The Safety and Efficacy of Sirolimus-eluting Stents and Evidence for Their Use in Specific Lesion Subsets

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The treatment of atherosclerotic coronary artery disease (CAD) using percutaneous coronary intervention (PCI) is a well-established procedure that is performed over one million times a year in the US. The Achilles heel of PCI has been the development of neointimal hyperplasia within the stent, resulting in in-stent restenosis (ISR). Sirolimus-eluting stents (SES) provide a platform that in pivotal early trials has been shown to dramatically reduce the problem of ISR.1,2 Recent papers published within the last year have raised concern over late stent thrombosis (ST) as a significant therapeutic complication. This paper will review the issues of safety and efficacy through data published over the last year. It will then review the efficacy of SES in specific population subsets, including ISR, left main disease, multivessel disease, long lesions, small vessels, diabetes, saphenous vein grafts (SVGs) and acute myocardial infarction (MI).


The issue of safety and concern about late ST gained widespread attention after the presentation of the Basel Stent Cost-Effectiveness Trial–Late Thrombotic Events Trial (BASKET-LATE) at the World Congress of Cardiology in 2006.3 BASKET-LATE was a Swiss cost-effectiveness trial that extended follow-up of patients randomised to drug-eluting stents (DES) compared with bare-metal stents (BMS). All patients with events in the first six months were censored, with the remaining patients followed for an additional 12 months. Using this landmark analysis, the investigators found an increase in the incidence of death and MI in months seven to 18 (4.9 versus 1.3%), although the overall rate of death and MI over the entire 18-month period was not significantly different. Because patients in the BMS arm were censored from – and therefore not included in – the prolonged follow-up period if they required target vessel revascularisation (TVR), it was unclear whether the actual rates of late ST were significantly different between the two arms.

In order to better understand these safety concerns, a number of investigators published meta-analyses of the pivotal randomised trials in addition to single-centre or multicentre registry data. These are often retrospective analyses applied to pre-existing data, and therefore are inherently limited. For example, many of these registries did not collect data on the duration of dual-antiplatelet therapy. Moreover, until recently4 the definition of ST was not standardised, and different studies used different methodologies in defining events. However, these studies provide the most meaningful data related to the safety of these devices.

The largest meta-analysis of SES with up to four years of patient follow-up provides significant insight.5 Using patient-level data from 4,958 randomised patients with a follow-up of one to five years, the investigators found no significant difference in rates of death or death and MI, but a sustained, significant reduction in MI and TVR with SES over the five-year period. The study showed a modest sustained increase in the risk of ST for SES compared with BMS after the protocol-required duration of dual-antiplatelet therapy had ended. The overall ST rate was low: over four years, the overall rate was 0.8% in the SES arms compared with 0.3% in the BMS arms. The study also looked specifically at a subset of patients without diabetes; although not statistically significant, there was a trend towards decreased survival in the patients receiving SES (hazard ratio (HR) 1.27, 95% confidence interval (CI) 0.83–1.95).

Multiple groups have published registry data using SES. Registry data incorporate higher-risk patients with more complex lesions than those in clinical trials. These patients reflect current usage of SES devices. Table 1 provides a summary of the registry data reporting specifically on SES.6–13 The largest data set is the E-Cypher registry,6 a non-US-based, international, post-marketing surveillance study. A total of 15,157 patients were enrolled; 59% of these patients would have been excluded from the SIRIUS trial. The patients were predominantly male, and a significant fraction of patients had a history of MI (30%), diabetes (29%) or bypass surgery (10.5%). MI was the presenting syndrome in 7% of the patients in the registry. Average vessel size was 3.0mm, and most patients received one stent delivered at an average of 14 atmospheres.

Post-hospitalisation, there was a sharp decline in the use of dual-antiplatelet therapy. At six months, 70% of patients were on dual-antiplatelet therapy, and at one year 43% of patients were still taking dual-antiplatelet therapy. All events were independently adjudicated. At 30 days, the overall major adverse cardiac event (MACE) rate was 1.4%, with an overall death rate of 0.6%. At one year, the overall MACE rate was 5.8%, with a mortality rate of 2.2%. The ST rate was low at 0.9%. Of the 126 patients who suffered ST, 16% were on no antiplatelet therapy. Twelve-month target lesion revascularisation (TLR) was remarkably low at 5%, despite the complexity of the lesions. The E-Cypher registry provides reassuring follow-up data, despite the higher-risk nature of these patients.

A less sanguine report comes from a recent two-institution cohort study.14 In a three-year follow-up of 3,823 patients who received SES, patients risked late ST at a continuous rate of 0.6% per year, without plateau. ST in this study was strictly defined as angiographically visible thrombus within the stent with corresponding acute coronary syndrome. The risk of late ST (after the first six months) with SES was 1.4%. Fewer than one-quarter of the patients were on dual-antiplatelet therapy at the time of ST, and only half were taking aspirin; 97% of those patients with late ST had their event after the recommended time period for thienopyridine therapy. The overall rate of ST with SES at three years was 2.5%.

Another sobering picture is provided by the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) study group, which evaluated all patients who underwent PCI over a two-year period and compared outcomes in patients who received BMS versus DES.

Although not specifically limited to SES, patients who received DES had an increased risk of death after the first six months after implantation. Using the same landmark analysis of excluding patients who had events in the first six months, the relative risk of death in patients receiving DES was 1.32 (95% CI 1.11–1.57). Patients who received DES were less likely to require repeat revascularisation by PCI or coronary artery bypass graft (CABG), and had a restenosis rate of 3.6 versus 5.9% for those receiving BMS.

Another link comes from the analysis of patients undergoing PCI at Duke University.15 This study performed landmark analysis after six and 12 months on patients who underwent PCI, and stratified them into four categories based on stent type and clopidogrel usage. Patients who received DES without being on clopidogrel had the highest mortality rate, while those patients who received DES with clopidogrel extended after the first six months had the lowest mortality (see Figure 1). The overall number of patients was small, and clopidogrel use after the first six months was not randomised and was self-reported. Nonetheless, these provocative findings, which need to be confirmed in randomised trials, suggest that prolonged dual-antiplatelet therapy in patients receiving DES may be necessary to mitigate the risk of ST.


The last year has seen papers published on various high-risk subgroups in which SES has been shown to be efficacious. These indications are off-label at present, but a reasonable amount of data supports this usage. ISR, once decreasing in frequency, has reappeared as more patients and interventionalists opt for BMS due to specific factors. A meta-analysis of randomised trials comparing DES with either balloon angioplasty (BA) or vascular brachytherapy (VBT) found a significant advantage for DES.16 Specifically, SES reduced tumour vasculature targeting (TVT) significantly (odds ratio (OR) 0.27, 95% CI 0.18–0.41) compared with BA or VBT. Because of problems with VBT, DES have become the treatment of choice for most ISR.

Left main disease is a surgically treated entity for most patients. Small registries have attempted to evaluate outcomes in patients undergoing unprotected left main coronary stenting. One example is the Multi-Center German Cypher Study.17 Approximately one-third of these 82 patients had distal left main disease; 80% were treated with a single stent. At six months, 7.4% of the patients had died, there were no MIs or strokes and TVR was limited to 6.7%. At 32 months, mortality was 15%. Although promising for the initiation of clinical trials, these lesions (especially those involving the distal left main artery) will likely remain for patients who are not considered candidates for CABG.

Limited data exist on the treatment of multivessel CAD with SES. Perhaps the best data come from the one-year follow-up of the Arterial Revascularization Therapies Study Part II (ARTS II) registry.18 In 607 patients (26% with diabetes) treated for multivessel CAD, one-year mortality was only 1%, stroke rate was 0.8% and MI rate – defined as any elevation in creatinine kinase (CK) – was 19%. If the definition of MI was new Q-waves on electrocardiogram or 3x CK upper limit of normal, the MI rate at one year was 3%. This study suggests that multivessel stenting is feasible with low risk at one year. Longer-term follow-up is pending, as are randomised trials addressing this question.

Severe diffuse disease is another common presentation of CAD. Previous attempts at treatment with BMS resulted in high rates of restenosis. DES has been studied in small series with reasonable results. In one series,19 250 patients treated with SES with an average stent length of 41mm had low event rates at nine months: death 0.8%, MI 8.8%, TVR 3.2% and ST 0.8%. In the seven patients who developed ISR, all patients had a focal pattern of restenosis, as opposed to diffuse proliferation.

In the other study,20 with 81 patients treated with a median stent length of 77mm, death occurred in 2.5%, MI in 11.2% and TVR in a remarkably low 7.5% of patients. These small registries suggest that diffuse stenting may be performed with relatively low TVR and MACE rates.

Smaller vessels may be more subject to diffuse ISR. A recent study evaluating 2.25mm-diameter SES was undertaken in 100 patients and compared with historical controls.21 At six months, the binary restenosis rate was 16.9%, lower than the historical 30.6% for BMS. Moreover, the study found that greater stent length was associated with greater TVR and more diffuse ISR, a finding not seen in the larger SES studies described above. This suggests that smaller vessels may have a different risk profile and presentation for ISR.

There are limited data regarding diabetics with CAD treated with SES. In the meta-analysis of SES,5 there was a trend towards lower survival in patients with diabetes (HR 1.27, 95% CI 0.83–1.95; p=0.26). The role of SES awaits more definitive answers from the National Heart, Lung, and Blood Institute-sponsored studies Bypass Angioplasty Revascularization Investigation in Type 2 Diabetics (BARI 2D) and Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes (FREEDOM).

One small, randomised, double-blinded trial with six-month follow-up evaluating SES and BMS in the treatment of SVG disease has been published.22 Only 38 patients were in the SES arm and 37 patients were in the BMS arm. Angiographic, intravascular ultrasound (IVUS) and clinical parameters all favoured SES. Although there was no difference in death or MI, there was a large reduction in TVR: 5.3 versus 27% (relative risk (RR) 0.19, 95% CI 0.05–0.83; p=0.012).

Multiple randomised trials have been published evaluating the role of SES in acute MI. The largest such trial, the TYPHOON study,23 studied 720 patients randomised to either SES or BMS. At one year, there was no significant difference in death or MI and TVR was decreased significantly in the SES arm (5.6 and 13.4%, respectively; p<0.001). Both arms had high rates of one-year ST (3.4 and 3.6%, respectively), a cause for concern that requires further study. Data continue to be limited for other patient subsets, such as patients with chronic total occlusions, low ejection fraction or cardiogenic shock. Future trials will hopefully address these important patient subsets.


SES have been studied in clinical trials and in observational studies. These studies consistently find a long-term reduction in ISR. There may be a small increase in late ST, which may be mitigated by prolonged dual-antiplatelet therapy; however, these hypotheses both are limited and require significantly greater amounts of trial data. SES have been found to be relatively safe and effective over a wide range of lesion and patient characteristics. Caution must be maintained in patients who may not be able to take prolonged dual-antiplatelet therapy, specifically in patients who may be undergoing new or intermediate-term surgery, and patients who are unwilling or unable to adhere to dual-antiplatelet therapy should have BMS or surgery considered as viable options.


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