Long-Term Clinical Outcome in STEMI Patients Treated With Primary PCI and Drug-Eluting or Bare-Metal Stents: Insights from a High-Volume Single-Center Registry

Abstract: Objective. Use of drug-eluting stents (DES) in patients with ST-elevation myocardial infarction (STEMI) during routine primary percutaneous coronary intervention (pPCI) is controversial. Methods. From January 2004 to July 2008, a total of 2,155 STEMI patients were treated with pPCI [DES or bare-metal stent (BMS)] at a single high-volume invasive center. We present 4-year outcomes in this observational registry study. Results. A total of 1,725 were treated with DES and 430 with BMS. Patients treated with DES were younger and had more complex angiographic characteristics compared to BMS patients. Patients treated with DES had lower adjusted risk of target lesion revascularization (TLR) [hazard ratio (HR) = 0.68; 95% confidence interval (CI): 0.40–0.98; p = 0.04], but had a trend toward increased risk of definite stent thrombosis (HR = 1.96; 95% CI: 0.83–4.61; p = 0.12). No difference was found when evaluating all-cause mortality and non-fatal myocardial infarction. Conclusions. In this study, we set out to evaluate the independent impact of DES or BMS treatment on long-term clinical outcomes in STEMI patients treated with pPCI in a real-life setting. DES use was associated with a reduced risk of TLR, but a trend toward increased risk of stent thrombosis was found. However, this safety issue did not translate into an increased risk of death or overall non-fatal myocardial infarction for DES patients.

J INVASIVE CARDIOL 2011;23:328–333

Key words: drug-eluting stent, bare-metal stent, ST-segment elevation myocardial infarction, primary percutaneous coronary intervention, stent thrombosis

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It is now generally accepted that when suitable local and regional emergency services and hospital capabilities are available, transfer of patients with ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (pPCI) is feasible and superior to on-site fibrinolysis.^1–7 The main purpose of pPCI is to rapidly restore flow in the occluded artery to reduce infarct size, and on long-term basis to ensure that the vessel remains open. In-stent restenosis is a relatively substantial problem in patients treated with bare-metal stents (BMS) and particularly with plain old balloon angioplasty. Consequently, drug-eluting stents (DES) were introduced as a tool to reduce the need for repeated revascularization (RR) without compromising safety.⁸ The pivotal trials showed that DES significantly reduced the need for RR without impairing 1-year clinical outcomes [stent thrombosis (ST), non-fatal myocardial infarction (MI) and mortality].⁹ However, these conclusions were largely based on results from “on-label” PCI procedures and thus from relatively simple non-acute lesions, and in patients largely free of severe comorbidity. In recent years, reports have suggested that DES may have some long-term safety issues, in particular an increased risk of the potentially catastrophic acute ST.^10,11 Especially in the subset of ischemic patients with STEMI, the use of DES in pPCI is controversial. The lesion pathology in STEMI patients is different compared to patients with stable plaques, e.g., the fissured plaque enables the drug to diffuse directly into the vessel wall and the presence of the thrombus complicates stent delivery. Proposed mechanisms for the increased risk of ST with DES use include increased hypersensitivity in the arterial wall¹² and lack of appropriate reendothelialization and delayed intimal healing.^13–15 The risk of insufficient reendothelialization may be a particular problem in STEMI, as the stent often is deployed within the thrombus, which in turn causes under-sizing/expansion of the stent.^16,17 A linkage between these pathological findings and actual clinical outcome has been described in studies comparing DES use in STEMI/acute coronary syndromes (ACS) and stable angina patients.^18,19 These studies suggested that STEMI patients had an increased risk of late ST. Furthermore, DES seem to induce a more pronounced positive remodeling of the vessel, which in turns increases the risk of stent malapposition.^20,21

In many regions, DES are now implanted in more than 80% of all STEMI patients undergoing pPCI. Our knowledge of long-term safety issues beyond 2 years regarding DES treatment in real-life STEMI populations is limited, and the long-term results from published randomized clinical trials (RCT) may not sufficiently elucidate this potential problem. Consequently, we examined the independent impact of DES use compared to BMS use on long-term clinical outcomes (up to 4 years) in consecutive STEMI patients routinely admitted to one single high-volume PCI center from 2004 to 2008.

Methods

Study population. Routine treatment with pPCI for STEMI, including inter-hospital transportation, was introduced and implemented in Denmark in 2002 following the presentation of the DANAMI-2 trial at the American College of Cardiology 2002 meeting.¹ The first DES at our institution was implanted in May 2003 and in June 2003, we treated the first STEMI patient with DES. Gentofte University Hospital has a pPCI catchment population of 1.2 million citizens, i.e., more than 20% of the total Danish population, and is the invasive hub for 10 non-pPCI centers, serving a predominantly urban population. On-site cardiac surgery is present and > 1,500 PCI procedures are performed annually (approximately 500 pPCI), with each individual PCI operator performing approximately 300 PCI and 100 pPCI per year (mean: 89 pPCI per year; median: 99 pPCI per year, range: 11–138 pPCI).

From January 2004 to July 2008, we identified 2,155 consecutive STEMI patients treated with either DES or BMS. In case of more than one pPCI-procedure within this period, the first procedure was defined as the index procedure. A comparison between DES and BMS in STEMI patients was scheduled ultimo  2003. Outcomes — mortality, non-fatal MI and RR — were pre-specified. Other angiographic outcomes — target vessel revascularization (TVR), target lesion revascularization (TLR) and ST — were defined at a later stage according to the Academic Research Consortium (ARC) definitions.²² All patients were part of a regional plan, including only one high-volume PCI center. No alternatives existed. STEMI was defined as presence of chest pain for > 30 minutes and < 12 hours, and cumulative persistent ST-segment elevation ≥ 4 mm in at least 2 contiguous precordial electrocardiographic (ECG) leads, or ≥ 2 mm in 2 or more contiguous limb ECG leads. A limited number of patients (n = 35) were admitted for acute coronary angiography when chest pain was present together with borderline ST-segment elevations or left bundle branch block (LBBB). All patients had significant angiographic findings compatible with acute MI.

DES or BMS. Patients were divided into two groups: A DES group treated with 1 or more DES, and a BMS group treated with 1 or more BMS. A total of 84 patients were treated with a combination of DES and BMS, and were excluded, leaving 2,155 STEMI patients in the study. The decision on which stent to implant was made at the operator’s discretion.

Baseline and procedural data. The baseline data were prospectively collected from all patients and entered in a dedicated registry. Hypertension was defined as use of blood-pressure lowering drugs on admission. Diabetes was defined as use of glucose-lowering drugs on admission, fasting plasma glucose concentration ≥ 7 mmol/L, or non-fasting plasma glucose concentration ≥ 11.1 mmol/L. Multivessel disease was defined as 2- or 3-vessel disease and complex lesions as type-C lesions.

Data regarding medication prior to admission and during follow up were extracted from the Danish Registry of Medical Product Statistics. This unique registry holds information about all prescription claims from Danish pharmacies and has been thoroughly validated.²³ Prescription claims within 180 days prior to the pPCI date and 180 days after the pPCI date were recorded.

Primary PCI procedure. Outside normal office hours, the catheterization laboratory staff was activated from their homes (< 30 minutes away) by the cardiologist at the invasive center, who had performed the triage for pPCI. During office hours, the crew was present at the catheterization laboratory. Primary PCI was performed according to contemporary interventional guidelines using pre-treatment with 10,000 IU unfractionated heparin, 300–500 mg acetylsalicylic acid, and 300–600 mg clopidogrel. Glycoprotein IIb/IIIa inhibitors were used at the operator’s discretion. Subsequent medical treatment included anti-ischemic, lipid-lowering and anti-thrombotic drugs according to current treatment guidelines. However, at our institution, all STEMI patients treated with pPCI after January 2004 were discharged with a prescription of 75 mg daily dose of clopidogrel for 12 months, regardless of the stent type implanted, and compliance was tested using the Registry of Medical Product Statistics.

Follow up and study endpoints. Follow up was 99.6% complete (8 patients were lost to follow up due to emigration). The primary study endpoints were all-cause mortality, non-fatal MI combined with a TVR (thus an MI in the culprit vessel), definite ST as proposed by the ARC,²² and TLR or TVR. Secondary endpoints were non-fatal MI, RR, and probable and possible ST as proposed by the ARC.²² All patients were followed for at least 1 year and for a maximum of 4 years, and mean follow-up times were 2.5 years in both the DES and BMS groups.

Follow-up data on mortality were collected from the National Person Identification Registry, which holds information on vital status (alive, death, or emigration), while follow-up data on re-MI and any kind of revascularization initially were collected from the highly validated Danish National Board of Health’s National Patient Registry, using ICD-10 codes.²⁴ If an event was registered, it was subsequently validated by cross-checking with hospital source data. Non-fatal MI was defined as recurrent chest pain combined with significant increases in creatine kinase MB (> 5 µg/L), troponin T (> 0.10 µg/L) or troponin I [> 0.5/0.05 µg/L (kit-dependent)], at least 5 days after the index STEMI.

Angiographic data related to revascularizations were validated and supplemented from our local PCI/CAG registry. In 25 cases, patients had a new revascularization performed at other invasive centers and relevant source data were collected from these institutions.

Statistics. Baseline characteristics were compared using χ² test and continuous Gaussian distributed variables with the Student’s unpaired t-test. We tested associations between the variable “DES or BMS” and other baseline variables using univariate logistic regression. In order to assess potential interaction between PCI operators and stent type for endpoints, every PCI operator was assigned a number and interaction analyses were performed.

Unadjusted Kaplan-Meier plots for main outcomes stratified by DES or BMS were compared using the log rank test. Curves for the entire period are displayed. Landmark analyses were performed from 0–1 year and 1–4 years (except for ST, where landmark analyses were performed from 0–30 days, 30 days to 1 year, and 1–4 years).

Relative risks were calculated by Cox proportional hazards regression analyses. The assumptions of linearity and proportional hazards in the models were assured. First-order interactions between “DES or BMS” and other baseline variables for endpoints were assessed in univariate models. In order to maintain a robust model, only 1 variable/10 events was allowed in the multivariable Cox analyses of each endpoint. In these analyses, the effect of “DES or BMS” was assessed after adjusted for the pre-specified variable “study year.” In addition, variables with the lowest p-values on univariate analysis were included, until the maximum allowed number of variables was reached.

In the statistical test, p ≤ 0.05 was considered to have statistical significance. SPSS for Windows, version 17.0 (Chicago, Illinois) was used.

The study was approved by the local scientific ethical committee and the Danish Data Protection Agency, and complied with the 2nd Declaration of Helsinki. The authors have full access to the data and take responsibility for its integrity. All authors have read and approved the manuscript as written.

Results

Patient population and baseline characteristics. A total of 1,725 patients were treated with DES and 430 were treated with BMS. Patients treated with DES were younger than BMS patients (62.7 years versus 66.3 years; p < 0.01). Otherwise, only minor differences were found in non-angiographic baseline variables between the two populations. The angiographic characteristics of patients treated with DES were significantly more complex compared to the BMS group, and the DES group was more frequently treated with glycoprotein IIb/IIIa inhibitors (Table 1). No other significant associations between the variable “DES or BMS” and other baseline variables were found. In particular, no association between PCI operator and stent type was found. In general, the two groups were treated with the same medication at admission and during follow up. Of interest, the compliance of clopidogrel medication was high (90%) and no difference in the proportion of patients treated with clopidogrel was found (Table 2).

The fraction of patients treated with DES increased from 70% in 2004 to 85% in 2006, but decreased to 80% in 2008.

Clinical long-term outcomes from 0–4 years. Unadjusted long-term outcomes are presented in Table 3 and Figure 1. A total of 285 patients died and 199 had a non-fatal MI. All-cause mortality was significantly higher in the BMS group compared to the DES group (16.3% versus 12.5%; p = 0.04; log rank p = 0.04). After adjustment for relevant baseline variables, no significant differences in relative risk of all-cause mortality or non-fatal MI in DES-treated compared to BMS-treated patients were found [hazard ratio (HR) = 0.87; 95% confidence interval (CI): 0.65–1.17; p = 0.34; and HR = 1.08; 95% CI: 0.72–1.64; p = 0.70, respectively). Patients treated with DES had lower adjusted risk of TLR (HR = 0.68; 95% CI: 0.40–0.98; p = 0.04) (Figure 2). On the other hand, DES-treated patients had increased adjusted risk of having a non-fatal MI in combination with a TVR (thus, an MI in the culprit vessel) (HR = 2.21; 95% CI: 1.05–4.66; p = 0.04). Otherwise, no significant differences in endpoints between the DES- and the BMS-treated patients were found in the multivariable analyses. A trend toward increased risk of definite ST for DES patients was found (HR = 1.96; CI: 0.83–4.61; p = 0.12). Interaction analyses between stent choice and PCI operator for endpoints were performed, and no interaction was found.

Landmark analyses of outcome. Unadjusted outcome from 0–1 year did not differ significantly between the two groups. From 1–4 years, DES-treated patients had significantly higher unadjusted risk of non-fatal MI in combination with a TVR and very late ST (Table 3 and Figure 1).

Discussion

In this study, we set out to evaluate the independent impact of DES or BMS treatment on long-term clinical outcomes in STEMI patients treated with pPCI in a real-life setting. After adjustment for relevant baseline variables, DES use was associated with a reduced risk of TLR. In DES patients, we found an increased risk of having a non-fatal MI in combination with a TVR and a trend toward increased risk of ST. However, this safety issue did not translate into an increased risk of death or overall non-fatal MI for DES patients.

Use of DES or BMS in STEMI patients has been evaluated in a number of RCTs and observational studies. However, when evaluating the results of these studies — and even more important, extrapolating those into routine clinical “guidelines” — two important issues have to be considered. First, patients treated within the controlled environment of the RCT do not necessarily resemble the patients treated in a real-life setting.²⁵ Second, while a 1- or 2-year follow-up period may be sufficient to compare two treatment strategies in many clinical circumstances, it appears to be inadequate when comparing DES treatment with BMS treatment. The latter is especially important, partly because clopidogrel treatment usually is given for a maximum of 1 year and partly because the risk of ST in DES patients appears to remain present even after 3–4 years of follow up.^26–29

In general, RCTs comparing DES or BMS treatment in STEMI patients treated with pPCI have shown that DES are superior in reducing TVR, without compromising safety (mortality and non-fatal MI) both on short- and long-term basis (1–2 years).^10,30 Compared to the present registry study — and registry studies in general — RCT populations were younger and had less severe angiographic characteristics. This indicates that the populations described in the RCT only reflect parts of the STEMI patients treated in real-life with pPCI.

Registry studies have yielded diverging results when analyzing this issue, although the general trends support the results from the RCT, i.e., that DES reduces the need for TVR, without compromising safety issues.³⁰ However, in a large study from the GRACE registry,³¹ DES treatment significantly increased mortality (adjusted HR = 4.90; p = 0.01), while Kukreja et al²⁷ found that ST seemed to be uniquely associated with the use of DES in ACS patients. That said, four studies have demonstrated that DES treatment is associated with a decreased risk of TVR, and similar risk of death and MI compared to BMS treatment within a period of 2 years of follow up.^32–35 In terms of “very long” follow up (> 2 years), a number of studies indicate that DES use in STEMI patients continues to decrease the risk of in-stent stenosis without compromising safety.^36,37 However, it is relevant to note that most studies indicate that rates of death, MI and ST are higher in DES patients compared to BMS patients when follow up is extended from 1 to 2 years, and while the risk of very late ST is very low for BMS-treated patients, it seems to persist for at least 3 years in DES patients.^26–29,38 In addition, long-term data from the DEDICATION trial, presented at the 2010 American College of Cardiology Congress, added to the concern regarding DES use in STEMI patients.³⁹ This randomized controlled trial found that DES use was associated with a significantly increased risk of cardiac death when follow up was extended from 8 months to 3 years. Our data confirm the long-term efficacy of DES in terms of preventing in-stent restenosis and importantly we did not detect a difference in long-term risk of death and overall non-fatal MI. However, our data indicate that DES are associated with an increased risk of very late ST and non-fatal MI in combination with TVR, thus a non-fatal MI in the vessel originally treated. The unadjusted Kaplan-Meier event rates for non-fatal MI and ST found in our study continued to diverge throughout a 4-year follow-up period, which obviously constitutes a potential problem since the advantage of reduced risk of in-stent stenosis could be ruled out by an continuously increasing risk of critical ST and MI. Nevertheless, these signals have to be viewed in a larger context, especially when the data are derived from observational registry studies. First, even though there might be a truly absolute increased risk of ST associated with DES use, this potential drawback seems to be inferior to affect overall mortality and non-fatal MI. Second, mortality due to other causes than ST and non-fatal MI may be more pronounced in BMS patients. For instance, stenotic vessels — which are more pronounced in BMS patients due to in-stent stenosis — may increase the risk of heart failure and consequently, death. This aspect disfavors BMS, but may be missed, especially in trials primarily evaluating MI and ST in DES and BMS patients.

Study limitations. Despite our efforts to reduce bias, the risk of unknown confounders exists in a non-randomized trial (residual confounding). This is particularly important in a registry study where the treatment strategy is decided at the operator’s discretion. In particular, our main variable (“DES or BMS”) could be biased — in this context “confounded by indication,” e.g., the PCI operator may have assumed that the overall coronary pathology combined with other co-morbidities would favor a DES stent over a BMS stent. On the other hand, some patients may have been treated with a BMS stent because future major surgery was anticipated. The stent choice is based on relatively complex considerations, which may have been missed in our adjustment. We performed interaction analyses between PCI operator and stent type for endpoints and no interaction was found. Consequently, we did not adjust for PCI operator in the multivariable Cox analyses.

Furthermore, we compared patients treated during a relatively long period. However, the fraction of DES patients did not change substantially over time and the follow-up time was identical in the two groups. In addition, no changes in treatment guidelines were implemented at our institution after 2004 — most importantly, all patients treated with a stent (both DES and BMS) were given clopidogrel for 12 months and we demonstrated an identical and very high compliance (90%) for both DES and BMS patients. Moreover, we included a time variable (“study year”) into the multivariable analyses.

We found a relatively low prevalence of diabetes, previous MI, and previous PCI. Identification of the variables “previous MI” and “previous PCI” were done in highly validated registries and later confirmed by hospital source data. The lower fraction of diabetes in our population could, to some extent, be explained by a lower background prevalence of diabetes in Denmark compared, e.g., to the United States. Furthermore, the prevalence of TVR (and TLR) was also relatively low in our population. All new revascularizations were evaluated thoroughly. The low prevalence may be attributed to our extensive use of clopidogrel in both groups. Care should be taken, though, if the results are to be extrapolated to populations with very different distributions of potential risk factors and logistic facilities.

Finally, our geographical and organizational conditions may not necessarily apply to other countries and regions, and our findings should not be extrapolated to settings without high-volume PCI centers.

Conclusion

In this study, we set out to evaluate the independent impact of DES use versus BMS use on long-term clinical outcomes in STEMI patients treated with pPCI in a real-life setting. DES were originally designed to reduce the risk of in-stent stenosis without compromising safety. In concordance with other studies, we found that DES use indeed reduced the risk of in-stent restenosis. We also found an increased risk of non-fatal MI in the culprit vessel (non-fatal MI in combination with a TVR) and a trend toward increased risk of ST in DES-treated patients. However, this potential safety issue did not translate into an increased risk of death or overall non-fatal MI among DES patients. Our results indicate that DES could be used in STEMI patients, although focus on stent delivery and clopidogrel compliance remains essential when deciding on the treatment strategy.

Acknowledgments. This work was supported by the Danish Heart Foundation (07-10-R60-A1822-B574-22414) and the Murermester Laurits Peter Christensen and Wife Kirsten Sigrid Christensen Foundation.

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From ¹the Department of Cardiology P, Copenhagen University Hospital Gentofte, Denmark, ²the Cardiovascular Research Unit, Department of Internal Medicine, Copenhagen University Hospital Bispebjerg, Denmark, ³the Clinical Institute of Surgery and Internal Medicine, Faculty of Health Science, University of Copenhagen, Denmark, and ⁴the Department of Medicine, Holbaek Hospital, Denmark.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 12, 2011 and accepted May 24, 2011.
Address for correspondence: Sune Haahr Pedersen, MD, PhD, Department of Cardiology P, Gentofte University Hospital, Niels Andersens Vej 65, DK-2900, Copenhagen (Denmark). Email: peidersen@hotmail.com