doi: 10.1161/CIRCINTERVENTIONS.108.769042
Original Articles |
Drug-Eluting Stents Versus Bare-Metal Stents for Off-Label Indications
A Propensity Score–Matched Outcome Study
From the Section of Public Health and Health Policy (D.A., R.S., J.P.P.) and Robertson Centre for Biostatistics (A.M.), University of Glasgow; Western Infirmary (K.G.O.); Glasgow Royal Infirmary (H.E.); Victoria Infirmary (R.J.N.), Glasgow; Edinburgh Royal Infirmary (A.D.F.); Western General Hospital (I.R.S.), Edinburgh; Aberdeen Royal Infirmary (K.P.J.), Aberdeen; and Monklands Hospital (A.C.H.P.), Airdrie, Lanarkshire, United Kingdom.
Correspondence to Jill Pell, MD, FESC, Section of Public Health and Health Policy, University of Glasgow, 1 Lilybank Gardens, Glasgow G12 8RZ, UK. E-mail j.pell{at}clinmed.gla.ac.uk
Received January 31, 2008; accepted May 15, 2008.
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Abstract |
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Background— The US Food and Drug Administration recently concluded that data on off-label drug-eluting stent (DES) safety are limited. However, in actual clinical practice, DES are often used for off-label indications, and observational studies demonstrate that complications are higher when compared with on-label use. We aimed to determine whether clinical outcomes differ after DES and bare-metal stent implantation in a patient cohort defined by DES off-label indications.
Methods and Results— We used the national revascularization registry in Scotland to identify patients who underwent coronary stenting for an off-label indication between January 2003 and September 2005. Individual-level linkage to comprehensive national admission and death databases was used to ascertain the end points of death, myocardial infarction, and target-vessel revascularization. We calculated propensity scores on the basis of clinical, demographic, and angiographic variables and matched DES to bare-metal stents on a 1:1 basis. The final study population consisted of 1642 patients, well matched for important covariables at baseline. Event-free survival was calculated over 24 months with the Kaplan-Meier method. All-cause death was more common after bare-metal stent implantation during follow-up (7.7% versus 6.6%; hazard ratio 0.63; 95% confidence interval, 0.40 to 0.99; P=0.04). No difference in the rates of myocardial infarction were noted (7.3% versus 7.5%; hazard ratio 1.02; 95% confidence interval, 0.69 to 1.54; P=0.92). Target-vessel revascularization was reduced in patients treated with DES (13.9% versus 10.7%; hazard ratio 0.67; 95% confidence interval, 0.49 to 0.93; P=0.02).
Conclusions— At 24 months, patients treated with DES for off-label indications had lower rates of death and target-vessel revascularization and similar rates of myocardial infarction, as compared with patients treated with bare-metal stents.
Key Words: angioplasty • coronary disease • stents • myocardial infarction • stents, drug-eluting
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Introduction |
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Drug-eluting stents (DES) were licensed for use in the United States and Europe on the basis of evidence of a reduced risk of restenosis and repeat revascularization obtained from randomized controlled trials (RCTs) conducted in selected patients.1–4 The indications for DES use approved by the US Food and Drug Administration were derived from the inclusion criteria from the pivotal trials. They comprise a de novo lesion
30 mm in a native artery, with a diameter of 2.5 mm to 3.5 mm inclusive for the sirolimus-eluting stent, and 28 mm in a native artery, with a diameter of 2.5 mm to 3.75 mm inclusive for the paclitaxel-eluting stent.3,4 Indications that fulfill the US Food and Drug Administration criteria are referred to as on label. Recent pooled analyses have confirmed sustained clinical efficacy and acceptable safety profiles with up to 4 years of follow-up among patients with largely on-label indications.5–9 In clinical practice, DES use during percutaneous coronary intervention (PCI) has extended beyond on-label indications to include many patients for whom evidence of safety is lacking. Off-label indications include patients with multiple lesions, bypass graft or bifurcation lesions, and those treated in the context of myocardial infarction (MI).
Clinical Perspective see p 45
Several observational studies of unselected patients have been published; some have raised concerns about the safety of DES and, in particular, the risk of late stent thrombosis. Daemens et al10 demonstrated a linear increase in stent thrombosis after DES insertion at a rate of 0.6% per annum between 30 days and 3 years. Both Basel Stent Kosten EffeKtivitäts Trial-Late Clinical Events (BASKET-LATE) and published research from the Swedish Coronary Angiography and Angioplasty registry (SCAAR) indicated an increase in MI and death beyond 6 months of follow-up when patients treated with DES were compared with those treated with bare-metal stents (BMS).11,12 However, an updated analysis (as yet unpublished) of the SCAAR data incorporating more patients and longer follow-up did not find an increase in death or MI with DES compared with BMS.13 Jensen et al14 demonstrated a small increase in late stent thrombosis among DES-treated patients and a corresponding increase in late MI. In contrast and more recently, Tu et al15 demonstrated no difference in MI in an unselected group after 2 years of follow-up, whereas rate of death at 3 years was lower for DES-treated patients.
Clinical predictors of stent thrombosis after DES implantation include several factors that are considered off label.14,16 This may explain why DES patients treated for off-label indications had a higher risk of MI and stent thrombosis than did those with on-label indications.17,18 However, data comparing DES and BMS specifically in off-label indications are limited. Therefore, we aimed to analyze medium-term clinical outcomes among a cohort of DES patients treated for off-label indications matched to a contemporary BMS control group.
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Methods |
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Data Sources and Clinical Outcomes
Since 1997, the Scottish Coronary Revascularization Register has collected detailed information prospectively on all PCIs performed in Scotland (population 5.1 million), including demographic information, disease severity, comorbidity, past medical history, and procedural details. Data entry is completed by a combination of clinical and administrative staff according to a predefined set of standard data definitions and centrally collated to form the Scottish register. Data are annually validated for completeness and consistency. Informed consent to collate data are obtained from patients before coronary revascularization. We obtained approval from the Scottish Privacy Advisory Committee to undertake patient-level linkage to routine databases in order to provide clinical outcomes.
The Scottish Morbidity Record collects data on all admissions to Scottish acute hospitals. The principal diagnosis is recorded according to the International Classification of Diseases (10th revision), and the procedure is recorded according to the Office for Population, Census and Surveys (4th revision) coding system; both are subject to regular quality assurance checks. The General Register Office collates information from all death certificates issued in Scotland, regardless of whether the person died in the community or in hospital. The cause of death is also coded according to the International Classification of Diseases classification. Ascertainment of outcomes via linkage to Scottish routine databases is well established and has been shown to be as complete and accurate as prospective follow-up.19 Thus, through the use of the Scottish Coronary Revascularization Registry and linked data, we defined 3 key clinical outcomes: MI, all-cause death, and target-vessel revascularization (TVR). MI was defined as admission to hospital with, or death from, MI (International Classification of Diseases codes I21 and I22). TVR was defined as subsequent coronary artery bypass grafting or repeat PCI on a vessel treated during the index procedure. Clinical outcome data were available up to June 30, 2006.
Study Population
Patients were considered for inclusion in the study if they underwent a PCI between January 2003 and September 2005 inclusive, during which they had 
1 stent inserted for 1 off-label indication. In keeping with the exclusion criteria from the pivotal trials,1,2 we defined off-label indications as acute MI (non-ST or ST elevation), chronic renal impairment or severe left ventricular dysfunction, stented length >30 mm, stent diameter <2.5 mm or >3.75 mm, PCI of >1 lesion, and intervention to the left main coronary artery, bypass graft, chronic total occlusion, restenosis, or bifurcation lesion. We excluded patients in whom both BMS and DES were used during the index procedure and patients who could not be linked to the outcome data sets.
Definitions
Type of DES and BMS was ascertained for descriptive purposes. BMS were characterized as either relatively thick-strut (0.1 mm) stainless steel stents or as thin-strut (<0.1 mm) or cobalt-chromium stents. Chronic renal impairment was defined as a serum creatinine >2.25 mg/dL or renal replacement therapy. Left ventricular dysfunction was defined as mild-moderate (ejection fraction 30% to 50%) or severe (ejection fraction <30%). Material deprivation was defined by the Carstairs’ index of deprivation,20 calculated by postcode sector according to 2001 census data for social class, overcrowding, car ownership, and unemployment.
Statistical Analysis
Among the patients who fulfilled off-label criteria, the baseline clinical and demographic characteristics varied significantly between DES- and BMS-treated patients (Table 1). To allow meaningful analysis of clinical outcomes, propensity scores21 (conditional probability) for receiving a DES rather than a BMS for each patient were calculated by using baseline covariates within a logistic regression model. A baseline model was defined and included demographic and clinical covariates selected a priori for entry if they were thought to influence both stent choice and outcome (MI, death, or TVR). Tables 1 and 2
list the factors that were included in the baseline propensity score model and include all factors that define off-label use. During the study period, DES were being adopted into clinical practice; therefore, a time variable (year of treatment) was entered into the propensity score model to avoid follow-up bias and ensure a comparable control group. Finally, because stent selection may have varied during the adoption of the device, all baseline covariates were allowed to interact with the time variable. Interaction terms were then individually tested within the baseline model and included in the final propensity score model if P<0.1. No significant collinearity was noted among covariates. The c-statistic for the final propensity score model was 0.89 indicating good discrimination, and the Hosmer-Lemeshow test was nonsignificant. Patients were then matched according to their individual propensity scores on a 1:1 "nearest neighbor" basis. A caliper width of 0.01 was predefined to ensure close matching of DES to BMS controls. Patients in either group who could not be matched on these criteria were not included in the final analysis.
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Categorical data were compared with the
2 test (unmatched) or McNemar test (matched). Continuous data were compared with the 2-sample t test (unmatched) or paired 2-sample t test (matched) and expressed as mean (SD). The cumulative probability of outcome-free survival was determined separately for death, MI, and TVR for matched DES and BMS cohorts with the Kaplan-Meier product-limit estimate. Follow-up was censored on June 30, 2006, or at 24 months. Clinical outcome rates were derived from the Kaplan-Meier analyses. Probability statistics and hazard ratios comparing outcome for matched DES and BMS were derived from Cox regression analyses stratified by matched pairs to account for the nonindependence of groups, with type of stent as the sole predictor variable. The proportional hazards assumption was checked by using the time varying coefficients method.22 A probability value of <0.05 was taken to indicate statistical significance. Propensity score matching was conducted with S-Plus for Windows v7.0 software (Insightful Co, Seattle, Wash), whereas all other analyses were performed with SPSS for Windows v15.0 software (SPSS Inc, Chicago, Ill). The authors had full access to the data and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Over the study period, 11 317 patients had PCI with
1 stent inserted. We excluded 639 patients (5.6%) who received both a DES and BMS during the same procedure and 332 patients (2.9%) who could not be linked to the outcome data sets. Of the remaining 10 346 patients, 7499 patients (72.5%) fulfilled the off-label criteria and were thus included in the propensity score calculation. Of the patients defined as off label, 1105 patients (14.7%) received a DES, and 6394 patients (85.3%) received a BMS. Marked differences in baseline clinical variables were noted between the BMS and DES groups. Table 1 summarizes the differences in patient characteristics for those treated off label before propensity score matching. Propensity score matching was successful in ensuring comparability of baseline clinical, demographic, and angiographic covariates (Table 2). No evidence of nonproportional hazards were found (mortality model, P=0.95; MI model, P=0.15). The final study population contained 821 well-matched pairs. Of the final DES cohort, 513 patients received the paclitaxel-eluting Taxus stent (Boston Scientific Corp, Natlick, Mass), 275 patients received the sirolimus-eluting Cypher stent (Cordis Corp, Miami, Fla), and 33 patients received different DES for separate lesions within the same procedure. Of the BMS cohort, 78.6% received thin-strut or cobalt-chromium stents. We had follow-up data over a median of 16 months (range, 9 to 24 months). During follow-up, there were 89 deaths, 99 MIs (54 nonfatal and 45 fatal MIs), and 173 TVRs.
In the analysis of all-cause death, a higher overall fatality rate was observed among BMS-treated patients (Figure [A], Table 3). During the first 6 months, there was a higher rate of death among patients in the BMS group, but this was not statistically significant (4.1% versus 2.9%; P=0.11). Beyond 6 months, case-fatality rates were similar (3.6% versus 3.7%; P=0.21). Overall, the absolute difference between the groups was 1.1% (7.7% versus 6.6%; hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.40 to 0.99; P=0.04). No statistically significant difference in the rate of MI was noted during follow-up (Figure 1 [B], Table 3). MIs were numerically, though not statistically, more common after BMS implantation during the first 6 months of follow-up (4.8% versus 3.7%; P=0.31). MIs were less common from 6 months to the end of follow-up but were nonsignificantly more common in the DES group (2.5% versus 3.8%; P=0.17). At 24 months, the net effect was that rates of MI were similar (7.3% versus 7.5%; HR 1.02; 95% CI, 0.69 to 1.54; P=0.92). The rate of TVR was lower among DES-treated patients (Figure 1 [C], Table 3). This was apparent at 6 months (7.1% versus 4.8%; HR 0.66; 95% CI, 0.44 to 0.99; P=0.04) and sustained at 2 years of follow-up (13.9% versus 10.7%; HR 0.67; 95% CI, 0.49 to 0.93; P=0.02). The absolute difference between BMS and DES arms was therefore 3.2% at 2 years, equating to a number needed to treat of 31 patients to prevent 1 TVR.
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Discussion |
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In this study of off-label patients matched by propensity score, all-cause death was more common after BMS than DES implantation, and no difference was observed in the rates of MI. TVR was lower in patients treated with DES, with an absolute risk reduction of 3.2%. Observational studies have compared unselected cohorts of BMS and DES11,12,14,15 or outcomes in DES patients treated off label and on label.17,18 To date, 3 published studies have compared clinical outcomes between BMS and DES for off-label indications, though all were limited by the use of historical control groups.23–25 This study is unique in comparing clinical outcomes over 2 years after DES implantation with a contemporary BMS cohort in an off-label population.
Off-label use of DES is of great clinical importance. The recent US Food and Drug Administration advisory panel meeting raised concerns about off-label use of DES, as the RCT evidence in this area is sparse.26 In our unselected population, off-label indications accounted for 72% of all PCIs. Worldwide, this represents several hundred thousand interventions per year. This proportion is higher than that of most other studies of off-label use17,18,23 but was similar to that of Applegate et al,24 who used the same definition that included, for example, all patients with MI. The presence of thrombus may also be considered an off-label indication. We did not apply this as a separate entry criterion in our study, because all patients with thrombus also had other inclusion criteria (such as MI) and were thus already included in the off-label group.
Given DES use in such off-label patients has become commonplace after the rapid adoption of these devices, the finding of no significant difference in MI after 2 years of follow-up is therefore reassuring. Indeed, for the outcome of all-cause death, there was a suggestion of reduced fatality after DES use. Tu et al15 also observed such a difference in their study of unselected patients at 3 years of follow-up. In our analysis, however, this observation was only of borderline statistical significance, and this has not been evident in patient-level meta-analyses of predominantly on-label patients from randomized trials of relatively simple single de novo lesions.5–9
An absolute reduction of 3.2% in TVR is considerably smaller than the difference demonstrated in RCTs.1,2,27–33 Given the relative complexity and high baseline risk of restenosis in patients treated off label, this could be viewed as a surprisingly low benefit. However, most RCTs have used relatively thicker-strut stainless steel comparator stents that have a high rate of restenosis when compared with thin-strut BMS.34 In addition, the use of protocol-mandated angiography and the well-described oculo-stenotic reflex within RCTs inflates the absolute difference between DES and BMS.35 In the United Kingdom, attempts to ration use of DES and control overall costs are ongoing.36 As a result of these financial considerations, use of thin-strut and cobalt-chromium BMS was commonplace during the study period and provided control patients treated contemporaneously for a broad range of indications. The comparison of DES with modern BMS in a real-world setting is therefore a strength of the current analysis. The finding of a 3.2% absolute risk reduction in TVR is comparable with the 2-year outcomes from the Ontario province.15 Such findings may have implications in resource-limited healthcare systems. It is likely, however, that the benefit of DES varies by subgroup, though we had insufficient power to undertake subgroup analysis of outcome by off-label characteristic. This aspect merits further study to assist ongoing efforts in targeting DES use in a cost-effective manner.
Follow-up information was ascertained via linkage to national administrative databases. Fewer than 3% of index cases could not be linked to the national data set at baseline, and therefore, follow-up information was not available. Missing linkage is unrelated to baseline patient characteristics, and thus there is no reason to believe this introduces a systematic error to the analysis. Indeed, ascertainment of clinical end points via this mechanism is well established and has been shown to be as complete as prospective follow-up.19 The Scottish Morbidity Record does not record stent thrombosis; thus we could not report this as a separate outcome. It is also acknowledged that, in common with most registries, we lack an independent clinical events committee and angiographic core laboratory. The end points of MI and death are, however, clinically pertinent, unbiased to stent type, and correspond with previous registry studies that used data linkage.12,14,15
A previous observational study by Eisenstein et al37 has provided important insight into the potential role of clopidogrel in preventing adverse outcomes in DES but not BMS. The clinical protocols active during the study recommended 6 months of dual-antiplatelet therapy after DES implantation and between 1 and 3 months after BMS implantation. However, duration of clopidogrel use was not recorded at patient level, and therefore, we cannot expand on this issue. Since our study, recommended duration of dual-antiplatelet therapy after DES implantation has been empirically extended to 1 year.26
Observational studies comparing BMS and DES provide a challenge owing to the pattern of events during follow up (ie, higher early events with BMS and higher late events with DES). Landmark analyses have been used to elucidate late risks of DES and to allow the proportional risks assumption to be met.11,12 Adjustment for baseline clinical risk is then possible. Such studies have been important in highlighting the potential impact of late stent thrombosis in DES, though they may exaggerate the importance of late events and increase the sensitivity of such analyses to bias. Using propensity scores to match patients by clinical variables at baseline confers some of the inherent advantages of experimental study design; the actual pattern of clinical events is preserved and outcomes can be compared over the whole period of follow-up. Differences in observational design may partly explain the varying conclusions from DES outcome studies.
We were unable to match 284 off-label DES patients (25.7%) with equivalent BMS controls. Of these patients, 10% had left main coronary artery PCI, 52% had stented length >30 mm, 25% had restenosis, and 11% had chronic total occlusions. As a consequence of these exclusions, the statistical power of the study was reduced. We would suggest, however, that the existence of DES technology may well have influenced the decision to proceed with PCI in such patients, and for many, a comparison with bypass surgery or medical therapy would be more appropriate. Thus, by excluding such DES-treated patients, the final subjects were a population for which selection bias was minimized and for whom a genuine choice between BMS and DES exists in current clinical practice. It is accepted, however, that as with all observational studies, there may be residual bias due to unknown or unmeasured factors (in particular, covariates relating to noncardiac comorbidity, such as dementia and malignant disease). Therefore, our results require corroboration by other studies and, in particular, RCTs.
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Conclusions |
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In this national study of off-label indications, the rate of death was lower among DES-treated patients at 24 months, and no difference was seen in the rates of MI between matched BMS and DES cohorts. Given the importance of off-label indications and the wide acknowledgment of very late risks, longer-term follow-up is warranted. The benefits of DES were evident, though the absolute reduction in TVR was lower than previously demonstrated in RCTs.
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Acknowledgments |
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We are grateful to the data coordinators and administrators at each contributing site and to the Information Statistics Division for providing follow-up information.
Source of Funding
This research was supported by the Scottish Government Health Department.
Disclosures
Drs Austin and Pell have received research funding from Boston Scientific. Dr Oldroyd has received speaker and consultancy fees from Boston Scientific, Medtronic, and Cordis. The remaining authors report no conflicts.
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CLINICAL PERSPECTIVE
Off-label use of drug-eluting stents (DES) during percutaneous coronary intervention is of great clinical importance. The recent US Food and Drug Administration advisory panel meeting raised concerns about off-label use of DES, for which randomized controlled trial evidence is limited. Off-label indications account for approximately two thirds of percutaneous coronary interventions in routine clinical practice. However, observational analyses suggest higher complication rates, such as stent thrombosis and myocardial infarction, when off-label and on-label DES use is compared. Data comparing DES with a contemporary bare-metal stent population for off-label indications are sparse. To address this gap in the current literature, we used the national revascularization registry in Scotland to identify a cohort of all patients treated off-label with either DES or bare-metal stent between January 2003 and September 2005. To ensure a fair comparison, propensity scores were calculated with important baseline demographic, clinical, and procedural variables. DES-treated patients were then matched on the basis of their propensity score to the closest bare-metal stent comparator, with the final study population comprising 1642 patients. Clinical outcomes of death, myocardial infarction, and target vessel revascularization were ascertained through linkage to national data sets. We found mortality to be lower among DES-treated patients at 24 months, with no difference in the rates of myocardial infarction between the matched bare-metal stent and DES cohorts. The benefits of DES were evident, though the absolute reduction in target vessel revascularization was lower than previously demonstrated in randomized controlled trials. Given the importance of off-label use, these findings were reassuring, though longer-term follow-up is warranted.
Circ Cardiovasc Interv 2008 1: 45-52.
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P. S. Douglas, J. M. Brennan, K. J. Anstrom, A. Sedrakyan, E. L. Eisenstein, G. Haque, D. Dai, D. F. Kong, B. Hammill, L. Curtis, et al. Clinical Effectiveness of Coronary Stents in Elderly Persons: Results From 262,700 Medicare Patients in the American College of Cardiology-National Cardiovascular Data Registry J. Am. Coll. Cardiol., May 5, 2009; 53(18): 1629 - 1641. [Abstract] [Full Text] [PDF]
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