Effectiveness and Safety of Drug-Eluting Stents in Ontario
Jack V. Tu, M.D., Ph.D., James Bowen, B.Sc.Phm., M.Sc., Maria Chiu, M.Sc., Dennis T. Ko, M.D., M.Sc., Peter C. Austin, Ph.D., Yaohua He, M.D., Ph.D., Robert Hopkins, M.A., Jean-Eric Tarride, Ph.D., Gord Blackhouse, M.B.A., M.Sc., Charles Lazzam, M.D., Eric A. Cohen, M.D., and Ron Goeree, M.A.
Background The placement of drug-eluting stents decreases thefrequency of repeat revascularization procedures in patientsundergoing percutaneous coronary intervention (PCI) in randomizedclinical trials. However, there is uncertainty about the effectivenessof drug-eluting stents, and increasing concern about their safety,in routine clinical practice.
Methods From the Cardiac Care Network of Ontario's population-basedclinical registry of all patients undergoing PCI in Ontario,Canada, we identified a well-balanced cohort of 3751 pairs ofpatients, matched on the basis of propensity score, who receivedeither bare-metal stents alone or drug-eluting stents aloneduring an index PCI procedure between December 1, 2003, andMarch 31, 2005. The primary outcomes of the study were the ratesof target-vessel revascularization, myocardial infarction, anddeath.
Results The 2-year rate of target-vessel revascularization wassignificantly lower among patients who received drug-elutingstents than among those who received bare-metal stents (7.4%vs. 10.7%, P<0.001). Drug-eluting stents were associatedwith significant reductions in the rate of target-vessel revascularizationamong patients with two or three risk factors for restenosis(i.e., presence of diabetes, small vessels [<3 mm in diameter],and long lesions [20 mm]) but not among lower-risk patients.The 3-year mortality rate was significantly higher in the bare-metal–stentgroup than in the drug-eluting–stent group (7.8% vs. 5.5%,P<0.001), whereas the 2-year rate of myocardial infarctionwas similar in the two groups (5.2% and 5.7%, respectively;P=0.95).
Conclusions Drug-eluting stents are effective in reducing theneed for target-vessel revascularization in patients at highestrisk for restenosis, without a significantly increased rateof death or myocardial infarction.
Drug-eluting stents have changed the practice of interventionalcardiology by significantly reducing the need for repeat revascularizationprocedures due to restenosis after percutaneous coronary intervention(PCI), as shown in multiple randomized clinical trials.1,2,3,4,5,6However, there is increasing concern about the safety of drug-elutingstents, in light of reports that they are associated with aslightly increased rate of late stent thrombosis and possiblyincreased rates of myocardial infarction and death after PCI.3,7,8,9Although the incidence of stent thrombosis can be reduced withthe use of aspirin and clopidogrel therapy, there is uncertaintyabout how long this therapy is needed, and there are concernsabout the costs of prolonged dual antiplatelet therapy and theassociated risk of bleeding.10,11,12,13,14
In this study, we examined a database, initiated in 2003 inOntario, Canada, in which outcome data from all patients undergoinga PCI and receiving a coronary stent are recorded. We comparedthe outcomes for the patients who received a drug-eluting stentand those for patients who received a bare-metal stent duringthe first 16 months of a new provincial program to monitor theintroduction and use of drug-eluting stents in Ontario.15,16During this period, Ontario had a policy of providing 1 yearof clopidogrel therapy after PCI for patients receiving eithertype of stent who were 65 years of age or older and who wereenrolled in the universal Ontario Drug Benefits plan.
We studied the effectiveness and safety of both types of stents,using a propensity-score–matched cohort of patients whoreceived either a drug-eluting stent alone or a bare-metal stentalone.17 We also studied the use of three well-established riskfactors for restenosis (presence of diabetes, small vessels,and long lesions) to predict which patients have the greatestbenefit from implantation of a drug-eluting stent.18,19
Methods
Data Sources
The Cardiac Care Network (CCN) of Ontario maintains a prospectiveclinical registry of all patients undergoing invasive cardiacprocedures in Ontario that are funded by the government. Clinicalnurse research coordinators gather information on each patientfrom cardiac-procedure referral forms completed by the referringphysician and from charts of patients. The registry includesinformation on demographic characteristics of patients and theircardiac history, cardiac procedures, and relevant coexistingconditions. All 12 PCI centers in Ontario were required to collectadditional data on patients receiving a bare-metal stent ora drug-eluting stent in this registry, as a condition of receivingincremental funding for drug-eluting stents.
For the current study, we used the detailed clinical and stentinformation captured in the CCN PCI registry and supplementedit by linking that information to other population-based administrativedatabases in Ontario, using unique encrypted identifiers ofpatients. We identified an index cohort of all 18,314 patientswho underwent a PCI with placement of either a single drug-elutingor bare-metal stent, or multiple stents (all the same type),in Ontario between December 1, 2003, and March 31, 2005. A totalof 4961 patients were excluded from this cohort. Patients whohad an invalid Ontario health card number were excluded becausewe could not ascertain their long-term outcomes. Patients whohad missing information on potentially important prognosticfactors such as socioeconomic status, type or location of lesion,or Canadian Cardiovascular Society angina classification wereexcluded because of our inability to use their propensity scoresfor matching. We also excluded from our index cohort any patientwho had undergone a previous PCI in the past year. Patientsundergoing PCI for left main coronary artery disease were excludedbecause of concern that there would not be a sufficient numberof patients receiving bare-metal stents to allow for propensity-scorematching. If a patient who had an index PCI had a second PCIwithin 1 year after the index (first) PCI, the second PCI wasnot included in the creation of the index PCI cohort.
We identified the presence or absence of various coexistingconditions using the CCN PCI database and supplemented thisinformation with data from the 24 secondary-diagnosis fieldsin the hospital-discharge administrative database of the CanadianInstitute for Health Information.20 The socioeconomic statusof patients was inferred from Statistics Canada census dataon the median household income for each geographic area.21 Studypatients were grouped into five quintiles, according to theincome level of their neighborhoods, with similar numbers ofpatients in the five quintiles.
Clinical outcomes were identified through linkages to clinicaland administrative databases, with the use of the most recentfollow-up data that were available; a minimum of 1 year of follow-updata was required for inclusion in the study. Target-vesselrevascularization was defined as a follow-up PCI performed inthe same vessel as the index PCI, a follow-up PCI without implantationof a stent, or coronary-artery bypass grafting, as recordedin the CCN database through March 31, 2006. We collected dataon admissions for myocardial infarction (codes I21 and I22 inthe International Classification of Diseases, 10th Revision),before and after the index PCI, through March 31, 2006, usinglinkages to the Canadian Institute for Health Information database.22Deaths from any cause were identified through November 30, 2006,by means of a linkage to the Ontario Registered Persons Database.The median duration of follow-up for death was similar in thedrug-eluting–stent group (840 days) and the bare-metal–stentgroup (817 days).
Our study was approved by the Research Ethics Board at SunnybrookHealth Sciences Centre. The requirement for written informedconsent from patients was waived, since participation in theCCN database is mandatory under Ontario's legislation regardingthe privacy of health information.
Statistical Analysis
Before performing propensity-score matching, we conducted aunivariate analysis of all potentially available explanatoryfactors for target-vessel revascularization, myocardial infarction,or death. A total of 21 factors were identified that were significantlyassociated with one or more of these three primary outcomes(P<0.05). We compared the prevalences of these risk factorsin the bare-metal–stent group and the drug-eluting–stentgroup before the propensity-score matching, using a t-test formeans and chi-square tests for percentages.
A propensity score for the predicted probability of receiptof a drug-eluting stent in each patient was estimated with theuse of a logistic-regression model fit with the 21 factors.We created a propensity-score–matched cohort by attemptingto match each patient who received a drug-eluting stent withone who received a bare-metal stent (a 1:1 match). A nearest-neighbor–matchingalgorithm with a "greedy" heuristic (one that always implementsthe best immediate, or local, solution) was used to match patientson the basis of their diabetes status (presence or absence ofdiabetes) and the logit of their propensity score, with matchingoccurring if the difference in the logits of the propensityscores was less than 0.2 times the standard deviation of thescores (the caliper width).23 In greedy nearest-neighbor matching,a patient with a drug-eluting stent was randomly selected andmatching was attempted with the "nearest" patient with a bare-metalstent. This process was repeated until matches had been attemptedfor all patients with drug-eluting stents. Each matched pairwas unique, and data for unmatched patients in either groupwere not used in subsequent analyses.
We also assessed the degree of balance in measured covariatesbetween the drug-eluting–stent group and the bare-metal–stentgroup. The distributions of categorical variables and continuousvariables between the two groups in the matched cohort werecompared with the use of McNemar's test and paired t-tests,respectively. We computed the standardized difference betweenthe two groups for each type of distribution, with differencesof less than 0.1 taken to indicate good balance in the matchedcohort.17 Kaplan–Meier survival curves were estimatedin the matched cohort for patients who received a drug-elutingstent and those who received a bare-metal stent. The survivalcurves were compared according to methods appropriate for matcheddata.24
In prespecified subgroup analyses of target-vessel revascularization,patients in the drug-eluting–stent group and those inthe bare-metal–stent group were matched on the basis oflesion length (long [20 mm] vs. short [<20 mm]), vessel diameter(small [<3 mm] vs. large [3 mm]), diabetes status (presencevs. absence of diabetes), and the logit of the propensity score.The total stent length was used as a proxy for lesion length,and the narrowest diameter of the inserted stents was used asa proxy for vessel diameter. Within each of the eight subgroups,the reduction in the risk of the outcome was compared betweenthe drug-eluting–stent group and the bare-metal–stentgroup with the use of a Cox regression model, with stent typeas the sole predictor variable. Robust standard errors thataccounted for the clustering of pairs in the matched cohortwere obtained. The number of patients who would need to be treatedto prevent one target-vessel revascularization with the useof a drug-eluting stent was also calculated for each of theeight subgroups.25
All reported P values are two-sided, and P values of less than0.05 were considered to indicate statistical significance. SASsoftware, version 9.1 (SAS Institute), and the R programminglanguage were used for statistical analyses.
Results
Characteristics of Patients
Before Propensity-Score Matching
A total of 13,353 patients met the study inclusion criteriaand met none of the exclusion criteria. The characteristicsof patients chosen to receive a drug-eluting stent alone ascompared with a bare-metal stent alone, according to Ontario'sselective funding policy for drug-eluting stents, are shownin Table 1. Overall, 38% of the stents implanted in patientsin Ontario during the study period were drug-eluting stents,with the percentage of patients receiving drug-eluting stentsremaining roughly constant (see the Supplementary Appendix,available with the full text of this article at www.nejm.org).Patients chosen by their cardiologists to receive a bare-metalstent were more likely than those chosen to receive a drug-elutingstent to have an admission for acute myocardial infarction onthe same day their PCI and stent implantation were performed(i.e., were more likely to require primary PCI or rescue PCI).The mean stent diameter was smaller, and the mean stent lengthwas longer, in the drug-eluting–stent group than in thebare-metal–stent group, showing that cardiologists didselectively implant drug-eluting stents in patients at increasedrisk for restenosis.
Table 1. Baseline Characteristics of Patients, According to Stent Group, before Propensity-Score Matching.
After Propensity-Score Matching
After propensity-score matching was completed, there were 3751matched pairs of patients (Table 2). There were no significantdifferences between the drug-eluting–stent group and thebare-metal–stent group in any of the 21 characteristics(P>0.20 for all comparisons). The standardized differencebetween the two groups was less than 0.03 for all variables.In the matched cohort, 82.9% of patients in the drug-eluting–stentgroup received a paclitaxel stent, and 17.1% received a sirolimusstent.
Table 2. Baseline Characteristics of Patients, According to Stent Group, after Propensity-Score Matching.
Rates of Target-Vessel Revascularization
Overall, 10.7% of the patients receiving a bare-metal stentand 7.4% of those receiving a drug-eluting stent required target-vesselrevascularization by year 2 of follow-up (P<0.001) (Figure 1Aand Table 3). The maximal reduction in the need for repeat revascularizationfrom the use of drug-eluting stents was seen at 6 months. Theeffectiveness of drug-eluting stents in reducing the need forrepeat target-vessel revascularization varied widely, with thefour subgroups of patients with two or three risk factors forrestenosis (i.e., presence of diabetes, small vessels, and longlesions) showing a significant benefit (Table 4). None of theother four subgroups had significant reductions in the ratesof target-vessel revascularization. The number needed to treatto prevent one target-vessel revascularization with the useof drug-eluting stents ranged from 10 to 167 among the eightsubgroups.
Figure 1. Event-free Survival in a Propensity-Score–Matched Cohort of Patients Who Received a Drug-Eluting Stent or a Bare-Metal Stent.
Kaplan–Meier curves are shown for target-vessel revascularization (TVR) (Panel A), myocardial infarction (MI) (Panel B), overall survival (Panel C), and MI-free or overall survival (Panel D) after the index percutaneous coronary intervention (PCI).
Table 4. Rates of Target-Vessel Revascularization in the Propensity-Score–Matched Cohort, According to Subgroup.
Rates of Myocardial Infarction and Death
The rate of myocardial infarction after PCI during the 2-yearfollow-up period did not differ significantly between the twogroups (P=0.95) (Figure 1B and Table 3). However, the rate was0.4 percentage point lower in the drug-eluting–stent groupthan in the bare-metal–stent group during the first 6months of follow-up, whereas the rates of myocardial infarctioncrossed over at approximately 15.6 months of follow-up; therate was 0.5 percentage point higher in the drug-eluting–stentgroup by year 2 of follow-up.
The rate of death after PCI in the matched cohort at year 3of follow-up was 7.8% among patients receiving a bare-metalstent and 5.5% among those receiving a drug-eluting stent (P<0.001)(Table 3), with the survival curves gradually diverging overtime in favor of drug-eluting stents (Figure 1C). The compositeoutcome of death or myocardial infarction also favored drug-elutingstents (Figure 1D). To investigate the potential contributionsof target-vessel revascularization and myocardial infarctionto the absolute differences in the survival rate, we comparedthe 30-day mortality among patients who had each outcome. The30-day mortality among patients who underwent target-vesselrevascularization was 2.5% in the bare-metal–stent groupand 2.4% in the drug-eluting–stent group. In contrast,the 30-day mortality among patients who had a myocardial infarctionwas 6.9% in both groups.
Discussion
Our study provides information from a large population-baseddatabase that could be used to help clinicians determine whethera bare-metal stent or drug-eluting stent is better for a particularpatient. We found that drug-eluting stents were most effectivein reducing the need for target-vessel revascularization inpatients at the highest risk for restenosis (i.e., those whohad two or three risk factors — presence of diabetes,small vessels, and long lesions). In contrast, we found smallreductions, which were not significant, in the rates of target-vesselrevascularization among patients at low or intermediate riskfor restenosis (e.g., those without diabetes and with largevessels or short lesions). The relatively low rate of clinicallydriven target-vessel revascularization in most of the subgroupsof patients with bare-metal stents in our study is in contrastto the rate of 15 to 20% or higher, in association with protocol-drivenangiography and other factors, reported in clinical trials ofdrug-eluting stents.1,3,4
Although the benefit of drug-eluting stents in reducing theneed for target-vessel revascularization in the real world hasbeen confirmed in a few other, recent registry reports,8,26there has been great concern expressed recently about whetherthis benefit is outweighed by the risk of late stent thrombosis.27,28,29,30Our results suggest that the risk–benefit equation foroverall mortality favors drug-eluting stents, since the overallrate of death at year 3 of follow-up was lower in the drug-eluting–stentgroup than in the bare-metal–stent group. A mortalitybenefit of drug-eluting stents has not been found in clinicaltrials conducted to date, but this could reflect the relativelysmall numbers of patients, limited long-term follow-up, or alower risk in the populations in many of these studies.1,2,3,4
Some have argued that the risk of restenosis, which may be manifestedas angina or myocardial infarction, may outweigh the slightlyincreased rate of late stent thrombosis found in recent studies.31We report a 30-day mortality of 2.5% among patients who receiveda bare-metal stent and underwent repeat procedures, showingthat the need for target-vessel revascularization is a clinicallysignificant adverse event. However, the increased incidenceof repeat procedures among our patients who received a bare-metalstent is insufficient to explain fully the small absolute differencein the survival rate in favor of drug-eluting stents. Alternatively,our mortality data could reflect unmeasured confounding factors,and we suggest caution in concluding, on the basis of our studyalone, that drug-eluting stents save lives.
Because we collected follow-up data from linkages to the administrativedatabases, it was not possible for us to ascertain the exactrate of late stent thrombosis. However, we found that the rateof myocardial infarction was slightly lower in the drug-eluting–stentgroup than in the bare-metal–stent group during the first6 months of follow-up, whereas this benefit was lost duringthe second year, with a slightly higher rate of myocardial infarctionin the drug-eluting–stent group at 2 years. This crossoverof rates of myocardial infarction in year 2 has also been reportedfor patients in the Swedish PCI stent registry and is consistentwith findings from other studies that have shown an increasedfrequency of late thrombotic events, such as nonfatal myocardialinfarction, among patients receiving a drug-eluting stent withina few months after clopidogrel therapy was stopped.8,12,14 Ifconfirmed in additional studies, these results would suggestthat dual antiplatelet therapy with aspirin and clopidogrelmay need to be continued beyond the 1-year period currentlyrecommended in American and European guidelines.10,32,33
Our study has many strengths but also important limitations.The strengths include the availability of a large population-basedcohort of patients who underwent PCI, which permitted a comparisonof outcomes among patients receiving drug-eluting stents andconcurrent controls receiving bare-metal stents with the useof a rigorous cohort analysis involving propensity-score matching.The opportunity to create our data set using multiple linkedclinical and administrative databases of Canada's single-payeruniversal health care system allowed us to achieve virtually100% follow-up of outcome rates for both groups of patients.Our study was entirely funded from public sources, without anyinvolvement from industry.
Important limitations of our study include its observationalnature and the fact that our findings may not be generalizableto countries without universal health insurance and drug-benefitplans. The benefits of drug-eluting stents are in part relatedto the prolonged use of dual antiplatelet therapy, which wasavailable for 1 year at a minimal cost to most patients in ourstudy. Although we were able to establish a large and well-balancedcohort of patients receiving bare-metal stents and patientsreceiving drug-eluting stents, matched on the basis of the propensityscore, our study was not a randomized clinical trial, and theremay still be unmeasured confounding factors that contributeto our findings. We did not have access to certain data (e.g.,subtypes of myocardial infarction) that would have been of interest.
In conclusion, the experience in Ontario, Canada, is that drug-elutingstents are more effective than bare-metal stents in reducingthe need for target-vessel revascularization in patients athighest risk for restenosis after PCI but offer minimal benefitto patients at lower risk. The small absolute difference inmortality in favor of drug-eluting stents in our study warrantsfurther investigation and should be confirmed or refuted throughlarge, randomized clinical trials with long-term follow-up.
Supported by operating grants from the Ontario Ministry of Healthand Long-Term Care to the Program for Assessment of Technologyin Health, the CCN of Ontario, and the Institute for ClinicalEvaluative Sciences; a Canadian Institutes of Health ResearchTeam Grant in Cardiovascular Outcomes Research; a Canada ResearchChair in Health Services Research and a Career InvestigatorAward from the Heart and Stroke Foundation of Ontario (to Dr.Tu); a Clinician–Scientist Award from the Heart and StrokeFoundation of Ontario (to Dr. Ko); and a New Investigator Awardfrom the Canadian Institutes of Health Research (to Dr. Austin).
Dr. Cohen reports receiving operating grants for clinical trialsand speaker's fees from Boston Scientific and Cordis–Johnson& Johnson. No other potential conflict of interest relevantto this article was reported.
We thank the staff members of the CCN of Ontario (Dr. KevinGlasgow, Amanda Dean, Joyce Seto, Saba Ateyah, and Dr. KevinTeoh), its member hospitals, referring physicians, interventionalcardiologists, and regional cardiac care coordinators for collectingthe clinical data that made this study possible; Francine Duquettefor administrative assistance with the manuscript; and LindaDonovan and Pam Slaughter for helpful comments on earlier versionsof the manuscript.
Source Information
From the Institute for Clinical Evaluative Sciences (J.V.T., M.C., D.T.K., P.C.A., Y.H.) and Sunnybrook Health Sciences Centre, University of Toronto (J.V.T., D.T.K., E.A.C.) — both in Toronto; McMaster University, St. Joseph's Healthcare, Hamilton, Ont. (J.B., R.H., J.-E.T., G.B., R.G.); and Trillium Health Sciences Centre, Mississauga, Ont. (C.L.) — all in Canada.
Address reprint requests to Dr. Tu at the Institute for Clinical Evaluative Sciences, G106-2075 Bayview Ave., Toronto, ON M4N 3M5, Canada, or at tu{at}ices.on.ca.
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Douglas, P. S., Brennan, J. M., Anstrom, K. J., Sedrakyan, A., Eisenstein, E. L., Haque, G., Dai, D., Kong, D. F., Hammill, B., Curtis, L., Matchar, D., Brindis, R., Peterson, E. D.
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Pfisterer, M., Brunner-La Rocca, H. P., Rickenbacher, P., Hunziker, P., Mueller, C., Nietlispach, F., Leibundgut, G., Bader, F., Kaiser, C., for the BASKET Investigators,
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Park, S.-J., Kim, Y.-H.
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Daemen, J., Kuck, K. H., Macaya, C., LeGrand, V., Vrolix, M., Carrie, D., Sheiban, I., Suttorp, M. J., Vranckx, P., Rademaker, T., Goedhart, D., Schuijer, M., Wittebols, K., Macours, N., Stoll, H. P., Serruys, P. W., on behalf of the ARTS-II Investigators,
(2008). Multivessel Coronary Revascularization in Patients With and Without Diabetes Mellitus: 3-Year Follow-Up of the ARTS-II (Arterial Revascularization Therapies Study-Part II) Trial. J Am Coll Cardiol
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Jensen, L. O., Maeng, M., Thayssen, P., Kaltoft, A., Tilsted, H. H., Bottcher, M., Lassen, J. F., Hansen, K. N., Krusell, L. R., Rasmussen, K., Pedersen, K. E., Pedersen, L., Paaske Johnsen, S., Sorensen, H. T., Thuesen, L.
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Brodie, B. R., Stuckey, T., Downey, W., Humphrey, A., Bradshaw, B., Metzger, C., Hermiller, J., Krainin, F., Juk, S., Cheek, B., Duffy, P., Smith, H., Edmunds, J., Varanasi, J., Simonton, C. A., STENT (Strategic Transcatheter Evaluation of New T,
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51: 2228-2229
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Anderson, H. V.
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51: 607-614
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Grines, C. L.
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20 mm]) but not among lower-risk patients. The 3-year mortality rate was significantly higher in the bare-metal–stent group than in the drug-eluting–stent group (7.8% vs. 5.5%, P<0.001), whereas the 2-year rate of myocardial infarction was similar in the two groups (5.2% and 5.7%, respectively; P=0.95). 
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