Author + information
- Received September 24, 2010
- Revision received November 8, 2010
- Accepted November 16, 2010
- Published online January 1, 2011.
- Maarten A. Vink, MD⁎,⁎ (, )
- Maurits T. Dirksen, MD, PhD⁎,
- Maarten J. Suttorp, MD, PhD‡,
- Jan G.P. Tijssen, PhD†,
- Jeroen van Etten, MD⁎,
- Mark S. Patterson, MBBS, PhD⁎,
- Ton Slagboom, MD⁎,
- Ferdinand Kiemeneij, MD, PhD⁎ and
- Gerrit J. Laarman, MD, PhD§
- ↵⁎Reprint requests and correspondence:
Dr. Maarten A. Vink, Amsterdam Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, 1091 AC Amsterdam, the Netherlands
Objectives The purpose of this study was to evaluate the long-term outcomes of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) trial.
Background In primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction (STEMI), the use of drug-eluting stents (DES) is still controversial. Several randomized controlled trials of DES, compared with bare-metal stents (BMS), with short-term follow-up showed a reduction in target lesion revascularization (TLR), but no differences in rates of cardiac death or recurrent myocardial infarction. Moreover, the occurrence of (very) late stent thrombosis (ST) continues to be of major concern, and, therefore, long-term follow-up results are needed.
Methods We randomly assigned 619 patients presenting with STEMI to a paclitaxel-eluting stent (PES) or the similar BMS. The primary end point was the composite of cardiac death, recurrent myocardial infarction, or TLR. We performed clinical follow-up at 5 years.
Results At 5 years, the occurrence of the composite of cardiac death, recurrent myocardial infarction, or TLR was comparable at 18.6% versus 21.8% in PES and BMS, respectively (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.58 to 1.18, p = 0.28). The incidence of definite or probable ST was 12 (4.2%) in the PES group and 10 (3.4%) in the BMS group (HR: 1.19, 95% CI: 0.51 to 276, p = 0.68).
Conclusions In the present analysis of PES compared with BMS in primary percutaneous coronary intervention for STEMI, no significant difference in major adverse cardiac events was observed. In addition, no difference in the incidence of definite or probable ST was seen, although very late ST was almost exclusively seen after the use of PES. (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation [PASSION]; ISRCTN65027270)
- drug-eluting stent
- primary percutaneous coronary intervention
- ST-segment elevation myocardial infarction
In acute ST-segment elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PPCI) with stenting has proven to be the optimal treatment compared with medical therapy or angioplasty alone (1,2). After their introduction, drug-eluting stents (DES) proved to reduce neointima hyperplasia compared with bare-metal stents (BMS), when implanted in patients with stable coronary artery disease (3,4). Subsequently, several registries and randomized controlled trials have tried to explore the possible advantage of the use of DES in STEMI (5–8). In most trials published, the implantation of either paclitaxel-eluting stents (PES) or sirolimus-eluting stents resulted in lower rates of repeat revascularization, but none of these trials showed an advantage in mortality or recurrent myocardial infarction (MI), compared with conventional BMS.
With the ongoing concern of a possible higher frequency of stent thrombosis (ST) occurring very late (beyond 1 year) after implantation of DES (9,10), routine implementation of DES in PPCI is still not widely accepted (11,12). Available data of retrospective studies suggest higher rates of ST, even several years after implantation of DES in PPCI, compared with stenting for stable angina (13,14). In the present analysis, we performed clinical follow-up 5 years after inclusion in the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) trial, in which patients were randomized to a PES or a conventional BMS in PPCI. The aim was to elucidate a possible long-term benefit of DES over BMS in STEMI in terms of major adverse cardiac events (MACE) and to address the concern of (very) late ST.
Between March 2003 and December 2004, 619 patients were included in the PASSION trial. The PASSION trial was a prospective, single-blind, randomized study, performed at 2 centers in the Netherlands (Onze Lieve Vrouwe Gasthuis, Amsterdam, and Sint Antonius Ziekenhuis, Nieuwegein). The study has been registered as an International Randomized Controlled Trial.
Both details of study design and the results of clinical follow-up have been published previously (5,15).
After arrival at the hospital, we first administered a loading dose of aspirin (100 to 500 mg) and clopidogrel (300 mg), followed by aspirin 80 to 100 mg once daily for life and clopidogrel 75 mg once daily for at least 6 months. A bolus of 10,000 IU of unfractionated heparin was administered before the procedure. The use of glycoprotein IIb/IIIa receptor inhibitors was at the discretion of the operator, as were the use of pre-dilation balloons and thrombus aspiration devices. After coronary angiography patients were randomized in a 1:1 ratio using permuted blocks of 50, to receive either a PES (Taxus Express2, Boston Scientific, Natick, Massachusetts) or a BMS with the same platform (Express2 or Liberté, Boston Scientific).
After the initial hospital discharge, patients were contacted by phone or mail at pre-defined intervals. All adverse cardiac events were recorded during each patient's hospital stay, as well as during follow-up visits at 30 days, 6 months, 1 year, 2 years, and 5 years after randomization. In the case of an event, information was obtained from hospital records or from the treating cardiologist. If the patient could not be reached, vital status and date of death (if applicable) was obtained from local authorities.
G.J.L. and M.J.S. adjudicated all end points in a blinded fashion. The primary end point was the first occurrence of MACE, defined as the composite of cardiac death, recurrent MI, or target-lesion revascularization (TLR), either by PCI or coronary artery bypass grafting. A secondary end point was the occurrence of ST, as determined by the Academic Research Consortium (16). Definite ST was defined as angiographic confirmation of vessel occlusion or proven ST either by angiography or at autopsy within, or adjacent to, the stented segment. Probable ST was defined as unexplained death within 30 days, or target-vessel recurrent MI without angiographic confirmation. When unexplained death occurred beyond 30 days, it was classified as possible ST. Stent thrombosis was categorized according to timing of the event after stent implantation and divided into acute ST (<24 h), subacute ST (between 24 h and 30 days), late ST (30 days to 1 year), and very late ST (beyond 1 year).
Baseline data are presented as proportions or mean (±SD) values and were compared using Student t test or Wilcoxon rank-sum test for continuous variables and Fisher exact test for categorical variables. A 2-sided p value <0.05 was considered to indicate statistical significance. We estimated the cumulative incidence rates of the primary and secondary end points at 5 years with the Kaplan-Meier method. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with Cox proportional-hazards models with treatment allocation as the only variable. The significance of differences in event rates between treatment groups was assessed by the log-rank test. Statistical analysis was done with SPSS (version 16.0 for Windows, SPSS, Inc., Chicago, Illinois).
A total of 310 patients were randomized to receive a PES and 309 to a BMS. Baseline clinical characteristics were well matched (Table 1). In addition, angiographic and procedural characteristics were similar between both groups (Table 2). Approximately 50% of patients underwent thrombus aspiration before stenting, and the use of a glycoprotein IIb/IIIa receptor inhibitor was comparable in the PES and BMS groups, with rates of 73.2% and 74.4%, respectively.
Clinical follow-up at 5 years
At 5-year follow-up, complete data on vital status was available for 98.7% of patients. Complete datasets on all clinical events were available for 97.6% of patients. The results are stated in Table 3. The composite end point of cardiac death, recurrent MI, or TLR was reached in 56 (18.6%) versus 66 (21.8%) patients in the PES and the BMS groups, respectively (HR: 0.82, 95% CI: 0.58 to 1.18; p = 0.28). Figure 1 shows the Kaplan-Meier curve for the incidence of the primary end point. With 7.7% in the PES group and 10.5% in the BMS group, a slight trend toward a lower incidence of TLR was observed in favor of PES (HR: 0.71, 95% CI: 0.41 to 1.23; p = 0.21). The occurrence of cardiac death or MI was comparable between both groups (15.0% vs. 14.6%; HR: 1.02, 95% CI: 0.67 to 1.55; p = 0.92). Cardiac death rates at 5 years were relatively low, at 8.9% in the PES group versus 11.5% in the BMS group (HR: 0.76, 95% CI: 0.46 to 1.25, p = 0.28). We performed a landmark analysis of the occurrence of the primary end point between 1 and 5 years (Fig. 2). At a rate of 10.8% in the PES group, and 10.2% in the BMS group (HR: 1.07, 95% CI: 0.63 to 1.82; p = 0.80), no difference in the occurrence of late events was seen.
The occurrence of definite or probable ST up to 5 years was comparable between both groups, with 12 (4.2%) in the PES group and 10 (3.4%) in the BMS group (HR: 1.19, 95% CI: 0.51 to 2.76; p = 0.68) (Fig. 3). Definite ST occurred in 11 (3.9%) and 5 (1.7%) patients in the PES and BMS groups, respectively (HR: 2.19, 95% CI: 0.76 to 6.29; p = 0.14). The incidence of (very) late definite or probable ST was higher in the PES group than the BMS group, at 10 (3.5%) versus 3 (1.1%), p = 0.06. Similarly, (very) late definite ST occurred in 9 (3.3%) patients in the PES group versus 2 (0.7%) in the BMS group, p = 0.04 (Table 4).
Previously, we published the 1-year clinical outcomes of the PASSION trial (5). This report did not show a difference in TLR and MACE rate after the use of PES compared with BMS. The present analysis shows there is still no significant difference observed through 5 years of follow-up. The hazard ratio for TLR at 5 years (HR: 0.71, p = 0.21) was identical to that observed at 1 year (HR: 0.68, p = 0.23). Although the hazard ratio for MACE (the composite end point of cardiac death, recurrent MI, or TLR) at 5 years still was in favor of PES, it had somewhat attenuated relative to that at 1 year (HR: 0.82, p = 0.28 at 5 years vs. HR: 0.69, p = 0.12 at 1 year). The attenuation was mainly due to a slightly higher incidence of ST-related MI in the PES group beyond 1 year. Moreover, no difference was seen in the occurrence of cardiac death or recurrent MI, neither early nor late after implantation.
Only short-term results have been published of the other randomized trials comparing DES with BMS for STEMI. Our study design was best comparable to that of the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, in particular with regard to stent usage and the absence of angiographic follow-up (6). The HORIZONS-AMI trial, the largest trial so far, reported a 1-year TLR incidence of 4.5% in PES-treated patients versus 7.5% in BMS-treated patients (p = 0.002). The HORIZONS-AMI 1-year results (HR: 0.59 for TLR in favor of PES) were similar to those observed in PASSION. The larger number of patients included in the HORIZONS-AMI trial explains its statistical significance, which our study lacked.
Smaller randomized controlled trials of DES in STEMI with short-term follow-up showed a similar pattern as HORIZONS-AMI, with no differences in the incidence of cardiac death or recurrent MI, although with differences in the need for TLR favoring DES. In the TYHPOON (Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated With Angioplasty) trial, which compared sirolimus-eluting stents (SES) with BMS, there was a significant difference in the occurrence of target-vessel revascularization at 1 year, at 5.6% versus 13.4% (HR: 0.41, p < 0.001) in SES and BMS, respectively (7). Likewise, the 1-year report of the SESAMI (Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction) trial showed a large absolute difference in TLR in favor of SES, at 4.3% versus 11.2% (p = 0.02) in SES and BMS, respectively (17). These differences, however, were larger than those observed in PASSION and HORIZONS-AMI. The larger differences in repeat revascularization between the 2 stent groups in both TYPHOON and SESAMI were mainly due to a much higher incidence in the BMS groups. Variations in study design may well explain this disparity. First, this difference could have been influenced by routine angiographic follow-up within the first year after implantation (18). Our protocol did not include planned angiography during follow-up, which might explain the smaller absolute difference in TLR between both groups. Furthermore, the stent platform of the DES used in our study was the exact same stent platform with which it was compared. This is an important difference with TYPHOON and SESAMI, in which a DES was compared with a range of types BMS, possibly resulting in less favorable outcome after the use of BMS. Except from the 3-year data of the SESAMI trial, which showed maintenance of the early benefit in TLR (19), no long-term clinical outcomes of both trials have been published.
At 1 year, no difference in the occurrence of ST was seen in our study, with a rate of 1.0% in both groups. These comparable results between DES and BMS were in line with those of the HORIZONS-AMI, TYPHOON, and SESAMI trials, although HORIZONS-AMI and TYPHOON showed a higher incidence in both stent groups, at 2.6% versus 3.0% and 3.4% versus 3.6%, respectively. This could be explained by a difference in the definition of ST and/or, given the low number of events, by chance. In the meantime, the definitions of ST established by the Academic Research Consortium provide the opportunity of an unambiguous comparison (16). At 5 years, we observed a similar incidence of definite or probable ST, with 12 patients (4.2%) in the PES group and 10 (3.4%) in the BMS group, at a hazard ratio of 1.19 (p = 0.68). This indicates the safety of both PES and BMS throughout follow-up. Worth mentioning, very late ST was almost exclusively seen after implantation of PES (p = 0.06 for definite or probable ST, p = 0.04 for definite ST). The present analysis suggests there might be a small but continuously present risk of ST in the PES group several years after cessation of dual-antiplatelet therapy. Our observation accords with observations from retrospective studies, showing that ST is associated with DES, with the emphasis on the risk of very late ST related to implantation in acute coronary syndromes (13,14,20). Noteworthy, in current daily practice, PES have been supplanted by newer generations of DES as subsequently conducted trials showed superiority in both efficacy and safety of everolimus-eluting stents compared with PES (21,22). Nevertheless, long-term follow-up of larger trials evaluating the efficacy and safety of DES in STEMI is necessary to substantiate our findings.
This study has some limitations. The event rates in both groups were lower than anticipated in our power calculations. As a result, the estimated relative risk reduction of 15% in the occurrence of MACE, using PES compared with BMS, lacked statistical significance. In addition, with 619 patients included, the PASSION trial was not powered to detect differences in the occurrence of the safety end point ST. Although we did find a notable difference in rates of very late ST between the 2 stent groups, our findings should be interpreted with caution. A much larger trial would have been needed to demonstrate statistical significance. Another limitation of this long-term follow-up study is the lack of autopsy data in patients who died suddenly, which may well have resulted in underestimation of the real incidence of ST.
Our present report is the first 5-year clinical follow-up of a prospective, randomized trial of DES in STEMI. We observed no significant difference in the occurrence of MACE and TLR in PES compared with BMS. Up to 5-years follow-up, no difference in the occurrence of definite or probable ST was seen, although there might be a higher incidence of (very) late ST using PES.
In current clinical practice guidelines, the use of DES in acute STEMI is mentioned only as a method to reduce restenosis. Because there is no evidence for a reduction in the occurrence of death, recurrent MI, or ST, the guidelines of the European Society of Cardiology or the American College of Cardiology/American Heart Association do not make a general recommendation for the use of DES in the setting of STEMI. Our present analysis is the first to provide long-term efficacy and safety data on DES in PPCI. The possibility of a higher risk of very late ST in PES supports the ambivalence of the guidelines on this matter, which needs to be substantiated in further clinical research.
The PASSION trial was entirely funded by the Department of Interventional Cardiology at Onze Lieve Vrouwe Gasthuis in Amsterdam. The authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- drug-eluting stent(s)
- major adverse cardiac event(s)
- myocardial infarction
- paclitaxel-eluting stent(s)
- primary percutaneous coronary intervention
- sirolimus-eluting stent(s)
- stent thrombosis
- ST-elevation myocardial infarction
- target-lesion revascularization
- Received September 24, 2010.
- Revision received November 8, 2010.
- Accepted November 16, 2010.
- American College of Cardiology Foundation
- Pfisterer M.,
- Brunner-La Rocca H.P.,
- Buser P.T.,
- et al.,
- BASKET-LATE Investigators
- Van de Werf F.,
- Bax J.,
- Betriu A.,
- et al.
- Kushner F.G.,
- Hand M.,
- Smith S.C. Jr..,
- et al.
- Kukreja N.,
- Onuma Y.,
- Garcia-Garcia H.M.,
- et al.,
- Interventional Cardiologists of the Thoraxcenter (2000 to 2005)
- Cutlip D.E.,
- Windecker S.,
- Mehran R.,
- et al.,
- Academic Research Consortium
- Menichelli M.,
- Parma A.,
- Pucci E.,
- et al.
- Uchida T.,
- Popma J.,
- Stone G.W.,
- et al.
- Violini R.,
- Musto C.,
- De Felice F.,
- et al.
- Nakazawa G.,
- Finn A.V.,
- Joner M.,
- et al.