The XIENCE V (Abbott Vascular, CA, USA; also distributed as the PROMUS stent by Boston Scientific, MA, USA) everolimus-eluting stent (EES) is a second-generation drug-eluting stent (DES) designed to overcome the limitations of earlier DESs. Clinical studies with first-generation sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) demonstrated a dramatic reduction in restenosis rates compared with bare-metal stents (BMSs) Citation[1,2]; however, reintervention rates were still high in patients with complex coronary artery disease Citation[3], and an ongoing propensity for stent thrombosis beyond 1 year raised further concerns regarding safety issues with these devices Citation[4]. Furthermore, as both of these devices were relatively high-profile stainless steel stents, they were difficult to deliver in complex anatomy, and the SES in particular was prone to a high fracture rate, contributing to late adverse events.
In the EES, everolimus, a rapamycin derivative, is released from a thin layer (7.8-µm) of a biocompatible fluoropolymer coated on an open-cell, thin-strut (81-µm) flexible and highly deliverable cobalt–chromium stent. The polymer is inert and noninflammatory, and the stent is extremely resistant to fracture. Two moderate-sized trials with the EES demonstrated a significant reduction in angiographic in-stent and in-segment late lumen loss compared with the first-generation TAXUS Express PES (Boston Scientific), and noninferiority in major clinical end points Citation[5,6]. These findings suggested that, if tested in larger populations, the EES might achieve superior clinical outcomes compared with the earlier predicate devices. However, given the favorable outcomes with PES, large studies would be required to elicit small differences in low frequency but important clinical end points. Toward this end, two large-scale randomized trials have been performed, the SPIRIT IV and COMPARE trials.
SPIRIT IV was a prospective, multicenter trial that randomized 3690 US patients in a 2:1 ratio to EES versus the TAXUS Express PES Citation[7]. The primary end point was a composite of target lesion failure (defined as cardiac death, target vessel myocardial infarction [MI] or ischemia-driven target lesion revascularization [TLR]); the major secondary end points were ischemia-driven TLR and a composite end point of cardiac death or target vessel MI at 1 year. SPIRIT IV is the largest completed randomized controlled trial comparing two DESs to date, and was powered for sequential testing of noninferiority and superiority in its primary and both major secondary end points. The trial was large enough to provide data on other secondary end points and important subgroups, particularly patients with diabetes mellitus, but excluded patients with acute coronary syndromes (ACSs) and ST-segment elevation MI (STEMI), large bifurcations and other complex lesion subsets.
Almost simultaneously, another prospective, randomized investigator-initiated, single-center study, the COMPARE trial, was performed in The Netherlands Citation[8]. This trial randomized 1800 ‘all-comer’ patients (i.e., with limited exclusion criteria) in a 1:1 ratio between the EES and TAXUS Liberté PES, which shares the same polymer, drug and release kinetics with the TAXUS Express PES, but has thinner struts and more uniform scaffolding. The primary end point of COMPARE was a composite of all-cause mortality, non-fatal MI and clinically driven target vessel revascularization (TVR). Like SPIRIT IV, COMPARE was also powered for both noninferiority and superiority testing. This trial population represents a real-world population as there were no exclusion criteria other than general contraindications for DES (e.g., inability to take dual antiplatelet therapy), and was large enough to provide data on complex patient subsets including those with ACS and STEMI. In contrast to many prior DES studies, routine angiographic follow-up was not performed in either SPIRIT IV or COMPARE to avoid unnecessary and unplanned revascularization procedures Citation[9–11].
Both trials independently showed that the EES was superior to the PES (regardless of the TAXUS platform) with regard to their respective primary composite safety and efficacy end points . These results were driven by significant reductions in clinically driven TLR and MI, findings that were in part due to a significant reduction in the rates of stent thrombosis with the EES, as well as to reduced late recurrent ischemia necessitating repeat percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). No significant differences were observed in the rates of all-cause or cardiac mortality between the different stent platforms at 1 year.
Based on the results of these two trials, the belief that had previously been held by some that clinically relevant differences between DES of various designs do not exist has clearly been discredited. These trials have also shown that low angiographic late loss (resulting in greater efficacy) as well as improved safety may be simultaneously achieved in a single DES platform.
Although the lower rates of TLR and TVR with EES were predictable from previous studies in which late loss with EES was significantly lower than with PES, the marked (nearly 75%) reduction in stent thrombosis observed with the EES was a surprising finding in its magnitude. Both trials showed strikingly similar relative risk reductions in thrombotic events with EES compared with PES at 30-day and 1-year follow-up, with the majority of the stent thromboses occurring during the first 30 days. EES reduced stent thrombosis compared with PES in both the early (<30-day) and late (30-day to 1-year) phases. Until recently, the interventional community has been focused on very late stent thrombosis (after 1 year) given the ongoing propensity of first-generation DES to occlude acutely after 1 year when compared with BMS Citation[4,12]. However, early stent thrombosis accounts for the majority of stent thrombosis events during follow-up Citation[13]. This is even more evident in complex populations. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Citation[14] and Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) Citation[3] trials, stent thrombosis rates at 1 year were 3.2 and 3.3%, respectively; 30-day stent thrombosis was responsible for approximately two-thirds of the events in both trials. SPIRIT IV and COMPARE have now demonstrated that use of EES during this critical time period can markedly reduce the incidence of stent thrombosis. Longer-term follow-up from both studies is required to determine whether these findings persist or become even more pronounced.
The mechanistic underpinnings of the marked reduction in stent thrombosis with EES (despite low angiographic late loss) are speculative, but may relate to certain stent design features. Specifically, the thinner stent struts in combination with a biocompatible fluoropolymer may result in more rapid strut coverage with functional endothelium Citation[15]. Fluorinated polymers are also known to resist platelet and thrombus deposition Citation[16,17]. Because these trials were not designed to study these issues, additional mechanistic studies are required to confirm the reasons underlying the enhanced safety of EES.
Another important finding from the SPIRIT IV and COMPARE trials is that significantly fewer adverse events were observed with EES in complex patient and lesion subgroups, such as multivessel and small-vessel disease, chronic total occlusions, long lesions and ACS. Based on data from the SPIRIT IV and COMPARE trials, we examined how the results of the randomized SYNTAX trial Citation[3], a 1700-patient study of PES versus CABG in patients with left main and three-vessel coronary artery disease, might have been influenced if EES was used in place of PES. SYNTAX showed superiority of CABG compared with PES at 1 year, a finding driven by more revascularization procedures in the PCI arm. In order to reach noninferiority between the PCI and CABG groups, a reduction of 20 events with PCI was needed. Use of EES rather than PES in SYNTAX might have led to a total reduction of 81 events in the PCI group, such that the SYNTAX trial could have declared noninferiority for PCI. This analysis, of course, is only a hypothesis-generating exercise; whether PCI with the EES is truly noninferior (or superior) to CABG in patients with complex coronary artery disease can only be determined by a dedicated large randomized controlled trial. Such a study has recently been announced. The international Evaluation of XIENCE Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, set to begin in late 2010, will randomize approximately 2500 patients with unprotected left main disease to CABG versus PCI with the next-generation EES (XIENCE Prime).
For many years the relative clinical utility of rapamycin analogue-based DES compared with PES in patients with diabetes mellitus has been debated. With nearly 5500 randomized patients in SPIRIT IV and COMPARE (1510 [28%] of whom had diabetes), these trials had significant power to examine clinical outcomes in this subgroup. Of note, while there was marked reduction in death or MI, stent thrombosis and TLR in nondiabetic patients in both studies with EES compared with PES, no statistically significant benefits were apparent with EES in diabetic patients. While differences may emerge between these devices with longer follow-up from SPIRIT IV and COMPARE, currently there is no conclusive clinical evidence that one stent is superior in diabetic patients. Larger dedicated randomized trials in diabetic patients would be useful. Considering that approximately 1 million patients with diabetes worldwide are treated with PCI each year, even small differences in treatment outcomes would have important implications for global health. Conversely, for every 1000 nondiabetic patients treated with the EES rather than the PES, approximately 14 stent thromboses and 52 occurrences of death, MI or TLR within 1 year would be prevented.
In conclusion, EES represents a major advance for patients with ischemic heart disease as they have demonstrated significantly improved efficacy while enhancing safety, even in complex patient subgroups. The SPIRIT IV and COMPARE trials have demonstrated that large-scale studies in complex patients and lesions are required to elicit important clinical differences between devices. These studies have also opened new horizons for interventional cardiology, such as prompting EXCEL, a large-scale randomized trial of EES versus CABG for left main disease, which if positive will establish PCI as the treatment of choice for the most complex patients with coronary artery disease. Greater mechanistic insights into how the design properties of the EES translate into improved safety and effectiveness compared with earlier designs will no doubt spur development of even safer and more effective devices. However, clinical results after DES can still be improved in patients with diabetes mellitus, representing an opportunity and mandate for the future development of novel stents to further improve outcomes in these high-risk patients.
Table 1. 1-year clinical outcomes in the SPIRIT IV and COMPARE trials.
Financial & competing interests disclosure
Gregg W Stone has served on the scientific advisory boards for and received honoraria from Boston Scientific and Abbott Vascular. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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