diabetics and non-diabetics treated with SES in the Arterial Revascularization Therapy Study (ARTS) II40 had satisfying results in comparison with the historical cohorts treated with BMS or CABG, findings also confirmed in single-centre experiences with both DES,41,42 with a similar three-year mortality in the DES and CABG groups in diabetics also reported by the Korean group. However, numerous other reports show a higher incidence of cardiovascular adverse events in multivessel diabetics treated with DES in relation to CABG.43–45 In the study by Javaid et al.,44 diabetics treated with DES for two-vessel disease (in contrast to non-diabetics) has more MACE and cerebrovascular events than those receiving CABG, while other studies45 show an increase of MACE in diabetics only due to increased repeat revascularisations. All of these studies have several limitations (including absence of randomisation, clear differences in anatomical complexity and medical co-morbidities, completeness of revascularisation and limited follow-up), which will hopefully be overcome by the contemporary RCTs (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease [FREEDOM], Coronary Artery Revascularization in Diabetes [CARDia], Synergy Between PCI With TAXUS and Cardiac Surgery [SYNTAX]).46 In the meantime, the optimal revascularisation strategy in diabetics must be tailored to individual patients, aiming for at least functionally complete revascularisation if PCI is chosen, being relatively confident about good compliance to a long-term dual antiplatelet therapy and trying to achieve optimal metabolic control in terms of HbA1c and cholesterol levels, which both have a great impact on progression and destabilisation of atherosclerotic disease.

Conclusions

DES, and in particular SES, have been shown in both RCTs and registries to improve the outcome of diabetic patients treated with PCI compared with BMS. However, caution must be exercised about their unrestricted use, especially in multivessel and diffuse coronary artery disease, while awaiting more definitive results from large randomised trials, keeping in mind safety hazards in cases of multiple and long DES implants and the need for optimal metabolic control. Ôûá

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