a EMO, Centro Cuore Columbus, Via M. Buonarroti 48, 20145 Milan, Italy
b San Raffaele Hospital, Milan, Italy
* Corresponding author. Dr. Antonio Colombo
E-mail address: info{at}emocolumbus.it
This editorial refers to "Drug-eluting stents: an early systematic review to inform policy"1 by R. Hill et al. on page 902
In this comprehensive review and meta-analysis of studies performed with drug-eluting stents (DES) Hill and co-workers1 give a complete and detailed overview of this entire field. One very important element of this study is that the authors provide a large amount of data regarding studies yet to be published thus giving the reader access to a body of information not readily available.
Before entering into any more detail, two important considerations need to be made. Firstly, while sirolimus-eluting stents represent a homogeneous group utilising one single device (CypherTM, Cordis J&J, NJ), paclitaxel-eluting stents represent a variety of devices: both non-polymer based and polymer based (plastic acrylic eluting a derivative of paclitaxel and polymer eluting paclitaxel). It is therefore relatively easy to put the results of the first group of studies into perspective, whilst the results of the second group of studies appear more difficult to interpret and put into clinical perspective. Indeed, some of the studies evaluating paclitaxel or paclitaxel derivatives never came to full completion due to an unacceptable adverse event rate (9.4% stent thrombosis in the active arm of the Study to COmpare REstenosis rate between QueST and QuaDS-QP2, SCORE trial)2 or did not yield sufficient clinical benefit to justify commercialisation of the device (i.e., the paclitaxel non-polymer eluting stents).
The second consideration pertains to the limitations of conducting studies on a low risk population and analysing end-points which are viewed as the surrogate of clinical events. While it is ethical and appropriate to evaluate a new device in a low risk population, thereby avoiding unsafely magnified side-effects, this practice removes any possibility to impact on hard end-points such as death or myocardial infarction. An angiographic end-point was chosen because of the need to obtain results within a reasonable time period, which was generally less than one year. Unfortunately, the routine angiographic follow-up invariably affects the outcome by introducing a modifier before evaluating the outcome. This includes the incidence of adverse clinical events which could be prevented by treatment of restenosis.3 It is important for the reader to be aware of this whilst examining this review in order to avoid the conclusion that the lack of an effect on important clinical events, such as mortality and myocardial infarction, is a limitation of the study device rather than of the protocols used to evaluate the device.
For practical purposes the reader need only take into account two groups of studies: the sirolimus-eluting stent studies (CypherTM) and the polymer-based paclitaxel-eluting stent studies (TAXUSTM, Boston Scientific, MA); the final message is not changed and the treatment effect between sirolimus and paclitaxel becomes similar. It is reassuring to notice that in this review, paclitaxel eluting stents maintain a significant impact in reducing adverse events rates at 1 year (Odds ratio (OR) 0.63, 95% Confidence Interval (CI) 0.470.84) despite the inclusion of some device formulations not considered efficacious.1
There are methodological considerations to be taken into account when approaching a meta-analysis of DES, due to the lack of a standard format to report study findings. Specifically, angiographic and clinical follow-up data have been collected at varying time points of 4, 6, 8, 9 and 12 months and each study used different end-points. The large variety of paclitaxel-eluting stents should lead us to consider that variations in drug-dosing, release kinetics, stent design, and stent-coating technologies can result in differing vascular reactions and efficacy. We should not forget that in the ASian Paclitaxel-Eluting Clinical Trial (ASPECT), two different types of antiplatelet therapy were given to patients treated with paclitaxel-eluting stents.4 This choice contributed to the relative increase in adverse events in the group treated with aspirin and cilostazol.
As the authors point out, the adverse event rates in these trials were composed primarily of new revascularisations and were reduced by up to 60%. An important concern raised is that the routine angiographic follow-up triggered an increase in revascularisations, thus artificially increasing the benefit of the device. Despite these limitations, angiographic binary restenosis is accepted as an appropriate surrogate for clinical events.5 Examining the TAXUS IV trial, the patients receiving angiographic follow-up as part of the group with mandatory angiographic follow-up, the incidence of target lesion revascularisation was 14.6% in the control group versus 3.8% in the TAXUSTM group. The degree of incidence in the patients not included in the angiographic follow-up group was 11.5% versus 2.8% (Gregg W Stone, personal communication).
Patient selection for DES is an evolving issue and patient characteristics are of great importance in evaluating the impact of DES in restenosis. For instance, differences in angiographic outcomes between the RAndomised study with the sirolimus-eluting Bx VELocity balloon-expandable stent (RAVEL)6 and SIRolImUS-eluting stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery (SIRIUS)7 have been attributed to the treatment of a higher-risk population in the US trial. The large number of patients enrolled in this latter trial permitted sub-analyses which demonstrated a larger benefit in terms of absolute reduction in restenosis among high-risk patients. Long-term follow-up data and experience in more complex lesions is now accumulating,8 but based on these preliminary findings, indications for DES are already expected to expand considerably in the near future. Data are also available supporting their advantage over non-DES in the treatment of bifurcational lesions.9 Conversely, it must be emphasised that only a relatively small number of diabetic patients, and even fewer insulin-dependent diabetics, have been studied. Moreover, diabetes is still a predictor of restenosis based on data from registries with DES.8 Similar results were found in the recently published SIRIUS trial7 with restenosis occurring after CypherTM stent deployment in 9% of all patients, 18% of all diabetics, and 18% of patients with small vessel disease. This highlights the fact that restenosis, after the use of DES, is minimised but not completely eliminated. Despite the above limitations, the advantage of sirolimus and paclitaxel polymer-based eluting stents compared to non-DES stents appears to be greatest in these high risk subgroups.
What relevance, if any, do the results of trials comparing non-DES and coronary artery bypass grafting (CABG) surgery trials have in the DES-era with regard to multi-vessel disease? Also, what role should economic considerations play when comparing therapies? Recent studies have addressed the economic impact and the money saved as a result of revascularisation performed with either DES or non-DES.10 The economic impact of a strategy of multi-vessel stenting with DES could be profound. It has been reported that at the end of the first year of follow-up the estimated cost difference between DES and non-DES is almost abolished due to the reduction in target lesion revascularisation (TLR).11 From the results of the DES trials, it seems likely that DES will result in similar reductions in the setting of multi-vessel percutaneous coronary intervention (PCI) and thus in the abolition of the difference in repeat revascularisation between CABG and stenting. Furthermore, it has been hypothesised that, given the approximate 7% frequency of in-hospital vein graft occlusion, DES may in fact be a more durable means of coronary revascularisation than CABG. In contrast, it has been reported that US hospitals lose money if more than 1.43 CypherTM stents (with only 50% DES utilisation) are implanted, per patient, during a single PCI procedure.12 Therefore, it is an over-simplification to assume that the reduced frequencies of TLR with the adoption of DES would favourably influence the relative costs of PCI versus CABG. We believe that these dynamics will change with the availability of other potent DES, currently used in trials, and with further price reductions due.
Stent thrombosis, and particularly subacute thromboses have been a lingering consideration within the cardiology community. It must be emphasised however that according to the randomised, controlled trials (as reported in this meta-analysis) and from the registry data in higher risk populations, the rates of acute and subacute thrombosis seen with DES, awarded with CE marking, approximate to the rates of non DES. In the Web-based TAXUS Intercontinental obServational Data transitiOnal program (WISDOM) registry the stent thrombosis rate within the first 30 days was 0.4%, and no late thromboses occurred. In TAXUS IV, at 12 months, the stent thrombosis rate was 0.6%.13 In the e-Cypher registry, the rate of acute thrombosis was 0.1%, of SAT 0.95%, and of late thrombosis 0.3%, suggesting that the real-life incidence of any thrombotic event can currently be estimated at 1.35%. The high incidence of stent thrombosis observed in the early paclitaxel studies14,15 may be due to high drug concentrations, inadequate anti-platelet therapy (ASPECT), or thrombogenic stent drug delivery platform (SCORE).
It has been demonstrated that stents can be safely and effectively placed in the majority of lesions without pre-dilatation. Direct stenting has modestly reduced the cost and procedural time needed for non-DES without improving the long-term outcomes. Until recently, operators were discouraged to implant DES without pre-dilatation as there was concern it would disrupt the polymer. Recent data from the Direct Stenting Using the Sirolimus-Eluting Stent (DIRECT) study support the safety and possible advantage of direct stenting when feasible.16 More specifically, the eight-month binary restenosis in 225 patients treated with direct stenting was no different in-stent but there was a trend indicating improved binary restenosis rates in-lesion compared to 412 historical controls who underwent pre-dilatation in the SIRIUS trial.16 It is worth noting that this trend was particularly strong in patients with small vessel sizes (2.3 mm) and in patients with insulin-dependent diabetes in whom the benefits of direct stenting were statistically significant.16 If direct stenting with DES proves to be advantageous or even non-detrimental, this finding will further enhance the user-friendly usage of these devices.
Can the results of the DES reported in this meta-analysis be validly applied to patients dissimilar to those enrolled in these trials? Operators are now using DES for a wide variety of clinical and anatomic situations, many of which have not been adequately studied. Evaluation of the clinical and economic impact of using DES to treat patients with small vessel disease, multi-vessel disease, or patients with a significant high risk characteristic, such as diabetes, awaits further evidence from multi-centre trials.
This meta-analysis demonstrated that even if myocardial infarction and death were not reduced, the need for new revascularisation, even if obtained in a selected setting, will make any new study in which the control arm will be constituted by non-DES untenable. Even for simple lesions, any new study evaluating the performance of a new DES will have another DES in the control group. When the control group becomes more complex, such as in multi-vessel stenting and diabetes, will the treatment of choice, against which DES is to be compared, be by-pass surgery (as in the Future revascularisation Evaluation in patients with Diabetes mellitus: Optimal management of Multi-vessel disease (FREEDOM) trial) or compared to a similar historical control (such as Arterial revascularisation Therapy Study II vs. Arterial revascularisation Therapy Study I surgical group)? These results and trends indicate the future disappearance of the non-DES. According to Evidence Based Medicine, the selection of the DES for every type of lesion may be premature and not supported. However, it is difficult to imagine that the non-DES will perform better or equally as well and, even if this possibility exists, we doubt that there will be any chance to test this hypothesis.
Footnotes
References
Related articles in EHJ: