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European Heart Journal Advance Access originally published online on July 25, 2007
European Heart Journal 2007 28(17):2118-2125; doi:10.1093/eurheartj/ehm297
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry

Alfredo E. Rodriguez1,*, Andrew O. Maree4, Juan Mieres1, Daniel Berrocal3, Liliana Grinfeld3, Carlos Fernandez-Pereira1, Valeria Curotto2, Alfredo Rodriguez-Granillo1, William O'Neill5 and Igor F. Palacios4

1 Cardiovascular Research Center (CECI)/Sanatorio Otamendi, Callao 1441, 4B (1024), Buenos Aires, Argentina
2 Medicine Department, Sanatorio Otamendi, Buenos Aires, Argentina
3 Hospital Italiano, Buenos Aires, Argentina
4 Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
5 William Beaumont Hospital, MI, USA

Received 7 January 2007; revised 2 May 2007; accepted 14 June 2007; online publish-ahead-of-print 25 July 2007.

* Corresponding author. Tel: +54 1149648721; fax: +54 1149648721. E-mail address: rodrigueza{at}sanatorio-otamendi.com.ar


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusion
 Appendix
 References
 
Aims: Long-term benefit from coronary revascularization with drug-eluting stents (DES) relative to bare metal stents (BMS) and coronary artery bypass grafting (CABG) has not been established. One year follow-up of the ERACI III registry study showed better outcome with DES. To compare major adverse cardiac and cerebrovascular event (MACCE) rates in patients with multivessel cardiovascular disease (CVD) who received DES with those patients treated with BMS or CABG in the ERACI II trial.

Methods and results: Patients with multivessel CVD who met the ERACI II trial, clinical and angiographic inclusion criteria were treated with DES and enrolled in the ERACI III registry. The primary endpoint was 3-year MACCE. ERACI III-DES patients (n = 225) were compared with the BMS (n = 225) and CABG (n = 225) arms of ERACI II. Patients treated with DES were older, more often smokers, more often high risk by euroSCORE and less frequently had unstable angina. They also had higher incidence of type C lesions and received more stents than the BMS-treated cohort. Three year MACCE was lower in ERACI III-DES (22.7%) than in ERACI II-BMS (29.8%, P = 0.015), mainly reflecting less target vessel revascularization (14.2 vs. 24.4%, P = 0.009). MACCE rates at 3 years were similar in DES and CABG-treated patients (22.7%, P = 1.0), in contrast to results at 1 year (12 vs. 19.6%, P = 0.038). MACCE rates in ERACI III-DES were higher in diabetics (RR 0.81, 0.66–0.99; P = 0.018). Death or non-fatal MI at 3 years trended higher in the DES (10.2%) than BMS cohort (6.2%, P = 0.08) and lower than in CABG patients (15.1%, P = 0.07). Sub-acute late-stent thrombosis (LST) (>30 days) occurred in nine DES patients and no BMS patients (P = 0.008).

Conclusion: In patients with multivessel CVD, the initial advantage for PCI with DES over CABG observed at 1 year was not apparent by 3 years. Furthermore, despite continued lower incidence of MACCE, initial advantage over BMS appeared to decrease with time. LST occurred more frequent in DES-treated patients.

Key Words: Drug-eluting stents • Multivessel disease • Myocardial revascularization


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Study limitations
 Conclusion
 Appendix
 References
 
Multivessel percutaneous coronary intervention (PCI) with balloon angioplasty and/or bare-metal stenting (BMS) is associated with high rates of restenosis and frequent need for repeat revascularization.1–8 However, the advent of drug-eluting stents (DES) had regenerated interest in multivessel PCI. Medium-term follow-up data from the ARTS II9 and ERACI III10 registry studies and the RESEARCH registry11 indicate that TVR rates associated with multivessel PCI with DES are lower than with BMS and comparable to the CABG arms of the ERACI II, ARTS I and SoS trials.6,12,13 Although several randomized controlled trials have demonstrated clinical advantage of DES over BMS,14–16 long-term (>1 year) efficacy of DES in multivessel PCI is largely unknown. Furthermore, recent reports of associated late-stent thrombosis (LST) (>30 days) have raised concerns regarding the long-term safety of DES.17–21

ERACI III is a prospective, multicenter registry that was designed to determine outcomes associated with multivessel PCI using DES. The aim was to compare outcomes in ERACI III-DES with the BMS and CABG arms of the previously published ERACI II trial. The present study reports 3-year safety and efficacy of multivessel PCI using DES in ERACI III and compares it with the historical arms of the ERACI II trial.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Study limitations
 Conclusion
 Appendix
 References
 
ERACI III is a multicenter, prospective, non-randomized, and open-labelled registry study designed to evaluate outcome associated with DES use in patients with multivessel CVD. ERACI III patients had to meet the angiographic and clinical criteria for the earlier ERACI II trial.6 In a further attempt to obtain a comparable population and equivalent revascularization strategy to that employed in ERACI II, the same centers and investigators took part in ERACI III.

Patient selection
The ERACI III study protocol has previously been published.10,20

Briefly, to be included in the study, patients had to have objective evidence of myocardial ischaemia and angiographic evidence of severe coronary obstruction (stenosis greater than or equal to 70% by visual estimation) in at least two major epicardial vessels. The target coronary lesions had to be amenable to revascularization by both PCI and CABG based on angiographic assessment. The revascularization strategy was planned prior to the procedure and the aim was to achieve complete revascularization. Percutaneous revascularization was considered complete when all severe stenoses (>70%) had been treated successfully with stents. Chronic totally occluded vessels supplying akinetic left ventricular segments were usually not attempted. Patients with unprotected left main coronary artery stenosis could be included if considered suitable for percutaneous treatment by the interventionalist.

Coronary artery lesions of 50–70% severity were treated at the discretion of the physician. Patients were excluded from the study if they had: prior CABG, PCI in the preceding year, in-stent restenosis, acute myocardial infarction in the preceding 48 h, poor left ventricular function (ejection fraction <35%), two or more chronic total occlusions, severe concomitant valvular or myocardial heart disease, limited life expectancy, history of cerebrovascular accident, neutropenia or thrombocytopenia, aspirin or thienopyridine intolerance, a requirement for concomitant vascular or general surgery, or if they were deemed unsuitable for long-term antiplatelet therapy, or not amenable to treatment with DES therapy.

Medication
All patients in ERACI III received an oral loading dose of 300 mg of clopidogrel plus 325 mg of aspirin prior to undergoing PCI. Administration of a glycoprotein IIb/IIIa inhibitor during PCI was strongly recommended in patients with unstable angina class III or C and in diabetics. After PCI, all ERACI III patients were prescribed 75 mg of clopidogrel daily. The recommended minimum treatment duration was 3 months for patients who received sirolimus-eluting stents (SES) and 6 months for those who received paclitaxel-eluting stents (PES), respectively. Treatment beyond this duration was at the discretion of the physician. Aspirin therapy was continued indefinitely. Lipid-lowering agents were prescribed for all ERACI III patients irrespective of cholesterol levels. In ERACI II, lipid-lowering agents were prescribed based on cholesterol level and thienopyridines (ticlopidine) were prescribed for 1 month.

Study endpoints
The predetermined primary endpoint of the study was incidence of, and freedom from, major adverse cardiac and cerebrovascular events (MACCE). This composite endpoint comprised death of any cause, non-fatal myocardial infarction (MI), major stroke, and need for target vessel revascularization (TVR). The endpoint was assessed after 1, 2, 3, and 5 years of follow-up. Outcomes in ERACI III patients treated with DES (ERACI III-DES) were compared with the BMS (ERACI II-BMS) and CABG (ERACI II-CABG) arms of the previously reported ERACI II trial (Figure 1).


Figure 1
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  		Figure 1 Flow charts from ERACI II and ERACI III.

 
Incidence of, and freedom from death, acute (fatal and non-fatal) MI (AMI), combined death and non fatal-MI, stroke, and TVR were assessed as secondary endpoints and compared across the three cohorts. Incidence of MACCE was determined among diabetic patients in each of the three revascularization groups. Further sub-analysis compared MACCE in diabetics and non-diabetics in ERACI III-DES. Occurrence of stent thrombosis in ERACI III during the 5 years of follow-up was also analysed.

Endpoints definitions
Death included mortality from any cause. AMI was considered to be either Q wave or non-Q wave. Only occurrence of Q wave MI was recorded during the hospitalization period, in keeping with the prior ERACI II trial protocol.6 Occurrence of both Q wave and non-Q wave MI was recorded in follow-up. A Q wave myocardial infarction was defined as the appearance of new pathologic Q waves or new left bundle branch block (LBBB) on an electrocardiogram in association with a more than threefold rise in serum creatine kinase-MB fraction (CK-MB). The diagnosis was adjudicated after review of all electrocardiograms (ECGs), which had been obtained as part of the study protocol or in association with the admission. Non-Q wave MI was defined as a greater than threefold risk in serum CK-MB in the absence of new pathological Q waves or LBBB on the ECG.

Stent thrombosis was predefined as:

  1. Suspected stent thrombosis, when the patient suffered unexpected cardiac or sudden death or had an ST-segment elevation myocardial infarction (STEMI) which correlated with the area of DES placement. Non-STEMI related to the treated vessel was not considered to represent stent thrombosis. Patients whose electrocardiogram from the time of the acute event could not be reviewed were not included in this category.
  2. Confirmed stent thrombosis, when the patient had angiographically documented stent thrombosis with TIMI flow 0 or 1 or the presence of flow-limiting thrombus (TIMI flow 1 or 2). Both suspected and confirmed stent thrombosis were counted as overall stent thrombosis.

All clinical events were adjudicated by Clinical Events and Safety Committee. Our definition was pre-defined and preceded the recently compiled Academic Research Consortium (ARC) definition of stent thrombosis.21 However, to facilitate comparison with other studies, stent thrombosis was re-adjudicated using the new ARC definition.22

According to the ARC definition, stent thrombosis was classified as:

  1. Acute if within 24 h of the index procedure
  2. Subacute when it occurred 1–30 days post-procedure
  3. Late if it occurred between 31 days and 1 year post-procedure
  4. Very late if more than 1 year after the procedure.

Stent thrombosis was further defined as:

  1. Definite when stent thrombosis was confirmed angiographically, with or without vessel occlusion, and associated with clinical or electrocardiographic signs of acute myocardial ischaemia or with a rise in creatine kinase of twice the normal laboratory value within 48 h of angiography.
  2. Probable, in the absence of angiographically confirmed stent thrombosis, if unexplained death occurred within 30 days of the index procedure, or if an MI occurred in a region subtended by the stented vessel at any time after the index procedure.
  3. Possible if unexplained death occurred more than 30 days after the index procedure.

The ARC definition of stent thrombosis included events, which occurred after repeated TVR.

Statistical analysis
Sample size of the study was determined based on an estimate of the incidence of the primary endpoint of MACCE at 1 year of follow-up among patients treated with DES relative to the ERACI II-BMS arm. In line with recently published randomized data regarding DES treatment (SIRIUS, E-SIRIUS, C-SIRIUS, TAXUS II, and TAXUS IV), and also based on previous ERACI trial data (35% of MACCE reduction among ERACI II with BMS vs. ERACI I with balloon angioplasty), we predicted that DES therapy would be associated with a 50% reduction in MACCE.6,8,14–16 Given the high-risk nature of our patient population, a 50% reduction in MACCE with DES therapy was felt to be more appropriate than the often proposed 70–75% treatment effect. Thus, based on the 22.3% incidence of MACCE at 1 year in the ERACI II-BMS arm, we predicted a 1 year incidence of MACCE of 10–12% with DES. Using a two-sided test for differences in independent binomial proportions with an {alpha} level of 0.05, we estimated that 210 patients needed to be treated with DES to guarantee a power of 80%.

Continuous variables were compared using ANOVA with Bonferroni correction. Categorical variables were compared using {chi}2 analysis or Fisher's exact test. Continuous variables were expressed as mean ± SD and categorical variables as percentages. Freedom from survival endpoints at follow-up was obtained using Kaplan–Meier curves and compared by log-rank test. Analysis was performed using SPSS v14.0.

Binary logistic regression analysis was performed using SPSS v14.0 intro mode (all variables introduced en block in a single step) to determine independent predictors of poor outcome at 3 years, thus correcting for demographic, clinical, and angiographic confounders. Variables of statistical significance after univariate analysis and clinically relevant covariates were included in the analysis. A P-value of <0.05 was considered statistically significant.10


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Study limitations
 Conclusion
 Appendix
 References
 
Baseline and procedural characteristics of the three study arms have been published previously.6,10 Patients in the ERACI III-DES arm were older, more likely to be smokers, more often high-risk by EuroSCORE, and less likely to have unstable angina than ERACI II-CABG and ERACI II-BMS patients. All three study arms had a high proportion of patients who presented with acute coronary syndromes. Three vessel diseases was less prevalent among DES patients, however, lesions were more complex, required placement of longer stents, and more stents per patient than in the BMS arm (Table 1). SES (Cordis-Johnson&Johnson. Miami Lakes, FL, USA) was used in 52% of patients and PES (Boston Scientific Corp., Boston, MA, USA) in the other 48%.


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  		Table 1 Demographic, clinical, and angiographic characteristics by subgroup

 
Outcomes at 30-day and 1 year
Thirty-day and 1 year results of the ERACI III-DES registry and comparison with the ERACI II-CABG and BMS trial arms have already been published.10 Briefly, incidence of MACCE at 1 month of follow-up in ERACI III-DES [10/225 (4.4%)] was similar to that in ERACI II-BMS [8/225 (3.6%), P = 0.81]. However, incidence of MACCE in both stented cohorts was significantly lower than in the ERACI II-CABG arm [28/225 (12.3%), P = 0.0035 for DES and P < 0.001 for BMS]. The latter primarily reflected a relatively high incidence of in-hospital death [13/225 (5.7%)] and non-fatal Q wave MI [13/225 (5.7%)] among CABG patients in the ERACI II trial.6 Procedural and clinical success rates and procedural and in-hospital adverse event rates were comparable in ERACI III-DES and ERACI II-BMS [death 2/225 (0.9%) vs. 2/225 (0.9%), P = 1.4; non-fatal Q wave MI 2/225 (0.9%) vs. 2/225 (0.9%), P = 1.4; stroke 3/225 (1.3%) vs. 0/225 (0%), P = 0.5, respectively).

At 1 year, ERACI III-DES patients had greater freedom from MACCE (88%) than ERACI II-CABG (80%, P = 0.038) and ERACI II-BMS patients (78%, P = 0.006). The relative advantage for DES-treated patients primarily reflected lower death and AMI rates when compared with the CABG cohort and a lower incidence of TVR than in the ERACI II-BMS arm (Table 2). Freedom from death and non-fatal AMI in patients treated with DES (94.2%) was comparable with that of the ERACI II-BMS arm (94.6%) and significantly greater than in the CABG arm (86.2% P = 0.01). Freedom from TVR was comparable in the DES (91.1%) and CABG cohorts (95.1%, P = 0.804) but both performed significantly better than the patients treated with BMS (83%), (P = 0.02 and P = 0.002, respectively).10


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  		Table 2 Incidence of clinical endpoints and univariate analysis at 1- and 3-years of follow-up

 
Three-year outcome
DES patients were followed for a mean of 36 months (range 26–60). Follow-up was complete in 97% of ERACI III-DES patients, 93.8% of the ERACI II-CABG arm and 95% of the ERACI II-BMS arm. Event-free survival curves and incidence rates for all clinical endpoints (MACCE, death, death, or non-fatal MI, TVR) are represented in Figure 2 and Table 2. At 3 years, 5.7% (13/225) of patients who were treated with DES had died when compared with 4.8% (11/225) in the ERACI II-BMS (RR 1.18; 95% CI 0.54–2.58; P = 0.83) and 9.8% (22/225) in ERACI II-CABG (RR 0.59; 95% CI 0.30–1.14; P = 0.16) arm. The incidence of AMI (fatal and non-fatal) in the ERACI III-DES cohort was 4.5% (10/225) when compared with 2.7% (6/225) in the ERACI II-BMS arm (RR 1.6; 95% CI 0.61–4.5; P = 0.45) and 6.2% (14/225) in the ERACI II-CABG cohort (RR 0.71; 95% CI 0.32–1.57; P = 0.53). At 3 years, the incidence of the composite secondary endpoint (death or non-fatal AMI) was higher in the DES cohort [10.2% (23/225)] than the ERACI II-BMS arm [6.2% (14/225)] but failed to reach statistical significance (RR 1.64; 0.86–3.11, P = 0.08) and was no longer significantly lower than in the ERACI II-CABG cohort [15.1% (34/225)] (RR 0.67; 95% CI 0.4–1.1; P = 0.07).


Figure 2
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  		Figure 2 Freedom from death (A), non-fatal myocardial infarction (B), TVR (C), and MACCE (D) from the ERACI III, ERACI II-PCI, and ERACI II-CABG.

 
Incidence of MACCE at 3 years remained lower in the ERACI III-DES cohort [22.7% (51/225)] than in the ERACI II-BMS arm (29.8%) (RR 0.68; 95% CI 0.50–0.92; P = 0.016). This was primarily due to sustained reduction in TVR (10.6% absolute reduction, RR 0.58; 95% CI 0.39–0.86; P = 0.008). The number of patients who needed to be treated with DES in order to avoid a new TVR at 3 years was 9.8.

Although 1 year clinical data indicated a significant advantage for ERACI III-DES patients over the ERACI II-CABG cohort, MACCE rates had converged by 3 years (Table 2, Figure 1). This catch up phenomenon appears to reflect a relatively greater late requirement (>1 year) for TVR [5.2% (12/225) vs. 0.9% (2/225), RR 1.76; 95% CI 1.39–2.22; P = 0.012] and a trend towards increased late death and non-fatal MI [4.4% (10/225) vs. 2.2% (5/225); RR 1.35; 95% CI 0.93–1.95; P = 0.29)] in the ERACI III-DES population.

Target vessel revascularization
Target vessel revascularization at 3 years remained significantly lower in the DES cohort than in the BMS group (14.2 vs. 24.4%, P < 0.01). Of the 14.2% in the DES group, 10% developed angiographic in-stent restenosis and 4.2% had disease progression of non-target lesions. Therefore, based on the 1 year data analysis (8.9%), in-stent restenosis in the intervening 2 years was 1.1%. Need for TVR remained significantly lower in the CABG cohort than in the DES arm at 3 years (5.8 vs. 14.2%, P < 0.002) (Table 2).

Stent thrombosis
Acute (<24 h) stent thrombosis rates were low in both the ERACI II-BMS and ERACI-III-DES cohorts (1.3 and 0.4%, respectively). In ERACI III, nine cases (3.5%) of subacute and LST were identified over the 3 years of follow-up vs. none in the ERACI-II-BMS study arm (P = 0.008). Five cases occurred in patients who had received SES, three had been treated with PES, and one patient with LST had received both SES and PES. Neither angiographic nor post-mortem confirmation of thrombosis was available in the latter patient, thus it was not possible to implicate one or the other stent. The stent thrombosis rate associated with DES was 2.6% after 1 year, 3.5% after 2, and 4.4% by the end of 3 years (P = 0.089 compared with BMS). The mortality rate associated with LST cases was 44.4% (4/9).

When the ARC definition of stent thrombosis was applied to the ERACI II-BMS cohort, there were three acute cases of stent thrombosis. This event met the ARC criteria for definite stent thrombosis. Re-adjudication of the ERACI III-DES cohort using the ARC definition determined that there was one acute, three subacute, four late, and two very late cases of stent thrombosis during the 3 years of follow-up. Of these cases, six met the criteria for definite stent thrombosis, two for probable stent thrombosis, and two for possible stent thrombosis cases.

Diabetics and non-diabetics in ERACI III
In the ERACI III registry, the incidence of MACCE at 3 years was significantly higher in diabetics than non-diabetics (RR 0.81, 0.66–0.99; P = 0.018). Higher rates of death and non-fatal AMI and a trend towards increased TVR among diabetics were the principal determinants of increased MACCE (Table 3). Incidence of death among diabetics increased threefold after the first year although failed to reach statistical significance, possibly reflecting the small numbers (2.7% at 1 year vs. 12.8% at 3 year follow-up; P = 0.148). Conversely, mortality in non-diabetics did not vary substantially beyond the first year (2.8 and 3.9% at 1 and 3 years, respectively).


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  		Table 3 Three years of follow-up in the ERACI III trial—non-diabetic vs. diabetic patients

 
When stratified by treatment modality, MACCE rates among diabetics at 3 years were 36.2% in the DES arm, 43.6% in the BMS arm, and 30.8% in the CABG group (P = 0.49). Of the components of MACCE, TVR was the only one that differed significantly across the three groups: DES (21.3%), BMS (38.5%), and CABG (15.4%); P = 0.048. However, TVR was not significantly different when compared directly between DES and CABG arms (RR 1.2; 0.76–1.84; P = 0.58) or DES and BMS arms (RR 0.66; 0.39–1.11; P = 0.10). There was a non-significant trend towards more death and non-fatal MI among diabetics in the ERACI III-DES cohort (19.1%) than in the BMS (12.8%), or CABG (15.4%) arms of ERACI II.

Multivariable analysis
Multivariable logistic regression analysis of the combined ERACI II (n = 450) and III (n = 225) cohorts identified diabetes, hypercholesterolaemia, and treatment modality as significant independent predictors of MACCE at 1 year.10 Diabetes and hypercholesterolaemia but not treatment modality remained independent predictor of outcome at 3 years. Specifically, CABG vs. DES and BMS vs. DES were significant independent determinants of MACCE at 1 year, however this was not the case at 3 years. The apparent advantage in terms of MACCE for DES-treated patients over the CABG- and BMS-treated cohorts at 1 year was not evident after 3 years. Current smoking was an additional predictor of outcome at 3 years. Age, gender, mode of presentation, and number of coronary arteries involved did not predict MACCE (Table 4).


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  		Table 4 Multiple variable analysis of factors influencing incidence of MACCE at 3 years

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Study limitations
 Conclusion
 Appendix
 References
 
In this prospective multi-center non-randomized registry study, multivessel PCI with DES in ERACI III conferred early clinical benefit (30 day and 1 year outcomes) relative to a strategy of PCI with BMS or CABG in the earlier ERACI II trial. The advantage for DES over BMS in terms of MACCE at 1 year narrowed, but remained significant at 3 years on univariate analysis. After correction for confounders by multivariable analysis, however, the difference between PCI treatment strategies was not a significant determinant of MACCE (Table 4). A non-significant trend towards more deaths and non-fatal AMIs in the DES cohort and convergence in the relative risk of TVR between PCI groups may underlie the loss in initial advantage. Incidence of the composite of death or non-fatal AMI was similar between PCI strategies at 1 year, however, had occurred more frequently in the DES cohort by 3 years (10.2 vs. 6.2% for BMS; P = 0.08). Higher TVR rates in the BMS group therefore did not translate into an increased incidence of death or AMI.

Rates of MACCE were significantly lower in the DES cohort than the CABG arm at 30 days and 1 year. By 3 years, however, both cohorts had identical incidence of MACCE. Late occurrence of AMI and greater TVR resulted in a relative increase in MACCE in the DES arm.

Randomized studies and pooled analyses of randomized trials demonstrate comparable incidence of death, AMI, and stroke in patients treated with BMS and those undergoing CABG despite lower TVR rates in the CABG cohort.1–8,12,13 However, outcome among diabetics treated with PCI has been consistently worse than non-diabetics5,6,12 Multivariable logistic regression analysis in the present study identified diabetes mellitus as an independent predictor of 3-year MACCE, which is consistent with the results of ARTS I and II.9,12

Lower TVR rates associated with DES placement have prompted a re-evaluation of a PCI strategy to treat multivessel disease in diabetic patients. One-year results from ARTS II, ERACI III, and single-center registries were promising.9–11 Indeed, rates of TVR associated with DES were lower than historical BMS controls. However, comparative data beyond 1 year, which evaluates alternative revascularization strategies in diabetics, is currently unavailable. Here, we report 3-year clinical outcomes associated with DES, BMS, and CABG treatment strategies in a diabetic subpopulation.

When compared with non-diabetics, the incidence of MACCE and death or non-fatal AMI was significantly higher in the DM population. Rates of TVR were also higher though failed to reach statistical significance (Table 3). When stratified by treatment modality, MACCE rates among diabetics were not significantly different among DES, BMS, or CABG groups. Of the components of MACCE, TVR was the only one that differed significantly across the three arms: DES (21.3%), BMS (38.5%), and CABG (15.4%), P = 0.048.

Three years after the index procedure, stent thrombosis had occurred in 4.4% (10/225) of DES patients and 1.3% (3/225) in the BMS arm. Consistent with recent reports, LST in our cohort (nine patients with DES) was strongly associated with discontinuation of dual anti-platelet therapy.17–21 The extent to which variable platelet response to aspirin and/or clopidogrel adds to the risk of stent thrombosis, despite ongoing therapy, remains to be established.23 Mortality associated with LST in ERACI III was 44.4%. In the BASKET LATE trial, LST carried four times higher risk of cardiac death and MI vs. non-thrombosis-related events.24

To facilitate comparison with other trials, stent thrombosis after 3 years was re-adjudicated applying the new ARC definition.22 Among patients treated with BMS in ERACI II, there were three acute cases of stent thrombosis. These events met the criteria for definite stent thrombosis. Among patients treated with DES in ERACI III, there was one acute, three subacute, four late, and two very late cases of stent thrombosis. Of these cases, six met the criteria for definite stent thrombosis, two for probable stent thrombosis, and two for possible stent thrombosis cases.

Animal and post-mortem human studies indicate that delayed healing and endothelial dysfunction may occur frequently following DES placement.25,26 Moreover, presence of incomplete neointimal coverage following DES has been confirmed by angioscopy.27 Thus, it may be that DES will remain prone to thrombosis until full coverage with functional endothelium is achieved.28

A recent report from the Thoraxcenter observed a lack of initial benefit with SES over BMS in diabetics at the second year of follow-up.29 The incidence of LST was significantly higher in those who received SES when compared with BMS (4.4 vs. 0.8%, P = 0.015). A large French Registry30 also determined that insulin-dependent diabetics treated with SES had an unacceptable (6.0%) rate of stent thrombosis, which translated into a higher incidence of death and myocardial infarction. Number of LST in our study preclude meaningful observations regarding an interaction with diabetes.

Efficacy and safety of DES use in high-risk populations remains to be established. Late catch-up in the incidence of MACCE observed in the DES cohort in our study is concerning. Higher rates of LST may be a contributing factor. Furthermore, relative benefit of DES use to treat diabetics with multivessel CAD remains in question. Although DES use among diabetics was associated with lower TVR than BMS, the difference was not statistically significant and concerns regarding an association with LST remain. MACCE rates did not differ significantly across treatment group in our diabetic subpopulation, however, the non-randomized nature of our study and small number of diabetics limit the conclusions that can be drawn. Long-term results of ongoing randomized trials such as FREEDOM and SYNTAX will clarify the role of DES in this particularly high-risk patient cohort.31

Finally, continuous need for TVR inbetween 4 years in the DES cohort was mainly related to progression of disease in non-target lesions or non-target vessels. This supports the hypothesis that the major benefit derived from DES use is suppression of neointimal hyperplasia, which is sustained at 3 years of follow-up.


   Study limitations
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
Conclusion
 Appendix
 References
 
As previously discussed, ERACI III is a non-randomized prospectively collected registry and it is well known that a randomized comparison is the most appropriate design to evaluate medical or surgical procedures in clinical practice. However, well-designed and controlled registries have also proven useful in evaluating revascularization techniques.

Secondly, the study was not performed with contemporary percutaneous coronary interventional equipment, techniques, and medication and the three treatment arms were not enrolled concurrently. Periprocedural and post-discharge antiplatelet and lipid-lowering therapies are now prescribed more rigorously and at higher doses and did vary between study groups. Differences however favoured the DES cohort if any of the 3 study arms.

Our stent thrombosis definition included patients without angiographically proven thrombosis. However, this endpoint was pre-specified and defined in the protocol and all events were analysed by a blinded Safety Committee. The ARC definition of stent thrombosis was also applied to facilitate comparison across studies.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusion
Appendix
 References
 
In this prospective multicenter registry, study of high-risk patients with multivessel coronary artery disease who underwent revascularization, the initial advantage for PCI with DES over CABG observed at 1 year was lost by 3 years of follow-up. Furthermore, despite a continued lower incidence of MACCE, initial advantage over BMS appeared to decrease with time. MACCE rates among diabetics were particularly high. Finally, LST occurred most frequently among patients treated with DES.

Conflict of interest: none declared.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusion
 Appendix
References
 
The following are the participants in ERACI III trial.

Steering Committee: Alfredo E. Rodriguez, Liliana Grinfeld, Daniel Berrocal, Igor Palacios, William O. Neill.

Safety and Ethics Committee: Alberto Lambierto, Jorge Pascual, Gustavo Poggi, Baldi Julio.

Clinical Events Committee: Miguel Russo Felsen, Valeria Curotto, Fernando Guerrico.

Coordinating Center and Statistics: CECI (Centro de Estudios en Cardiologia Intervencionista) Alfredo Rodriguez, Andrew O. Maree, Carlos Fernandez Pereira, Alfredo M. Rodriguez-Granillo.

Participating Hospitals and Clinical Investigators (numbers in parenthesis indicate the number of patients randomized) Otamendi Hospital, Buenos Aires (138) Alfredo E. Rodriguez, Carlos Fernandez-Pereira, Cesar F. Vigo, Curotto Valeria Sanatorio Las Lomas, San Isidro, Buenos Aires (17) Alfredo E. Rodriguez, Maximo Rodriguez-Alemparte, Juan Mieres, Clinica IMA, Adrogue, Buenos Aires (13) Carlos Fernandez-Pereira, Carlos Mauvecin, Hospital Italiano, Buenos Aires (31) Liliana Grinfeld, Daniel Berrocal, Jorge Gabay, Hospital Español, La Plata, Buenos Aires (26) Liliana Grinfeld, Diego Grinfeld.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Study limitations
 Conclusion
 Appendix
 References
 

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A. J. Rastan, E. Boudriot, V. Falk, A. P. Kappetein, M. A. Borger, P. W. Serruys, G. Schuler, and F. W. Mohr
Frequency and pattern of de-novo three-vessel and left main coronary artery disease; insights from single center enrolment in the SYNTAX study
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