Drug-Eluting Stents versus Bare-Metal Stents in Acute ST-Segment Elevation Myocardial Infarction

Drug-Eluting Stents versus Bare-Metal Stents in Acute ST-Segment Elevation Myocardial Infarction. A Single-Center Experience with Long-Term Follow Up

ABSTRACT: Objectives. To compare the efficacy and safety of drug-eluting stents (DES) vs. bare-metal stents (BMS) in patients with acute ST-segment-elevation myocardial infarction (STEMI). Background. DES effectively reduce restenosis in elective percutaneous coronary intervention. Limited data are available about the use of DES in patients with STEMI. Methods. 453 consecutive patients who presented with STEMI between July 2003 and May 2006 were studied. The procedural characteristics, 30-day, 12-, 18- and 26-month outcomes of 277 patients treated with DES were compared with 176 patients treated with BMS. Results. At 26-month follow up, DES therapy was associated with a significant decrease in major adverse cardiac events (MACE) (relative risk [RR] -35%; p = 0.01) and target lesion revascularization [TLR], RR -64%; p = 0.009). The DES group included more diabetic patients (20% vs. 9%; p Conclusions. DES reduce the incidence of TLR and MACE in patients with STEMI without evidence of additional risks at 2-year follow up. DES therapy was associated with more complex interventional techniques, which yielded similar procedural results and clinical outcomes that may be influenced by prolonged combined antiplatelet therapy. J INVASIVE CARDIOL 2010;22:151–158 Key words: myocardial infarction, stent, percutaneous coronary intervention
Primary percutaneous coronary intervention (PCI), with or without stenting, has been shown to result in superior long-term outcomes compared with thrombolytic therapy in patients with acute myocardial infarction (AMI).^1, Routine stent implantation has been shown to have better procedural success rates and clinical outcomes than balloon angioplasty in patients presenting with AMI. ^2,3 Studies of patients with AMI treated with bare-metal stents (BMS) have reported an incidence of repeat revascularization procedures between 8% and 16%.^4,5 Drug-eluting stents (DES) have dramatically reduced the risk of restenosis after stent implantation, ^6,7 which rapidly resulted in an unrestricted use of DES in patients with STEMI as well. ^8,9 Although several registries have shown that DES can be safely used in AMI and are associated with a significant decrease in risk of restenosis and of new revascularization procedures, ^4,5,10,11 the use of DES in this patient population is discouraged¹² because of conflicting efficacy results reported in randomized trials^9,13 and safety concerns reported by registry studies.¹⁴ Moreover, the widespread use of DES has challenged previously accepted limits of PCI. ¹⁵ In particular, the feasibility of DES seems to have substantially impacted the procedural techniques, so that a far higher number of high-risk coronary lesions are now addressed when compared with the pre-DES era. ¹⁶ However, the role of DES in AMI has not been fully elucidated. More recently, two randomized, prospective trials presented conflicting results on the role of DES in AMI. In a selected patient population, sirolimus-eluting stents (SES) demonstrated a beneficial impact when compared with BMS, while no such difference was present in the comparison of paclitaxel-eluting stents (PES) versus its bare-metal equivalent, raising the question of the benefit of DES in this acute setting. ^9,13 To address these questions in an unselected “real-life” patient population, we compared the interventional techniques and the incidence of major adverse cardiovascular events (MACE) in consecutive patients with AMI treated with DES and BMS. Methods Patients. Since July 2003 to May 2006 a total of 6,758 diagnostic and interventional catheterization procedures were performed (Figure 1). This single-center, retrospective analysis was performed on 453 consecutive patients admitted during this period (when sirolimus and paclitaxel-eluting stents first became available at our institution) to Gabriele Monasterio Foundation, and the Institute of Clinical Physiology CNR, National Research Council “G. Pasquinucci” Hospital, Massa, Italy, with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary or rescue PCI of the infarct-related artery within 24 hours of the onset of symptoms (Figure 2). Patients were divided into two cohorts according to the type of stent implanted: 176 patients who received BMS in the infarct-related artery (BMS group), and 277 patients who received a DES (DES group) a PES (Taxus, Boston Scientific Corp., Natick, Massachusetts) or a Cypher SES (Cordis Corp., Miami, Florida). All procedures were performed according to current standard procedural guidelines with the interventional approach left to the discretion of the operating physician. Both SES and PES were used based on availability or physician preference. Procedures and Post-intervention Medications Before the procedure, all patients received aspirin (300–500 mg) and clopidogrel, an inhibitor of adenosine diphosphate-induced platelet aggregation, was given as a bolus of 300 or 600 mg immediately after the procedure depending on glycoprotein (GP) IIb/IIIa receptor blocker use (in particular, patients treated with a GP IIb/IIIa receptor blocker received 300 mg of clopidogrel). A GP IIb/IIIa receptor blocker was administered at the discretion of the operator. A bolus of 5,000 IU of unfractionated heparin was administered prior to the interventional procedure. Coronary angiography was performed through either the radial or the femoral artery. Post intervention, patients received aspirin 100 mg/day indefinitely in addition to beta-blockers, angiotensin-converting enzyme inhibitors and statins, if these agents were not contraindicated. At least 1 month of clopidogrel treatment (75 mg/day) or ticlopidine (500 mg/day) was recommended for patients treated with BMS. The duration of dual-antiplatelet therapy has been gradually lengthened for our patients; in particular, for those treated with DES, the clopidogrel was prescribed for 6 months then, on the basis of new recommendations, it was prescribed for up to 1 year (Figure 3). This protocol reflects our institution’s health policy and the need to minimize the risk of bleeding. The infarct-related artery (IRA) determined the target of the procedure. Intra-aortic balloon pump counterpulsation was used in situations of hemodynamic deterioration. Angiographic analysis. Epicardial blood flow in the IFR before and after stent implantation was determined according to the thrombolysis in myocardial infarction (TIMI) classification. ¹⁷ Cineangiograms were obtained immediately after the procedure, according to standard guidelines. Successful coronary intervention was defined as TIMI flow grade ³ and residual in-lesion stenosis 50%) luminal stenosis and concomitant angina or evidence of myocardial ischemia. Stent thrombosis was categorized as: acute (occurring within 24 hours after the procedure); subacute (occurring from 1 to 30 days after the procedure); or late (occurring from more than 30 days to one year) and very late (after 1 year). To capture all possible adverse events attributable to stent thrombosis, we used the new Academic Research Consortium definitions for thrombosis. Stent thrombosis was defined as definite when confirmed by angiography or when pathologic confirmation of acute thrombosis in ACS patients was made. Probable stent thrombosis was defined as any unexplained death occurring within 30 days after the procedure or as target-vessel myocardial infarction without angiographic confirmation of thrombosis or other identified culprit lesion. Possible stent thrombosis was defined as unexplained death after 30 days. ¹⁸ In addition to the earlier-mentioned parameters, each patient’s clopidogrel intake was noted during follow up. Follow up. Clinical follow up was performed utilizing the institutional medical record system as well as the records from the referring physicians and institutions to which patients were discharged in the post-interventional period. All data on percutaneous and surgical coronary interventions were retrospectively collected. During each patient’s hospital stay, we recorded all adverse events; during follow up at 26 months, we recorded all major adverse cardiac events (MACE) (death from cardiac or noncardiac causes, recurrent myocardial infarction, revascularization of the target lesion or target vessel), as well as interventions to nontarget vessels. No routine follow-up angiography was performed. Study endpoints. The primary endpoint was the first occurrence of MACE at 26 months, including death from cardiac causes, recurrent myocardial infarction requiring hospitalization and ischemia-driven revascularization of a target lesion. The secondary endpoint of the study was revascularization of a target lesion. All deaths were considered to have been from cardiac causes unless a noncardiac cause could be identified. Statistical analysis. Baseline data are presented as proportions or mean (± standard deviation) values and were compared with the use of the Student’s t-test or the Wilcoxon rank-sum test for continuous variables and with the chi-square test or Fisher’s exact test for categorical variables. A two-sided p-value of 19 Data on patients who were lost to follow up were excluded. Relative risks were calculated by dividing the Kaplan-Meier estimated rate of an event at 26 months in the DES group by the rate in the BMS group. The 95% confidence interval (CI) for the relative risk was calculated with the use of the standard errors from the Kaplan-Meier curve. The significance of differences in rates of the end points between treatment groups was assessed by the log-rank test. Potential associations between MACE and clinical or technical variables were first tested in univariate analysis by using the Spearman correlation for continuous variables and the Wilcoxon rank-sum test for categorical variables. Univariate variables with a p-value Results A total of 453 patients were analyzed. We treated 176 patients with BMS, 134 patients with PES and 143 with SES. The baseline clinical characteristics of both groups are shown in Table 1. Patients in the DES group were younger compared to those in the BMS group. The proportion of men was similar in both groups. There was a significantly higher prevalence of diabetes mellitus in the DES group compared to the BMS group. There was no significant difference between the two groups in terms of ejection fraction, hypertension, hyperlipidemia, hypotension on presentation, smoking and serum creatinine. The mean duration of combined antiplatelet therapy in the BMS and DES groups was 3.7 ± 0.2 versus 7.1 ± 0.2 months, respectively (p Clinical Outcomes Table 3 shows the clinical outcomes for MACE at 26 months. Ninety percent of patients in the BMS group and 92% of those in the DES group underwent complete clinical follow up. Forty-six patients (26%) in the BMS group and 50 patients (21%) treated with DES met the primary endpoint. The most lethal of events was present in the first 30 days post PCI: 7.3% in the BMS group and 5% in the DES group. However, during this period, there was no significant difference between BMS and DES in terms of MACE, death, new myocardial infarction, need for a new revascularization procedure and definite stent thrombosis. On the contrary, a significant difference in TLR was reported in the successive follow-up period out to 12 and 18 months, showing a significant reduction in MACE. Also in the subsequent period of followup to 26 months was a significant reduction in TLR (Table 3). The overall incidence at 26 months for definite stent thrombosis was of 5.6% in the BMS group and 3.2% in DES group (p = NS). Of note, there was 1 case of very late stent thrombosis in the DES group (13 months) and in the BMS group (21 months). Furthermore, a subanalysis of thrombotic events did not show any significant difference in acute, subacute, late or very-late stent thrombosis (Table 4). Kaplan-Meier curves shows how the patients treated with DES had a reduced cumulative risk of MACE at 26 months, attributable to a significant reduction in TLR (Figures 4 and 5). Multivariate analysis (Table 5) shows how the length of treatment with dual-antiplatelet therapy was a significant predictor of freedom from MACE at 26 months post AMI. Table 5 also shows that elevated serum creatinine levels and insulin-dependent diabetes were associated to an increased risk of MACE. A comparison within the DES group between patients treated with PES and SES did not reveal any significant differences in terms of MACE or need for new revascularization procedures involving the segments previously treated (Table 6). Discussion The purpose of this study was to compare the outcomes of unselected patients with AMI undergoing primary PCI with DES versus BMS. Importantly, our data were collected for a long follow-up period when compared with previous studies. ^10,13,20,21 Data from this study provide three major results: (1) DES therapy is associated with a markedly reduced rate of TLR when compared with BMS therapy, showing a reduction in MACE; (2) DES therapy in current interventional practice is associated with a substantial increase in complex interventions when compared with the immediately preceding era of BMS therapy; and (3) the rates of late and very late stent thrombosis in the DES group were low and did not differ from those in the BMS group. In-stent restenosis and vessel reocclusion remain significant clinical problems limiting the long-term success of percutaneous intervention. ^2,3 In contrast to the two recently presented randomized trials of BMS versus DES in selected patients with AMI, ^9,13 we observed a significant reduction in the number of repeat revascularization procedures involving the stented segments. There was a 35% overall reduction in the rate of adverse events at 26-month follow up in DES group compared with the BMS group. This reduction in MACE was predominantly determined by a 64% decrease in the rate of the TLR (Figure 4). A 53% reduction in TVR was not significant (Figure 5). These data underscore how restenosis, but not the atherosclerotic disease progression in other coronary segments, may be the most important factor determining a significant difference between the use of DES and BMS, as also was reported in a recent metanalysis. ²² The rate of repeated revascularization in both cohorts is consistent with previous studies involving BMS (4–26.6%)^23,2,24 and DES (1.1–7%),^25–27 respectively. The TLR rate in our BMS cohort (14%) is not surprising, given a TLR rate of 26.6% previously described in complex and long lesions. ²⁴DES treatment in our series was associated with a relative reduction of recurrent myocardial infarction of 50% (Figure 4). However, the reduction in recurrent infarction in our series is markedly greater than in previous studies, which reported variable reduction rates between 0 and 37%.^26,28,29 This difference from prior reports would seem to reflect the population we studied. In these reports, the cohort was not exclusively comprised of patients with myocardial infarction. Our study, therefore, suggest that DES could have a particular advantage in the management of AMI. Importantly, the significant reduction of TLR occurred with no difference in recurrent myocardial infarction, definite thrombosis and mortality. The somewhat higher death and stent thrombosis rates in both treatment groups, when compared with previously published studies, ³⁰ are explainable in the context of life-saving procedures in the clinical setting of AMI with increased platelet activation.³¹ While previous trials^9,13 excluded patients with cardiogenic shock, the TYPHOON trial additionally excluded patients at the highest risk for reinfarction, including those with prior myocardial infarction, Killip class > 2, ejection fraction 30 mm, and the presence of a significant stenosis proximal or distal to the target lesion. However, in a tertiary referral center such high-risk patients are commonly treated. For this reason, our data seem to more closely resemble the results that are obtained in the current practice of interventional cardiology. Patients treated with DES underwent more extensive coronary interventions when compared with patients treated with BMS, as evidenced by the significantly higher rate of long lesions treated with smaller stents for the infarct-related vessel. These variables have previously been shown to be independent predictors of TVR, ^32,33,34 yet in our series, these parameters were not associated with increased rates of TVR and TLR. However, these improved outcomes cannot be solely attributed to the use of DES as opposed to BMS. Recently, the Horizons-AMI trial showed that treatment with DES reduced ischemic TLR (primary endpoint) at 12 months by 41% compared with BMS, while the incidence of mortality and stent thrombosis was comparable.35 Another study comparing DES and BMS use in AMI described similar results in terms of the need for repeat revascularization. Furthermore, they found a significant reduction in 2-year mortality rates, which were lower in the DES group than the BMS group.36 Mauri et al also suggested that the duration of dual-antiplatelet therapy, which is known to provide benefit in acute coronary syndromes, might have had a role in determining the results. ³⁶ In our study, the duration of clopidogrel use in patients treated with DES markedly exceeded that indicated for BMS. In fact, more than 12% of the patients had been taking clopidogrel for at least 12 months, and more than 83% for at least 6 months, which is likely the consequence of the heightened awareness of late stent thrombosis among the treating physicians. ^21,37 In the context of the finding that clopidogrel use is an independent predictor of a reduced incidence of MACE, results of this study support the notion that the combination of both DES and prolonged clopidogrel treatment was mitigating the incidence of MACE after an AMI. Furthermore, renal impairment and insulin-dependent diabetes are independent predictors of an increased rate of events. Also in our study, thrombotic events in both groups were commonly associated with antiplatelet withdrawal as a result of moderate-to-severe bleeding or inadequate adherence to therapy. Use of DES was not associated with an increased risk of stent thrombosis up to 2-year follow up. The results achieved in our patients treated with DES and BMS are similar to those reported. ^17,20,22,38 Only 1 case of late stent thrombosis occurred in both groups. Study limitations. This is a registry study illustrating “real-life” decisions in every single patient, and the choice of BMS or DES was at the physician’s discretion. BMS were mostly used in older patients who were at higher risk of bleeding and had a higher probability of antiplatelet therapy discontinuation; DES were preferentially used in patients with diabetes, longer lesions and smaller target vessels, configuring a profile with a higher risk of restenosis. All of these factors may have affected outcomes, thus influencing the study results. Furthermore, the predictive power of multivariate analysis may be limited, given the small number of outcome events. Finally, it is important to mention that our study compares non-concurrent coronary therapies, hence, our results involve other factors than the stents themselves. The differences we observe may also reflect increased operator experience, improved catheterization devices other than stents, imaging modalities and postprocedural management. However, these improved outcomes cannot only be attributed to the use of DES as opposed to BMS, since the duration of clopidogrel therapy was considerably longer in patients treated with DES. Moreover, the retrospective nature of patient follow up may have introduced some reporting errors. As a consequence, our study is a comparison of contiguous stenting eras rather than of the stents alone. Conclusions Our study suggests that the utilization of DES in unselected patients with acute STEMI in real-world practice is feasible and safe. DES can greatly reduce the need for new revascularization in patients with AMI, without any evidence of additional risks at 2-year follow up. Compared with BMS use, DES therapy was associated with more complex interventions, which yielded similar procedural results and clinical outcomes. The improved long-term outcomes may also be linked to prolonged combined antiplatelet therapy.

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From the “Gabriele Monasterio” Foundation, and Institute of Clinical Physiology CNR, National Research Council “G. Pasquinucci” Hospital, Massa, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted August 21, 2009, provisional acceptance given September 24, 2009, final version accepted January 12, 2010. Address for correspondence: Marcello Ravani, MD, Gabriele Monasterio Foundation, and Institute of Clinical Physiology CNR, National Research Council “G. Pasquinucci” Hospital, Via Aurelia Sud 54100 Massa, Italy. E-mail: ravanim@ifc.cnr.it