From the Los Angeles County Hospital/University of Southern California Medical Center, Department of Cardiovascular Medicine, Los Angeles, California.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 10, 2009, provisional acceptance given March 23, 2009, and final version accepted March 24, 2009.
Address for correspondence: Leonardo Clavijo, MD, 1510 San Pablo Street, Suite #322, Los Angeles, CA 90033. E-mail: lclavijo@usc.edu
ABSTRACT: The development of drug-eluting stents (DES) is one of the critical milestones in the advances of interventional cardiology. However, clinical stent thrombosis still poses a serious potential complication. In acute ST-segment elevation myocardial infarction (STEMI), acute total vessel occlusion has a larger thrombus burden, and the use of DES in this particular setting raises safety concerns. Published data from randomized, controlled studies, observational studies and recently published meta-analyses mostly support the safety of DES use in acute STEMI. However, these studies have limited study populations and follow-up periods, so the long-term safety of DES in the setting of STEMI is still unclear, and careful consideration should be given in clinical decision-making. In this article we reviewed the findings of randomized and nonrandomized trials on the use of drug-eluting versus bare-metal stents in the setting of acute STEMI.
J INVASIVE CARDIOL 2009;21:E206–E212
Primary percutaneous coronary intervention (PCI) with stenting has been proven to be a superior reperfusion strategy in acute ST-segment elevation myocardial infarction (STEMI) when compared to intravenous thrombolytic therapy or balloon angioplasty.1–3 Drug-eluting stents (DES) were first approved by the FDA (U.S. Food and Drug Administration) in 2003, and by end of 2006, nearly 6 million DES were placed worldwide, making up more than 90% of all coronary revascularization procedures.4 However, the discovery of late stent thrombosis in 2005 raised caution and controversy in the increasingly routine “off-label” use of DES. A meta-analysis of randomized clinical trials including 6,675 patients showed that the incidence of late thrombosis is five times higher with DES than with bare-metal stents (BMS).5
There is concern regarding a larger thrombus burden in patients with acute STEMI and whether the use of DES in this setting is safe. Sianos et al showed that an angiographic large thrombus burden is an independent risk factor for major adverse cardiac events and late stent thrombosis in patients treated with DES for STEMI.6 Recent pathological studies by Nakazawa et al showed that patients who received DES in the setting of acute myocardial infarction (AMI) had a higher prevalence of delayed culprit-vessel healing and late stent thrombosis compared to those who underwent received DES implantation for stable angina.7 A study utilizing intravascular ultrasound (IVUS) also revealed that among patients who received DES, there was a trend toward a higher rate of very late stent thrombosis in STEMI patients than in matched controls.8 On the other hand, stent malapposition, another risk factor for late stent thrombosis, is also more prevalent when a DES is implanted in the setting of AMI.9 Given this constellation of potential risk factors, it is crucial to investigate the safety profile and risk of thrombosis when using DES in STEMI. This article will review the outcomes of major randomized and then nonrandomized studies comparing the use of BMS and DES in STEMI patients.
Randomized Trials
Randomized studies to date have largely shown that DES use is safe in acute STEMI (Table 1). These studies are of modest size and have a limited follow-up period, but they minimize bias and confounding variables. One of the first randomized trials was the STRATEGY trial (The Single High Dose Bolus Tirofiban and Sirolimus-Eluting Stent vs. Abciximab and Bare-Metal Stent in Myocardial Infarction) by Valgimigli et al in 2005.
10 In this single blind, randomized control study, 175 patients with AMI were randomized to receive either a high-dose bolus of tirofiban paired with a sirolimus-eluting stent (SES), or abciximab with a BMS. At 8-month follow up, there was no statistical difference in the composite outcome of death or reinfarction in the SES group versus the BMS group (hazard ratio [HR], 0.71, 95% confidence interval [CI], 0.34–1.5; p = 0.39). The need for target vessel revascularization (TVR) was lower in the SES group (7%) versus the BMS group (20%) (HR 0.30, 95% CI, 0.12–0.77; p = 0.01). This study served as one of the first randomized studies comparing DES and BMS in acute STEMI, and showed that DES was as safe as BMS up to eight months. However, due to the study design, one cannot draw direct conclusions about individual contributions of the glycoprotein (GP) IIb/IIIa inhibitor and the stent type.
In 2006, two prospective, single-blind, randomized trials: TYPHOON (Trial to Assess the use of Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty) and PASSION (Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) were published concurrently in the New England Journal of Medicine.
11,12 In TYPHOON, 715 patients with acute STEMI were randomized to receive SES or BMS and were followed for 1 year. There was no significant difference between the stents in the outcomes of death (2.3% vs. 2.2%; p = 1.00), reinfarction (1.1% vs. 1.4%; p = 1.00), or stent thrombosis (3.4% vs. 3.6%; p = 1.00). Angiographic follow up at 8 months was available for 81% of the enrolled patients, and in-stent late luminal loss was significantly lower in the SES than in the BMS group (0.14 ± 0.49 mm vs. 0.83 ± 0.52 mm; p 14 At 1-year follow up, the composite of death from cardiac causes, reinfarction and TLR was 6.7% in SES patients and 11% in BMS patients (p = 0.402). There was a trend toward a lower TVR rate in SES versus BMS groups (0.0% vs. 5.7%; p = 0.064). No angiographic follow up was performed.
The SESAMI trial (Sirolimus-Eluting Stent versus Bare-Metal Stent in Acute Myocardial Infarction) compared SES and BMS in AMI, but focused on the primary endpoint of binary restenosis at 1 year angiographic follow up.
15 Among the study population, 17.8% received thrombolysis. Patient characteristics were mostly evenly randomized, except the rate of prior MI was higher in the BMS group. Of the 320 patients, 160 were assigned to each group. In addition, the average length of stents placed was longer in the BMS group, and the average stent diameter was larger in the SES group. Though only 50% of the original study group received a follow-up angiogram at 1 year, the rate of binary restenosis was lower in the SES group compared to the BMS group (9.3% vs. 21.3%; p = 0.032). There was no difference between groups in the rate of death or reinfarction, but TLR was lower in the SES group (4.3% vs. 11.2%; p = 0.02), as was TVR (5% vs. 13.1%; p = 0.015). Like the TYPHOON trial, SESAMI provided angiographic follow up, but extended that period from 8 months to 1 year.
Chechi et al further evaluated the rate of neointimal hyperplasia with PES by performing angiographic follow up.
16 Their study, SELECTION (Single-Center Randomized Evaluation of Paclitaxel-Eluting Stent versus Conventional Stent in Acute Myocardial Infarction), was a much smaller study that included 80 patients with acute STEMI randomized to receive either PES or BMS. In this study, patients > 75 years of age were excluded. At 7 months, angiographic follow up with IVUS was performed in 95% of the patients and revealed that the primary endpoint of neointimal hyperplasia was higher in the BMS group versus the PES group (20% vs. 4.6%; p 17 Angiographic follow up was available for 82% of patients. At 9-month angiographic follow up, in-segment late stent luminal loss, defined as a reduction in minimal lumen diameter, was 0.68 mm in the BMS group and 0.12 mm in the SES group (p 18 Instead of limiting patients to either SES or PES, this trial tested DES as a whole (47% SES, 40% PES and 13% zotarolimus-eluting stents). At 8-month angiographic follow up, which was available for 83% of the study patients, the mean lumen loss was lower in those treated with DES than BMS (0.06 mm vs. 0.47 mm; p 19 provides the largest randomized trial to date involving more than 3,000 patients from eleven countries. Among patients with STEMI, 2,257 were randomized to receive PES and 749 received BMS. While about three times more patients received PES, the baseline characteristics among the two groups were similar except for a higher rate of smokers in the BMS group than in PES group (51.9% vs. 46.3%; p = 0.009). Clinical follow up to 12 months showed that the composite endpoint of all-cause mortality, reinfarction, stroke and stent thrombosis was similar in the PES and BMS groups (8.1% vs. 8.0%; p = 0.92). Unfortunately, the study was not powered to show the difference in all-cause mortality or stent thrombosis. The rate of TLR, as expected, was lower in the PES group compared to the BMS group (4.5% vs. 7.5%; p = 0.002). At 13-month angiographic follow up, the rate of binary stenosis per patient was also lower in the PES group (10.9% vs. 24.9%).
Given the small sample size of the published randomized trials, several meta-analyses have been performed to compile the data. The meta-analysis by Pasceri et al examined seven randomized trials comparing DES and BMS in AMI patients.
20 There was no evidence of heterogenicity or publication bias among the seven trials. A total of 2,357 patients — 1,177 with DES and 1,180 with BMS — were followed for 8–12 months. The composite endpoint of death, reinfarction and revascularization was lower in the patients treated with DES than with BMS (9.3% vs. 17.6%; p 21 Similarly, they found that the TLR rate was significantly lower in DES than in BMS patients (5% vs. 13.3%; p 22 This study reconfirmed the results of the two prior studies. At 12-month follow up, there was no significant difference between DES and BMS patients in terms of death, reinfarction or stent thrombosis rates. On the other hand, the rate of TVR was lower in the DES patients (5.0% vs. 12.6%; p Observational Studies
Observational studies have shown varying results regarding the safety of DES in STEMI (Table 2). Some of these studies offer longer follow-up periods, but results should be interpreted with caution because observational studies draw inferences that can be susceptible to bias. Lemos et al evaluated the outcome of 369 patients with STEMI who received either SES or BMS from 2002 to 2003 at the Erasmus Medical Center in the Netherlands.
23 All patients with STEMI were included regardless of their clinical presentation and lesion location, with the exception of those who received thrombolytics. At 300-day follow up, the patients with SES had a lower incidence of the combined endpoint of death, reinfarction and TVR (9.4% vs. 17%; p = 0.02, HR 0.52, 95% CI 0.30–0.92), mainly due to the lower rate of TVR in the SES patients (1.1% vs. 8.2%; p = 0.01).
Newell et al studied 306 STEMI patients who received either SES or BMS over 6 months.
24 Patients who received SES had a lower rate of mortality (1.9% vs. 10.1%; p = 0.003), reinfarction (0.6% vs. 4.0%; p = 0.05) and TVR (1.3% vs. 8.1%; p = 0.005). At 6 months, the stent thrombosis rate was higher in the BMS group (4% vs. 0%; p = 0.01). However, the baseline characteristics of the two patient groups were significantly different, with the BMS group consisting of older patients (65 years vs. 61 years; p = 0.012) who had a higher troponin level (3.16 vs. 2.03; p = 0.006), a higher creatinine level (1.29 vs. 1.08; p = 0.0009), a lower ejection fraction (46% vs. 49%; p = 0.02), and a greater number of stents placed (1.47 vs. 1.21; p = 0.0006) compared to the SES group. A multivariate discriminant analysis was performed due to biased baseline characteristics favoring the SES group, and showed that age was as significant as stent type in predicting 6-month events, mainly the composite endpoint of death, reinfarction and TVR (p = 0.01). On the other hand, stent type was the only significant factor altering the need for revascularization (p = 0.02).
The GRACE registry (Global Registry of Acute Coronary Events) combined acute coronary events data across fourteen European countries.
25 Utilizing this database, Steg et al studied 1,313 (26%) patients who underwent DES implantation and 3,780 (74%) patients who received BMS.
25 Patients who received DES had a higher body mass index, a history of dyslipidemia, previous MI and PCI. Patients who received BMS received more thrombolysis and had a higher Kilip Class. The delay from symptom-onset to coronary intervention was shorter in patients who received BMS. Multiple logistic regressions were performed and the results were adjusted for the GRACE risk score in an attempt to minimize bias. During the first 6 months, there was no significant difference in mortality between the two groups. However, from 6 months to 2 years, the all-cause mortality rate was higher with DES than BMS (5.3% vs. 3.9%; p = 0.04). This was the first registry study with an extended follow-up period of 2 years, and also the first to show a statistically significant increased mortality rate with the use of DES compared to BMS.
Shishehbor et al studied 699 patients with STEMI who received either DES or BMS.
26 The DES group consisted of more Kilip Class IV patients (52% vs. 38%; p 27 identified 1,926 STEMI patients from the New York State Percutaneous Coronary Interventions Reporting System and followed them over 2 years through New York vital statistics data and the Cardiac Surgery Reporting System. A total of 1,154 patients received DES and 772 patients received BMS. Baseline patient characteristics were similar in the two groups except for the higher rate of Hispanic ethnicity (9.6% vs. 6.7%; p = 0.024) and the higher rate of GP IIb/IIIa use (65.4% vs. 56.8%; p 12 and the study by Diaz et al,
14 there was no statistically significant difference in the composite rate of death, reinfarction and TLR between DES and BMS. The HAAMU-STENT
13 and DEDICATION
18 trials showed a trend toward increased cardiac death in DES over BMS, which was again not statistically significant. Therefore, it is reasonable to conclude that the randomized data support the safety of DES use in acute STEMI at least up to 1 year. However, larger randomized studies with a longer follow-up period are needed to truly delineate the long-term safety of DES in STEMI. The nonrandomized trials provided longer follow-up periods up to 2 years.
25–28 The GRACE registry data showed an alarming increased mortality rate in DES patients from 6 months to 2 years.
25 On the other hand, the recent study by Mauri et al
28 also provided a large study population, which did not show the same results. However, data from nonrandomized studies should still be interpreted with caution, given the possibility of nonidentified confounding factors. Recent registry data show that BMS are often used in older patients with more prior coronary bypass surgery and a lower ejection fraction.30 Baseline patient characteristics from the Mauri et al study
28 also pointed toward a sicker patient population selected for BMS implantation. The potential selection bias may contribute to the favorable outcomes of DES patients in these nonrandomized studies.
Conversely, the BMS is also a safe and effective stent choice in STEMI patients. Although the exact TVR rate after BMS implantation in STEMI is difficult to determine, given the wide range of TVR rates among the various randomized studies — from as low as 5.7% in the Diaz et al study,
14 to as high as 20% in STRATEGY,
10 — the absolute TVR difference between DES and BMS was as small as 2.9% in the HORIZONS-AMI study.
19 Furthermore, in everyday practice, one must weigh the benefit of the reduced TVR rate of DES use against the potential consequence of stent thrombosis in patients who are noncompliant with their thienopyridine therapy. One study found that among 500 patients who received DES for AMI, 13.6% of patients stopped taking their thienopyridine at 30 days, and those patients had a markedly higher mortality rate over the following year (7.5% vs. 0.7%; p 31 Therefore, in the absence of long-term randomized data regarding the safety of DES use in STEMI patients beyond 1 year, BMS still represent a very reasonable stent choice in this setting.
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