In both randomised trials, compared with bare metal coronary stents, and in observational registries, treatment with drug-eluting stents (DES) has been associated with considerable reductions in angiographic restenosis and the need for repeat coronary revascularisation procedures. Despite these established benefits in selected patient populations, relatively little is known regarding the safety and efficacy of DES in patients with acute coronary syndromes (ACS).
Drug-eluting Stent Utilisation in ACS
At present, expanded use of DES in percutaneous coronary revascularisation has been limited primarily by issues related to cost, product availability and the absence of data supporting the safety and efficacy of DES in more complex clinical settings. Most reports describing the prevalence of DES utilisation in high-risk patient subgroups have been limited to market analyst summaries or manufacturer reports derived from relatively few hospitals and a fixed and narrow time period. These analyses, in addition to post-market surveillance studies intended to identify patient characteristics and indications for DES usage beyond the context of clinical trials, have not routinely included bare metal stents (BMS) or competing DES, restricting their applicability to clinical practice. Recently, the frequency, predictors and early clinical outcomes of DES utilisation were characterised among patients with high-risk non-ST-segment elevation ACS who underwent percutaneous coronary intervention and were enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry.1 In addition to myocardial infarction, this analysis included patients with other characteristics not routinely represented in DES trials and for whom few data exist, including those with advanced heart failure and renal insufficiency. Overall, DES use increased considerably over a nine-month period. Higher-risk clinical characteristics were associated more commonly with BMS treatment, possibly reflecting some uncertainty regarding DES safety and efficacy in patients presenting with high-risk clinical presentation or coronary anatomy. However, it was also remarkable that the use of DES did not correlate with guideline recommended therapies intended to improve clinical outcomes in ACS patients.
Despite this finding, in a multivariate model that included clinical and hospital characteristics, in-hospital adverse events were significantly less frequent among patients treated with DES. Specifically, the occurrence of death, cardiogenic shock and recurrent myocardial infarction were significantly less common among patients treated with DES compared with BMS. Importantly, clinical outcomes were restricted to in-hospital events, precluding any assessment of potential treatment differences regarding intermediate and long-term outcomes.
Clinical Investigations
As previously stated, most clinical trials evaluating DES have systematically excluded patients with high-risk clinical characteristics, in particular those with thrombotic coronary lesions such as those with ST-segment elevation and non-ST-segment elevation ACS. Among subgroup analyses reporting outcomes for patients with ACS, these studies have been limited by non-randomised, observational trial designs, small patient populations and abbreviated clinical follow-up. In the e-Cypher registry examining clinical outcomes in patients treated with sirolimus-eluting stents (Cordis Corporation, Miami Lakes, FL), 7% and 5.5% of patients were identified with acute and recent myocardial infarction, respectively.2 Clinical events were not specifically reported for ACS patients. However, in multivariable analysis, presentation with ACS was not described as a significant predictor of one-year major adverse events. Similarly, the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry did not report an increased risk of adverse events among patients treated with sirolimus-eluting stents.3 Limited data also exist regarding outcomes with paclitaxel-eluting stents in ACS in the Taxus-stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry.4 Although results of patient sub-groups were not independently reported, it is noteworthy that all six cases of angiographically-determined stent thrombosis occurred in patients initially presenting with either unstable angina or myocardial infarction (MI).
More recently, randomised trials have specifically examined the safety and efficacy of both sirolimus-and paclitaxel-eluting stents in primary percutaneous coronary intervention for acute MI (AMI). In the Trial to Assess the Use of the CYPHER Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON)5 overall, there were no clinically relevant differences between treatment groups regarding baseline clinical characteristics.
Time to treatment and procedural characteristics were also similar, except for a significantly smaller stent diameter and longer stent length in the sirolimus group. At one year, the primary composite endpoint of target vessel failure occurred in 14.3% of patients in the bare metal group and in 7.3% in the sirolimus group, a difference principally driven by the lower incidence of target vessel revascularisation in the sirolimus cohort. Although there were no significant differences in death or recurrent MI, target lesion revascularisation (TLR) was significantly lower with sirolimus-eluting stents. Further, among patients undergoing angiographic follow-up, measures of in-stent late loss and binary restenosis were significantly lower in the sirolimus-eluting stent group.
In the Paclitaxel-eluting Stent versus Conventional Stent in Myocardial Infarction with ST-elevation Myocardial Infarction (PASSION) trial, patients presenting within six hours of onset of AMI symptoms were randomised to treatment with either the paclitaxel-eluting TAXUS stent or a conventional, BMS (Express stent, Boston Scientific Corp).6 The primary endpoint was the one-year occurrence of major adverse events, defined as the composite of cardiovascular death, recurrent MI or TLR. Baseline clinical characteristics did not statistically vary between the two treatment groups but were remarkable for a low prevalence of diabetes. There were no major differences in baseline angiographic characteristics or procedural outcomes. At one year, despite a trend toward fewer events in the paclitaxel group, the primary endpoint of major adverse events did not statistically differ compared with the BMS cohort. In particular, there were no significant differences regarding outcomes of death and ischaemia-driven TLR. Stent thrombosis occurred in three patients in each group. Although outcomes of death and repeat myocardial infarction have not routinely differed between DES and BMS, compared with the TYPHOON study, the absence of a significant reduction in target lesion revascularisation in the PASSION trial is likely, in part, related to the lack of protocol-specified follow-up angiography, in which clinical restenosis-rather than angiographic restenosis-predominantly determines the need for repeat revascularisation. Further, compared with the TYPHOON trial, the PASSION study did not include angiographic follow-up in a subgroup of patients, limited randomisation to only one type of bare metal stent, and included patients with complex lesion morphologies and Killip class ≥2 myocardial infarction. The inability to compare outcomes between these two trials therefore merits further comparative trials of DES in AMI.
Conclusions
Recent observations regarding use of DES in ACS patients have extended the understanding of their role in patients who are not routinely included in contemporary clinical trials. However, while in many instances these findings reflect routine clinical practice and raise awareness of the expanded use of DES in high-risk clinical settings, they also understate the need for more systematic evaluation of DES in broad clinical settings. Further, given varying trial designs and results, a 'class effect' with all DES cannot be assumed. Finally, a more detailed understanding of the interaction between the optimal duration of antiplatelet therapy and DES placement in ACS patients is required. In the recent multi-centre Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER), nearly one in seven AMI patients discontinued their prescribed thienopyridine therapy by 30 days following revascularisation with DES.7 During the next 11 months of follow-up, patients who had discontinued therapy were significantly more likely to experience death or re-hospitalisation. Ongoing post-market follow-up of selected patient cohorts and forthcoming prospective trials dedicated to evaluating various DES in specific indications should provide further insight to their clinical efficacy and safety in these understudied patient populations.