Long-Term Comparative Analysis From an All-Comer Cohort of Coronary Patients Treated Using First- and Second-Generation Drug-Eluting Stents

Abstract: Aims. Second-generation drug eluting stent (DES) implantation gradually replaced the first-generation DES in clinical practice. Whether the new DESs in use differ from one another, in terms of clinical outcomes, is still not known. We explored potential differences among DESs. Methods and Results. We followed 9584 consecutive patients undergoing percutaneous coronary intervention at our institution (2004–2012; mean follow-up, 2.8 years). Patients treated with bare-metal stent (BMS; n = 5599; 58.4%) were compared to 3985 DES counterparts (41.5%). The sirolimus-eluting stent (SES) served as the prototype for comparison to other DES types, using propensity matching. The primary outcome was a composite endpoint of total mortality, myocardial infarction, and clinically driven target vessel revascularization or coronary artery bypass graft. At 3 years, the composite endpoint was significantly lower in the DES vs BMS group (17.9% vs 25.3%; P<.001). Comparisons between SES and each of the five other stent types yielded no significant differences for the primary composite endpoint: SES vs paclitaxel-eluting stent (n = 350 pairs; 18.1% vs 17.7%; P=.70); vs zotarolimus-eluting stent (n = 474 pairs; 21.8% vs 23.2%; P=.35); vs Resolute zotarolimus-eluting stent (n = 434 pairs; 16.9% vs 11.7%; P=.70); vs everolimus-eluting stent (n = 824 pairs; 14.2% vs 14.1%; P=.60); and vs biolimus-eluting stent (n = 117 pairs 13.7% vs 13.4%; P=.60). Conclusions. Cardiac prognosis did not differ between sirolimus and other DES types. The use of DES was associated with better clinical outcomes compared to BMS.

J INVASIVE CARDIOL 2014;26(8):378-384

Key words: drug-eluting stent, bare-metal stent, sirolimus-eluting stent

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Since the introduction of the drug-eluting stent (DES), the incidence of stent restenosis and the need for target vessel revascularization (TVR) have decreased dramatically.^1,2 However, late stent thrombosis events have been of great concern with use of the first generation of DES platforms,³ and a better safety profile has been reported with the newer second-generation DES versions.⁴ Nonetheless, the long-term comparative safety and effectiveness of the different stents in clinical use still require exploration.

The aim of this study was to establish potential differences in safety and efficacy among the different stents used in our clinical practice. Outcomes for patients treated with bare-metal stent (BMS) implantation were initially compared to those of their DES-receiving counterparts using propensity score–matching analysis. Then, the different DES types in use over the years were compared to outcomes with a sirolimus-eluting stent (SES) (Cypher, Cordis Corporation), the first DES in use in clinical practice. Because not all DES types are alike in terms of metallic platform properties, polymer coating, and anti-proliferative agent, we aimed to explore potential differences among the patient groups depending on stent type.

Methods

Study population. A cohort of all-comer consecutive patients with coronary artery disease (n = 9584), treated with angioplasty and stent implantation in the two hospitals that comprise the Rabin Medical Center between 2004 and 2012 were included in our analysis. 

For our first analysis (ie, DES vs BMS), patients were divided into two cohorts according to the type of stent implanted. A comparison between these two groups for demographic, clinical, laboratory, and echocardiographic characteristics, as well as angiographic findings was performed. Then, SES was taken as the prototype of the DES group and compared, using propensity score matching, to BMS and to each of several different DES types: paclitaxel-eluting stent (PES) (Taxus, Boston Scientific), zotarolimus-eluting stent (ZES) (Endeavor Sprint, Medtronic), ZES-R (Resolute, Medtronic), everolimus-eluting stent (EES) (Xience V Prime, Abbott Vascular or Promus, Boston Scientific), and biolimus-eluting stent (BES) (Bio-Matrix, Biosensors Interventional Technologies, Ltd or Nobori, Terumo Corporation).

The composite endpoint of all-cause mortality, myocardial infarction (MI), need for coronary artery bypass graft (CABG), and/or need for target vessel revascularization (TVR), ie, major adverse cardiac event (MACE) rate was tracked and verified, and event rates were calculated. MACE was the primary endpoint of our study; additional endpoints were all-cause mortality, need for CABG or TVR, and death or MI. 

The policy for DES implantation in Israel has changed over time. After introduction of the DES in Israel in 2004, guidelines and reimbursement rules were formulated by the Israel Heart Society and the Ministry of Health. A DES is to be used preferentially in proximal main vessels, diabetic patients, long lesions, stent restenosis, and chronic total occlusions, and among patients who can tolerate long-term intake of dual-antiplatelet medications. Since 2010, the decision about whether to implant a DES or a BMS relies on clinician criteria, based on clinical data, angiographic characteristics of the treated lesion, and reimbursement policy.

All patients were initially prescribed lifelong aspirin and clopidogrel for at least 3 months after BMS implantation and for 3-12 months following DES implantation. Since 2007, all patients with a DES have been prescribed clopidogrel for at least 1 year after implantation and treated with percutaneous coronary intervention (PCI) following an acute coronary syndrome (ACS) event, regardless of the stent type implanted.

All data regarding the index and subsequent procedures and clinical and echocardiographic data were extracted and processed from each patient’s electronic record. Demographic data and death dates were obtained from the medical center’s demographic information system, which is linked to the Israel Ministry of the Interior system and the General Sick Fund (health organization) data warehouse. The accuracy of the mortality data was verified with the Israel Central Bureau of Statistics. All data regarding prior and subsequent hospitalizations was retrieved from the medical center’s data warehouse. 

Data collection was approved by the hospital ethics committee in compliance with the declaration of Helsinki, with a waiver for the need for individual informed consent.

Definitions. All patients with at least 1 DES implanted in the index PCI were included in the DES group. A total of 6784 patients (70.7% of the cohort) had echocardiographic data prior to the PCI date. All patients with a left ventricular ejection fraction of ≤40% were flagged as “moderate to severe left ventricular dysfunction.”

All patients who arrived at the PCI laboratory after resuscitation or with cardiogenic shock were flagged as sustaining a “critical state.” The following clinical definition of myocardial infarction was used for the present study: patients with chest discomfort or other ischemic symptoms that develop ST elevation in two contiguous leads were diagnosed as ST elevation MI (STEMI) and patients without ST-segment elevation at presentation were designated as having a non-ST elevation MI (NSTEMI) if they presented with typical signs and symptoms of myocardial ischemia combined with elevated cardiac troponin values; those without elevated values of cardiac troponin received the diagnosis of unstable angina. PCIs for acute/recent MI or acute coronary syndrome (ACS) were defined according to the indication as noted on the electronic record. Primary PCI for STEMI was defined by the prerequisites for inclusion in the STEMI registry: within 12 hours of symptoms onset, without prior thrombolysis. The number of vessels with coronary disease was determined by analyzing the diagnostic catheterization report, with a designation of significant disease when >50% stenosis was noted. Treated territories were defined by analyzing the angioplasty report. For each territory, PCI sites were counted (eg, proximal left anterior descending [LAD] and mid-LAD, first or second diagonal branch) and a simple score of sites/territories, termed “complexity,” was defined, which reflects the number of lesions treated per territory. Whenever treatment involved at least one ostial or proximal main vessel or left main, the procedure was flagged as “proximal main vessel.” Total stent length and “stent length/lesion” were calculated for each procedure. Repeat hospitalization was categorized as MI, ACS, or CABG according to the main relevant diagnosis. TVR was defined as a subsequent PCI to the same vessel as the index PCI.

Statistical methods. Statistical analysis was performed using SPSS version 16 (SPSS). All tests were two tailed, and a P-value <.05 was considered significant. Baseline parameters were compared between DES and BMS patient groups using the Student’s t-test for continuous variables and the Chi-square test for categorical variables.

Propensity scores were computed using multivariable logistic regression models, where SES was the independent variable and all pre-PCI and intraprocedural variables were used as covariates. Using this method, SES was compared with BMS and with each of the different types of DES: PES, ZES, ZES-R, EES, and BES.

Because non-parsimony is encouraged in the construction of the propensity score,⁵ we included all variables without using a pre-analysis to choose any relevant ones. The variables used were age, sex, diabetes mellitus, hypertension, prior heart failure, smoking, prior creatinine, prior hemoglobin, prior platelet count, prior use of anticoagulation, prior CABG, known moderate to severe LV dysfunction, prior dementia, prior malignancy, PCI for ACS, severe state, number of diseased vessels, territories treated, complexity score, treatment of proximal main vessel, and total stent length. 

Cases were then subclassified by quintiles of the propensity score, both for checking the balancing effect of the score and for the initial outcome analysis of the entire cohort. The balancing effect on the variables used for the propensity score was checked by logistic or linear regression (according to the variable) with each variable as the dependent variable and DES vs BMS and dummy-coded strata variables as covariates. Survival analyses were performed using the Kaplan-Meier method with stratified analysis of the log-rank statistic by quintiles of the propensity score.

Propensity score matching analysis. Propensity score matching was performed using a “closest neighbor, greedy” algorithm, attempting to match each SES patient with a BMS or a PES, ZES, ZES-R, EES, or BES patient (for each one of the analyses performed), with the closest propensity score and with a maximal difference of less than 0.25 times the standard deviation of the scores. Each pair was used once, and unpaired cases were not used in further analyses. Survival analysis was performed with the Kaplan-Meier method. Multivariate Cox regression analysis was performed with stent type, propensity score, and any unbalanced variables as covariates. One-way sensitivity analysis was performed to assess the possible effect of an unknown confounder.⁶

Results

The entire cohort consisted of 9584 consecutive patients; 3985 patients (41.5%) had DES implantation and 5599 patients (58.4%) had BMS. The minimal and maximal follow-up times were 6 months and 3 years, respectively. Mean and median follow-up times were 2.8 years and 3 years, respectively. 

Different DES types were used at the following frequencies during the study period: 37.5% SES, 8.7% PES, 11.7% ZES, 10.6% ZES-R, 20.1% EES, and 3.0% BES. A total of 8.1% of the patients received two or more different DES types, and this group was included in the unmatched comparison between DES and BMS, but excluded from the comparison of the SES vs the other DES types. The relative distribution of the different stents in use over time is depicted in Figure 1. 

DES versus BMS. In the unmatched group of patients (n = 9584) distinguished by stent type, BMS-implanted patients were more likely to be older, suffer from prior congestive heart failure, dementia, or malignancy, and have lower values of creatinine clearance compared to DES-treated patients (Table 1). ACS cases and/or severely decompensated patients were more frequently treated with BMS. In contrast, patients with diabetes mellitus were more often treated with a DES (Table 1). The DES was the more common choice for revascularization of proximal LAD, left main, multivessel PCI, and complex angioplasties. 

The MACE endpoint was significantly lower in the DES group compared to the BMS group (17.9% vs 25.3%, respectively; P<.001). In the initial follow-up period, a significant mortality advantage was noted in favor of the DES group compared to the BMS group (2.1% vs 5.3% at 6-month follow-up [P<.001] and 7.6% vs 13.3% at 3-year follow-up [P<.001], respectively). The composite endpoint of death or MI was also substantially higher among BMS-treated vs DES-treated patients (16.1% vs 9.2%, respectively; P<.001). No significant differences between the two groups were found in the rate of need for CABG (2.3% in the DES group vs 2.8% in the BMS group; P=.07). However, the rates of the composite endpoint of need for TVR or CABG were higher in the BMS group (11.7% vs 10.3%; P=.01).

Propensity-matched DES comparisons. Within each group, a propensity score was used, for matching between the BMS and SES groups (n = 1496 patients in each), and for comparison between SES and each of the other DES counterpart groups. The scores were overall balanced between groups, with the vast majority of baseline clinical, laboratory, and angiographic characteristics showing no differences (see Supplementary Table 1 for subgroup demographics and angiographic data).

In comparison to the SES group, death rates were substantially higher in the BMS group throughout the follow-up (hazard ratio [HR] = 0.6; 95% confidence interval [CI], 0.5-0.7; P<.001) (Figure 2). Similarly, rates of death or MI and clinically driven CABG or need for TVR were significantly higher in BMS-treated patients compared to their SES counterparts (HR = 0.6; 95% CI, 0.5-0.8; P<.001; and HR = 0.8; 95% CI, 0.6-0.95; P<.01, respectively) (Figure 2). In concordance, the MACE rate was significantly lower in the SES group compared to the BMS group, indicating a persistent benefit of DES over BMS through time (HR = 0.7; 95% CI, 0.6-0.8; P<.001; Figure 2).

SES versus other DES types. The propensity-matched cohort was then used for the comparison of SES vs PES (n = 350 in each group), SES vs ZES (n = 474 pairs), SES vs ZES-R (n = 434 pairs), SES vs EES (n = 824 pairs), and SES vs BES (n = 117 pairs) (Table 1, Supplementary Table 1). The comparison between SES and each of the five other well-matched DES subgroups did not yield significant differences for any of the analyzed endpoints (Table 2; Figure 3). During a follow-up period of 3 years, clinical outcomes of all-cause deaths, death or MI, TVR, and TVR or need for CABG and MACE were all similar for each of the DES-delineated subgroups. Thus, according to our experience, SES, PES, ZES, ZES-R, EES, and BES were each associated with similar clinical outcomes for all analyzed endpoints.

Discussion

To the best of our knowledge, our study is the largest single-center (two-hospital) registry of consecutive coronary patients treated for expanded indications, comparing DES vs BMS and first- and second-generation DES types with a long follow-up. 

The main finding of the current investigation is the lack of significant differences between the various DES-treated subgroups in comparison to SES. This absence of difference held true for all of the studied endpoints. Among our patients, we found no added prognostic benefit in favor of the use of an additional first-generation or newer second-generation DES over SES. Our findings seem to be robust because the DES subgroups were very well balanced. Nonetheless, our study does not refute the potential benefits of the second-generation DES types over older DES versions. However, according to our experience, the clinical merits of such a presumed benefit do not manifest prognostically or clinically as a reduction of the hardest cardiovascular endpoints over time.

Several studies have demonstrated the superiority of DES over BMS in terms of efficacy.^1,2,4 Here, we have confirmed and reinforced our prior findings that the use of DES improves long-term outcomes by reducing rates of all-cause mortality, need for TVR or CABG, and MACE, compared to BMS.^7-9  The rate of TVR-CABG in our cohort of patients should be considered throughout the time elapsed from the PCI. The differences, in our experience, in overall TVR between DES and BMS at 1, 2 and 3 years are 3.2%, 2.1%, and 1.6%, respectively. We believe that the main reason for such narrower differences is due to the lower than expected TVR-CABG rate in our BMS group, and this is a consistent finding in our cohort. Mauri et al from the Massachusetts Stent Registry reported a rate of TVR at 2 years of 16.8% vs 11.0% using BMS vs DES (P=.01).¹⁰ We also believe that the lack of profound difference in the surgical TVR-CABG endpoint between DES and BMS is due to the practice of placing DES or even drug-eluting balloon in case of BMS restenosis without referring these patients, in most cases, to CABG surgery. The prognostic advantages of DES over BMS were evident in both the unmatched and the propensity-matched comparisons. 

The main hurdle associated with a first-generation DES (eg, Cypher and Taxus) was the excess of late events of stent thrombosis and the need for long-term dual-antiplatelet medications. The newer-generation DES has thinner struts formed by cobalt-chromium instead of stainless-steel and more biocompatible or even biodegradable polymers.¹¹ These features should reduce adverse neointimal response, resulting in diminished inflammatory response and a more rapid reendothelialization.¹² 

In the SPIRIT II trial, a randomized multicenter and single-blind study, EES (n = 223) was prospectively compared with PES (n = 77). Lower rates of cardiac mortality and MACE were registered in the EES vs the PES group at 5 years of follow-up.¹³ Analogous findings were reported in the single-center randomized COMPARE trial.¹⁴ A pooled analysis from the SPIRIT II, SPIRIT III, SPIRIT IV, and COMPARE trials confirmed these findings in both stable and ACS patients.¹⁵ In our experience, the comparison between EES (n = 824) and SES (n = 824) did not yield significant differences for any of the studied outcomes, including the composite endpoint of MACE.

A comparative analysis of all-comer patients stratified by stent type was performed based on data from the SCAAR registry. In this trial, two types of second-generation DES (ZES-R, EES Xience V/Xience Prime and Promus) in comparison with SES, PES, and ZES were associated with a 38% lower risk of restenosis, 43% lower risk of STEMI, and 23% lower risk of death.¹⁶

On the other hand, the SORT OUT III trial evaluated the efficacy and safety of ZES vs SES in patients with either stable CAD or ACS. In this multicenter, single-blind trial, at 9 months and 18 months of follow-up, the composite endpoint of MACE occurred in a higher proportion of patients treated with the ZES than in those treated with the SES (6% vs 3%; HR = 2.15; P=.01 and 10% vs 5%; HR = 2.19; P<.001, respectively).¹⁷

The same group of investigators randomized 2774 all-comer patients with CAD to angioplasty using either SES or EES; in that study, similar to our findings, no significant differences in the rates of MACE between the two groups were identified at 9, 18, and 24 months of follow-up. Remarkably, rates of definite stent thrombosis were higher in the SES group.^18,19

From the present findings and in conjunction with the above-presented published data comparing the DES types, we can classify differences between the various types and “generations” of DES as inconsistent or robust. The main benefits provided by a newer-generation DES might be the lower incidence of late stent thrombosis and the relatively shorter regimen of dual-antiplatelet treatment required in comparison with SES and PES.²⁰ However, whether treatment with a second-generation DES reduces the major cardiovascular endpoints is still a topic of debate.

Study strengths and limitations. We report the experience of a single center. However, this is a large tertiary center with homogeneity of policy, practices, and standards. We chose an all-comer cohort of patients, reflecting our real-world experience. Nonetheless, our study is not a randomized prospective trial; thus, we cannot totally exclude the possibility that an unmeasured confounding factor could have influenced the observed mortality data and that a selection bias concerning the mode of stent use (ie, DES vs BMS) could have played a role in the outcomes. We approached this potential bias by using a propensity-matching scheme that balanced all known confounders. 

In the unmatched comparison, we found a prognostic advantage in patients treated with DES over those treated with BMS. This finding should be interpreted cautiously due to the heterogeneity between the compared groups. However, in the well-matched comparison between SES vs BMS patients, this advantage persisted.  

We could not present data regarding stent thrombosis because the definitions have evolved over the years and reporting in the medical record was not homogeneous. 

Lastly, our study was self-funded, without any industry involvement.

Conclusion

From the analysis of this large cohort of our single-center all-comer coronary patients, DES implantation with either first-generation or second-generation stent showed a significant reduction in the rates of death, MI, and need for TVR in comparison to BMS. No further benefits in the studied outcomes were achieved with the use of a newer second-generation DES in comparison with the first-generation SES. The study results support the widespread use of DES for the revascularization of coronary artery disease, whenever clinically indicated. 

References

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From the Interventional Cardiology Department – Beilinson and Hasharon Hospitals – Rabin Medical Center and the “Sackler” Faculty of Medicine Tel-Aviv University, Israel.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 30, 2013, provisional acceptance given November 22, 2013, final version accepted January 29, 2014.

Address for correspondence:  Ran Kornowski MD, FACC, FESC, Head of Cardiology Department, Beilinson Hospital – Rabin Medical Center, Jabotinski St. 39, Petach Tikva, 39100, Israel. Email: ran.kornowski@gmail.com