Cordis Corporation recently announced that it has received CE mark approval for the treatment of acute myocardial infarction (AMI) using the CYPHER® SELECT™ PLUS sirolimus-eluting coronary stent. CE marking means conformity to the applicable European Directive, and in the specific context of AMI permits the CYPHER stent to be placed on the market for treatment of AMI in all Member States of the EU, the European Economic Area and Switzerland.
The role of drug-eluting stents (DES) in AMI has been a contentious issue for some time due to conflicting efficacy results and the concern of an increased risk of late stent thrombosis compared with bare-metal stents (BMS). Patients with AMI were excluded from the pivotal studies of all DES; however, several dedicated studies on the use of the CYPHER stent in AMI were recently published or presented at major congresses and showed positive results, with a long-term benefit of the CYPHER stent versus both thin- and thick-strut BMS.1-9 These nine randomised trials included more than 3,000 patients with AMI.
Randomised Controlled Trials
TYPHOON was the first randomised controlled trial (RCT) to show definitive improvements with a DES (the CYPHER stent) over BMS in AMI.1 The one-year follow-up results showed a significant reduction in target vessel failure (TVF, defined as a composite of target vessel revascularisation [TVR], recurrent infarction and target-vessel-related cardiac death) associated with the CYPHER stent (7.3%) versus BMS (14.3%; p=0.004), driven by a decrease in the rate of target lesion revascularisation (TLR) (5.6 versus 13.4%; p<0.001). Rates of death (CYPHER 2.3%, BMS 2.2%), recurrent MI (1.1 versus 1.4%) and stent thrombosis (3.4 versus 3.6%) were similar for the two groups.1 The non-adjudicated event rates at three years in TYPHOON are illustrated in Figure 1. Rates of death and MI remain similar at this time-point (data presented by Professor Spaulding at EuroPCR 08). The collection of data for four-year adjudicated events is ongoing.
The STRATEGY trial evaluated the clinical and angiographic impact of single high-dose bolus tirofiban plus CYPHER stent (87 patients) versus abciximab plus BMS (88 patients) in the setting of primary angioplasty for AMI.2 The end-point, a composite of death, non-fatal MI, stroke and binary restenosis at eight months, was significantly lower in the tirofiban plus CYPHER stent group (19 versus 50%, hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.18-0.60; p<0.001).
At three years (Valgimigli et al., ESC 2007), the TVR rate was 10% in the CYPHER stent group and 25% in the BMS group, while death/MI and ST rates were similar (20-23 and 5.7-6.8%, respectively). Overall MACE rates are shown in Figure 2. Long-term reports on the benefits and safety of the CYPHER Stent are available in other studies. The SESAMI trial included 320 patients with AMI who were assigned to receive the CYPHER stent or BMS.3 The primary end-point, binary restenosis at one year, was significantly lower for the CYPHER stent (9.3%) than the BMS group (21.3%; p=0.032), as were the rates of TVR (5 versus 13.1%; p=0.015), major adverse cardiac events (MACEs) (6.8 versus 16.8%; p<0.005) and target vessel failure (8.7 versus 18.7%; p=0.007). The incidence of angiographically documented stent thrombosis was similar (1.2% [n=2] for CYPHER and 0.6% [n=1] for BMS). At a mean follow-up of 38+7 months (Menichelli et al., TCT 2007), TLR was 6% for the CYPHER stent and 12.7% for BMS (p<0.05), while death, MI and ST rates were not statistically different. Further studies such as MISSION5 supported the safety and efficacy profile of the CYPHER stent in AMI, and are detailed in Table 1.
The most recently published RCT of CYPHER in AMI, MULTISTRATEGY,4 was designed after the STRATEGY and TYPHOON trials; therefore, many limitations in these two trials were addressed in this pivotal trial. In particular, the inclusion criteria were broader and high-risk patients, such as patients with cardiac failure, were included.
Furthermore, no angiographic control was performed, therefore eliminating a bias induced by an 'occulo-stenotic reflex' during the control angiograms. This 2x2 factorial trial simultaneously studied treatment effects between two intravenous antiplatelet agents (abciximab and tirofiban) and between the CYPHER stent and BMS in 745 patients with ST-segment elevation MI (STEMI) or new left bundle branch block. At eight months, MACE (7.8 versus 14.5%; p=0.004) and TVR (3.2 versus 10.2%; p<0.001) rates were significantly lower with the CYPHER stent compared with the BMS (see Figure 3). The incidence of death (3 versus 4%; p=NS), MI (3.2 versus 4.6%; p=NS) and definite or probable stent thrombosis (2.7 versus 4%) were similar in the Cypher stent and BMS groups, reinforcing the clinical evidence that there is no increased risk of stent thrombosis with the CYPHER stent compared with a BMS. On the other hand, it has been shown that the presence of a large thrombus at the site of a lesion treated for AMI is a strong predictor of further stent thrombosis,10 but this is also the case for BMS, so as yet no difference could be found in any study between the BMS and the CYPHER stent groups (see Table 1).
Debate on Safety and Long-term Efficacy of Drug-eluting Stents in Acute Myocardial Infarction
Two registry reports have questioned either the long-term efficacy or safety of DES in patients with AMI. The RESEARCH registry11 concluded that: 'in this relatively small consecutive patient cohort, the use of [sirolimus-eluting stents] SES and [paclitaxel-eluting stents] PES was no longer associated with significantly lower rates of TVR and major adverse cardiac events in patients with STEMI after three years of follow-up. A high frequency of stent thrombosis was observed in the two DES groups.' In addition, a post hoc analysis of the GRACE Registry reported that in almost 2,300 primary percutaneous coronary intervention (PCI) patients, DES use was associated with a significantly higher mortality rate at two years compared with BMS (8.6 versus 1.6%; p=0.001).
Such negative results prompted Dr Adnan Kastrati (Munich, Germany) to perform a meta-analysis of RCTs on DES versus BMS in acute MI. This was published in the European Heart Journal in November 2007.12 A total of eight studies involving 2,786 patients were analysed. Follow-up data (12-24 months) confirmed that DES implantation benefits patients in terms of a significantly reduced rate of TLR compared with BMS, while there were no differences between the two groups in terms of the rate of stent thrombosis, death or recurrent MI.
New Long-term Registry Data
In addition to the findings from this meta-analysis, larger registries of STEMI patients receiving either DES or BMS have been presented over the last year. For example, at the American College of Cardiology (ACC) 2008, Dr Laura Mauri (Boston, US) presented two-year follow-up data from the observational Massachusetts Registry. This registry includes all patients treated with stents between 1 April 2003 and 3 September 2004 at non-government hospitals in Massachusetts. Using propensity score matching, researchers assessed 2,629 matched pairs who received DES and BMS. They found that mortality rates were significantly reduced in DES-treated patients compared with BMS-treated patients (see Figure 4); this was also true with STEMI patients specifically, but there was no significant difference in mortality among non-STEMI matched pairs. Rates of TVR were also significantly lower in DES-treated versus BMS-treated patients; this was the case for all AMI patients and in both STEMI and non-STEMI subgroups. Dr Mauri concluded: 'There has been concern about whether there are late events that might counterbalance the early benefits of DES; we saw no evidence of that. Although our aim was to detect whether there is a signal of harm, we actually observed lower two-year mortality in STEMI patients treated with DES.'
Considerations
Overall, the risks and benefits should always be considered for each patient before using a DES. Patient selection factors to be assessed should include a judgement regarding the risks of antiplatelet therapy. Special consideration should be given to those patients with recently active gastritis or peptic ulcer disease, pre-morbid conditions that increase the risk of a poor initial result or the risks of emergency referral for bypass surgery. A review of the vessel location, reference vessel size, lesion length, qualitative target lesion characteristics and the amount of myocardium in jeopardy from acute or subacute thrombosis must also be considered. After stenting, the persistence of a thrombus or dissection should be considered a marker for subsequent thrombotic occlusion. These patients should be monitored very carefully during the first month after stent implantation.
The optimal duration of dual antiplatelet therapy (DAPT: aspirin with clopidogrel or ticlopidine) remains unknown and DES thrombosis may still occur despite continued therapy. Data from several studies suggest that a longer duration of clopidogrel than was recommended post-procedurally in the pivotal DES trials might be beneficial. In TYPHOON, DAPT was recommended for at least six months. At one-year follow-up, in both the CYPHER stent group and the BMS goup 50% of the patients were still under DAPT. In MULTISTRATEGY, DAPT was recommended for at least three months. At eight months, in both groups one-third of the patients were still on DAPT.
Based on consensus opinion, practice guidelines recommend that patients receive aspirin indefinitely plus a minimum of three months of clopidogrel therapy extended to 12 months in patients at low risk of bleeding.13,14 It is very important that patients are compliant with the post-procedural antiplatelet recommendations, and their potential non-compliance to DAPT should be evaluated. Early discontinuation of prescribed antiplatelet medication could result in a higher risk of thrombosis, MI or death. Prior to PCI, if a surgical or dental procedure is anticipated that requires early discontinuation of antiplatelet therapy, the interventional cardiologist and patient should carefully consider whether a DES and its associated recommended antiplatelet therapy is appropriate.
Sirolimus-eluting Stents versus Other Drug-eluting Stents
In contrast to TYPHOON and MULTISTRATEGY, which demonstrated a significant benefit of the CYPHER stent versus BMS in STEMI patients regardless of angiographic follow-up, the PASSION study reported no significant benefit for Taxus® compared with BMS for similar one-year end-points in patients with acute MI.15,16 It is clear that not all DES are equal and there is no DES class effect. This was recently reinforced by the results of the PROSIT trial,9 which showed superior angiographic outcome in the CYPHER stent group (n=154) compared with the Taxus group (n=154), with a significantly lower late in-stent loss (0.19 versus 0.43mm; p=0.004). There were also fewer MACE at 12 months: 5.8% for the CYPHER stent versus 11.7% for Taxus (p=0.07). These data remind us that DES are complex devices that incorporate drugs, stents, polymers and elution, which all play a role in their respective safety and efficacy profiles. In AMI, differences may be compounded due to the platelet milieu pre- and post-implantation, which could influence such items as uniform drug delivery or optimal stent deployment. No randomised data are currently available on the treatment of AMI patients with either the Endeavor or Xience Stent.
In conclusion, the CYPHER stent remains the most studied DES in AMI, with >3,000 patients enrolled in dedicated trials - more than the 1,748 simple to moderately complex patients enrolled in the four pivotal trials of the CYPHER stent. These randomised data, in addition to the 'real-world' results assessed by carefully monitored registries, provide confidence that the CYPHER stent has an excellent safety and efficacy profile for primary PCI in patients presenting an AMI.