Drug-Eluting or Bare-Metal Stenting in Patients With Diabetes Mellitus
Results From the Massachusetts Data Analysis Center Registry
Background— Patients with diabetes mellitus (DM) are at high risk for restenosis, myocardial infarction, and cardiac mortality after coronary stenting, and the long-term safety of drug-eluting stents (DES) relative to bare-metal stents (BMS) in DM is uncertain. We report on a large consecutive series of patients with DM followed up for 3 years after DES and BMS from a regional contemporary US practice with mandatory reporting.
Methods and Results— All adults with DM undergoing percutaneous coronary intervention with stenting between April 1, 2003, and September 30, 2004, at all acute care nonfederal hospitals in Massachusetts were identified from a mandatory state database. According to index admission stent type, patients were classified as DES treated if all stents were drug eluting and as BMS treated if all stents were bare metal; patients treated with both types of stents were excluded from the primary analysis. Mortality rates were obtained from vital statistics records, and myocardial infarction and revascularization rates were obtained from the state database with complete 3 years of follow-up on the entire cohort. Risk-adjusted mortality, myocardial infarction, and revascularization differences (DES−BMS) were estimated with propensity-score matching based on clinical, procedural, hospital, and insurance information collected at the index admission. DM was present in 5051 patients (29% of the population) treated with DES or BMS during the study. Patients with DM were more likely to receive DES than BMS (66.1% versus 33.9%; P<0.001). The unadjusted cumulative incidence of mortality at 3 years was 14.4% in DES versus 22.2% in BMS (P<0.001). Based on propensity-score analysis of 1:1 matched DES versus BMS patients (1476 DES:1476 BMS), the risk-adjusted mortality, MI, and target vessel revascularization rates at 3 years were 17.5% versus 20.7% (risk difference, −3.2%; 95% confidence interval, −6.0 to −0.4; P=0.02), 13.8% versus 16.9% (−3.0%; 95% confidence interval, −5.6 to 0.5; P=0.02), and 18.4% versus 23.7% (−5.4%; confidence interval, −8.3 to −2.4; P<0.001), respectively.
Conclusions— In a real-world diabetic patient population with mandatory reporting and follow-up, DES were associated with reduced mortality, myocardial infarction, and revascularization rates at long-term follow-up compared with BMS.
Received September 8, 2008; accepted October 3, 2008.
Patients with diabetes mellitus (DM) have a higher prevalence of ischemic heart disease than the general population. In the United States, approximately one third of percutaneous coronary intervention (PCI) procedures are performed on patients with DM,1 a proportion that is increasing. PCI has several unique limitations in the diabetic patient population: increased propensity for restenosis, increased extent of coronary artery disease, and a higher risk of subsequent cardiac death and myocardial infarction (MI) compared with the general population.2,3
Clinical Perspective p 2285
Drug-eluting stents (DES) have been shown to reduce the need for repeat revascularization procedures compared with bare-metal stents (BMS) in randomized trials.4,5 In diabetic patients, a similar or greater absolute reduction in restenosis risk is seen with DES.6,7 However, data on the long-term safety of DES in the diabetic population are conflicting.8
We sought to evaluate the long-term safety of DES versus BMS specifically in patients with DM. We have previously examined 2-year mortality in patients treated with DES and BMS in a study of all PCI procedures performed in Massachusetts.9,10 Here, we report on the group of diabetic patients from this cohort undergoing PCI with DES and BMS with complete 3-year follow-up. We used propensity-score matching to minimize bias because the choice of stent was not randomized.
In 2002, the Massachusetts Department of Public Health established a requirement that all Massachusetts hospitals providing interventional cardiology services collect data on all PCI procedures. These data are prospectively collected by trained hospital personnel using the American College of Cardiology’s National Cardiovascular Data Registry’s (NCDR) data collection instrument (http://www.accncdr. com/WebNCDR/Common) for PCI and the Society of Thoracic Surgeons’ National Adult Cardiac Database instrument (www.sts. org/sections/stsnationaldatabase) for cardiac surgery. The data are then submitted electronically to the Massachusetts Data Analysis Center (Mass-DAC) at Harvard Medical School, where they are cleaned, audited, adjudicated by a committee of interventionalists, and verified by internal and external procedures.11
Our analysis was performed using the Mass-DAC database. The study was designed and conducted by the authors and funded by the Massachusetts Department of Public Health. Data collection was approved by the Harvard Medical School’s Committee on Human Studies (M10774–145).
All adults (≥18 years of age) undergoing PCI with stenting between April 1, 2003, and September 30, 2004, at all acute care nonfederal hospitals in Massachusetts were identified. Subjects were excluded from this analysis if they were not Massachusetts residents at the time of the procedure or if they could not be linked to hospital discharge billing data to avoid incomplete ascertainment of subsequent adverse events in these patients. Although follow-up extended beyond 3 years for mortality in a proportion of these patients at the time of analysis, we restricted the follow-up to 3 years in all patients to avoid bias introduced by incomplete follow-up.
Study subjects were assigned to either the DES group or the BMS group according to the stent type used during the index admission. Individuals receiving both DES and BMS during the index admission were excluded from the analysis.
DM was defined as past or current diagnosis of DM and/or the need for medical therapy, according to the American College of Cardiology’s NCDR definition. Patients on insulin therapy for the control of diabetes mellitus at the time of the index procedure were classified as insulin requiring.
The primary outcome was death from any cause within 3 years of the index procedure. In-hospital mortality information at the time of the index procedure is reported directly to Mass-DAC by the hospitals and is verified by linking to the Vital Records and Statistics data. The Massachusetts Registry of Vital Records and Statistics included 3-year mortality data for all study participants at the time of analysis. We used the Social Security Death Index Interactive Search to confirm death dates and mortality status in cases in which the Massachusetts vital statistics data disagreed with the Mass-DAC data and contacted the hospitals in the cases in which the Social Security website was not enough to resolve the disagreement.
Subsequent MI during index hospitalization was determined from the mandatory recording of in-hospital events in the Mass-DAC database according to the NCDR definitions. MIs occurring during any subsequent hospital admission were identified by hospital discharge billing data (a principal diagnosis of International Classification of Diseases, ninth revision, code 410.x1), as well as MIs associated with presentation or follow-up from any procedures after the index admission collected in the Mass-DAC database. Target vessel revascularization (TVR) was defined as PCI within a vessel treated during the index procedure or any CABG after the index procedure. Information on repeat TVR was obtained from the Mass-DAC database and hospital discharge billing data.
Because this is an observational study, we developed a list of potential confounders and then mapped these to the Mass-DAC database. The types of confounders included patient demographic factors, insurance status, history and risk factors, cardiac status of the patient, procedure medications, and lesion characteristics. Because some patients had multiple lesions treated during their index procedure, we created patient-specific lesion-based variables: maximum percent diameter stenosis, any high-risk lesion, any restenotic lesion, and any use of embolectomy or atherectomy. Because some hospitals in Massachusetts are pilot programs that perform only primary angioplasty without cardiac surgery on site, we also included a variable that indicated whether the patient underwent the PCI in a pilot program.
Additional confounders not available in the NCDR instrument were collected from hospital discharge billing data from the index admission. We coded history of gastrointestinal bleeding as present if the following International Classification of Diseases, ninth revision, clinical modification, codes were present in the index admission: 578.0 through 578.99 inclusive and 531.0 through 534.99 inclusive. Similarly, history of neoplasm was coded as present if codes for neoplasms were present during the index admission (140.0 through 239.9 inclusive). Although we adjusted for use of and contraindications to dual antiplatelet therapy, we were not able to adjust for duration of and compliance with therapy.
Creating Treatment Groups: Propensity-Score Analysis
Because patients in our study were not randomized to receive either DES or BMS, propensity-score matching of subjects with DM was used to adjust for observed characteristics of patients in the 2 treatment groups.12 A 1:1 matched analysis was performed without replacement on the basis of the estimated propensity score of each patient in the study. The log odds of the probability that a patient received a DES (the “logit”) was modeled as a function of the potential confounders we identified and contained in our data set. Using the estimated logits, we first randomly selected a DES patient and then matched the DES patient to the “closest” BMS patient. BMS patients who had an estimated logit within 0.6 SD of the selected DES patients were eligible for matching.13
We assessed the success of the matches by examining standardized differences (measured in percentage points) in the observed confounders between the matched DES and BMS groups. Small (<10%) standardized differences support the assumption of balance between treatment groups14 based on observed confounders.
Continuous variables were reported as mean±SD. Categorical variables were reported as percentages, and the χ2 test was used for comparison. Using the matched pairs, we conducted paired t tests to determine whether mortality, MI, and revascularization rates were different between DES and BMS patients. Estimates of the adjusted differences in risks are presented with 95% confidence intervals (CIs) of the difference. Kaplan-Meier curves also were constructed for study outcomes in the matched cohort. All statistical tests were 2 sided, and a value of P<0.05 was considered statistically significant. All analyses were performed with SAS 8.2 (SAS Institute, Inc, Cary, NC).
Because matching on the propensity score cannot be expected to balance unobserved confounders that are not related to observed confounders, we undertook several sensitivity analyses. First, we examined differences in mortality between DES and BMS patients 2 days after stent placement. If this difference was clinically large, it would indicate residual confounding because such an early benefit would be unlikely.
Second, because the initiation of this study coincided with the introduction of DES in Massachusetts in late April 2003, we evaluated whether these temporal trends in stent choice influenced the study results. We reestimated the propensity scores that, in addition to our initial set of confounders, included time (measured as days since April 1, 2003), a quadratic term for time, and an interaction between time and type of hospital program (pilot programs) and compared risks after DES and BMS treatment in this restricted matched cohort.
Dr Normand had full access to the data; Drs Mauri and Normand take full responsibility for the integrity of the data analysis. All authors have read and agree to the manuscript as written.
Patient and Lesion Characteristics
Between April 1, 2003, and September 30, 2004, 21 045 patients received PCI with stenting in Massachusetts performed by 138 operators at 21 hospitals; 6008 (29%) had a diagnosis of DM (Figure 1). We excluded 416 patients who were not residents of Massachusetts, 169 patients who could not be linked to hospital discharge data and Mass-DAC data, and 372 patients who were treated with a combination of DES and BMS. This yielded a cohort of 5051 adult patients with DM undergoing PCI: 3341 patients treated with DES and 1710 patients treated with BMS. Of patients treated with DES, 73% received sirolimus-eluting stents (SES) only, 25% received paclitaxel-eluting stents (PES) only, and 2% received both types. Overall, 33% of diabetic patients were on insulin therapy.
Diabetic Versus Nondiabetic Patient Characteristics
Compared with nondiabetic patients, diabetic patients were older with a higher prevalence of risk factors for coronary artery disease, comorbidities, and multivessel disease (Tables 1 and 2⇓). Unadjusted clinical outcomes were significantly worse in diabetic patients compared with those without diabetes (Table 3).
Diabetic Patient Characteristics: DES Versus BMS
Clinical and procedural characteristics differed significantly between diabetic patients treated with DES and BMS before propensity matching (Tables 1 and 2⇑). Diabetic patients presenting for emergency procedures or with MI (ST-segment elevation MI or non–ST-segment elevation MI) were more likely to be treated with BMS. Younger diabetics and diabetics with hypertension or hyperlipidemia were more likely to be treated with DES. Left anterior descending artery lesions also were more likely to be treated with DES. Although the number of diseased vessels was slightly higher in the BMS group, the number of vessels actually treated was higher in the DES group.
Unadjusted Clinical Outcomes
Overall, patients with DM had higher rates of mortality, MI, and TVR than patients without DM. Within the diabetic cohort, unadjusted mortality, MI, and TVR rates at 3 years were each significantly lower in the DES group compared with the BMS group (Table 4).
Propensity-Score Model and Matched Cohort
The propensity-score models included 67 variables. In total, 1476 DES-treated patients were matched to 1476 BMS-treated patients (area under the receiver-operating characteristic curve, 0.67). Standardized differences were <10% for all matched variables except elective procedure status (more common in BMS), and HMO insurance; high-risk lesion, and glycoprotein II/IIIa pretreatment (more common in DES), where the standardized differences were <12%, indicating that the 2 groups were well balanced (Tables I and II of the online-only Data Supplement).
Clinical Outcomes in Matched DES and BMS Patients With DM
Comparisons between DES and BMS groups, after propensity-score matching, showed that diabetic patients treated with DES had a lower mortality (risk difference, −3.2%; 95% CI, −6.0 to −0.4; P=0.02), a lower rate of subsequent MI (−3.3%; 95% CI, −5.6 to −0.5; P=0.02), and TVR at 3 years (−5.4%; 95% CI, −8.3 to −2.4; P<0.001) compared with diabetic patients treated with BMS (Table 5 and Figure 2).
The adjusted mortality rate at 2 days after stent placement was not significantly different between DES and BMS (0.4% for DES versus 0.7% for BMS; absolute difference, −0.3%; 95% CI, −0.8 to 0.3; P=0.32). Adjustment for time on market of DES confirmed the results of the primary analysis with regard to the clinical outcomes of mortality, MI, and TVR at long-term follow-up (Table III of the online-only Data Supplement).
Despite the important role of stenting in diabetics, there has been limited information on the long-term efficacy or safety of DES use in this population. To the best of our knowledge, this is the largest observational study to assess the long-term outcomes after stenting in the diabetic population. We observed a significant reduction in risk-adjusted mortality, MI, and repeat revascularization associated with DES versus BMS at long-term follow-up.
Previous randomized studies have raised concerns about lower survival rates in diabetics receiving DES compared with BMS, but these findings have not been confirmed in other analyses.8,15,16 Smaller randomized trials evaluating DES specifically in diabetic patients have been designed mainly to detect restenosis prevention and not powered to compare long-term important clinical end points or designed to follow up patients beyond 1 year.6,7,17 A recent network meta-analysis of 35 randomized trials showed no difference in rates of death or MI in diabetic patients who received DES versus BMS.16
Although our primary goal was simply to evaluate whether DES was associated with increased rates of MI and mortality in long-term follow-up, we observed small absolute differences in mortality and MI favoring drug-eluting stenting. Previous studies have noted an association between restenosis and the risk of death or MI, and patients with diabetes mellitus are at higher risk of presenting acutely with an acute coronary syndrome in the setting of restenosis.18,19 It is possible that a reduction in revascularization procedures to treat restenosis could account for some of the reduction in mortality and MI that we observed, particularly in this inclusive patient population.
Some of the reduction in the risk of MI and death was apparent within the first 6 months, before the maximum impact of restenosis prevention would be manifest. Additional factors such as different durations of dual antiplatelet therapy might have an important effect after stenting.20,21 Although we adjusted for the use of and contraindications to dual antiplatelet therapy with aspirin and thienopyridine therapy, we were not able to adjust for the duration of therapy (which, during the period we studied, was likely to be 1 month for BMS and 3 to 6 months for DES on the basis of the antiplatelet regimen used in the pivotal DES trials4,5 rather than 12 months22) or compliance. It is possible that this differential use of dual antiplatelet therapy in the patients receiving DES may account for some of the reduction in the risk of MI observed in this group. Diabetic patients, who are at increased risk for platelet aggregation and thrombotic events,23 might derive greater relative benefits from longer duration of antiplatelet therapy than those without diabetes.
We found that the use of DES was associated with a significant 5.4% absolute risk reduction in TVR at 3 years in the matched diabetic cohort. The adjusted TVR curves separated by 6 months and remained roughly parallel for the duration of the study, confirming durable benefit of DES in the prevention of clinical restenosis in diabetics. However, the extent of TVR reduction was lower than that seen in randomized studies of DES versus BMS in diabetics, which have shown a 13% to 27% absolute risk reduction (or 65% to 75% relative risk reduction) in target lesion revascularization at 9 to 12 months.6,7,24–26 This discrepancy may be explained by the use of protocol-mandated angiography in the randomized trials, leading to higher target lesion revascularization rates. The effect of angiography may be particularly relevant for diabetic patients in whom clinical restenosis may be less apparent because of the increased likelihood of silent ischemia.27,28 Nevertheless, our results are consistent with other observational studies that have shown a similar magnitude of TVR reduction.15
DM is characterized by metabolic abnormalities of hyperglycemia and insulin resistance, and a variety of mechanisms, including endothelial dysfunction, abnormal platelet function, and coagulation abnormalities,23,29 are responsible for accelerated atherosclerosis and excessive neointimal formation after coronary intervention.30 Regardless of stent type, patients with DM have worse long-term outcomes than patients without DM.3,15,31 The antiproliferative effects of DES target only the local responses to stent-induced injury through prevention of smooth muscle cell proliferation; they do not address the underlying systemic derangements that affect the entire coronary circulation. Hence, although DES reduce restenosis significantly in diabetics, they may not affect non–target lesion–related disease progression and plaque rupture. We compared DES and BMS PCI in diabetic patients, but the role of coronary artery bypass graft surgery is still important, particularly in patients with multivessel disease, in whom bypass may confer greater protection against MI than local therapy.32 Comparison of long-term outcomes of coronary artery bypass graft surgery to PCI with DES is warranted.33,34
Among diabetic patients receiving DES in our study, 73% received SES, and the rest received PES. We did not examine the outcomes related to the type of DES used because the main clinical question of interest was the comparison of outcomes between DES and BMS in those with diabetes. Whether these DES differ in their treatment efficacy and safety in diabetic patients is controversial. The Intracoronary Stenting and Antithrombotic Regimen—Diabetes (ISAR-DIABETES) trial showed that SES was associated with a significant reduction in late loss, but the study was not powered to assess differences in target lesion revascularization.35 A network meta-analysis of 35 trials of SES and PES compared with BMS found no differences in the efficacy or safety of SES versus PES in diabetic patients.16 Similarly, no significant differences between SES and PES were noted in observational studies in diabetic patients.36,37
The strengths of our analysis include the availability of a large, contemporary US population–based cohort of patients with diabetes mellitus undergoing PCI with mandatory reporting to evaluate the impact of stent choice on hard clinical end points at long-term follow-up. Nevertheless, the data are observational. The method of adjustment we used, propensity-score matching, sacrifices power (by restricting the sample size to matched patients) for better control of bias. Although it is expected that adjustment on observed potential confounders also adjusts for correlated unmeasured confounders, some effect from residual confounding cannot be excluded. For example, we did not have data on quantitative angiographic characteristics, a potential limitation given that DES were not available for smaller-diameter vessels known to be at increased risk for adverse events in follow-up. Although we performed multiple sensitivity analyses including adjustment for changes in practice over time, other potential sources of bias include the possibility of better penetration of optimal medical therapy or more complete revascularization in DES-treated patients. In addition, stent thrombosis rates could not be ascertained accurately from this database. Although our study would be expected to manifest differences in clinical end points if present, we cannot exclude a small difference in stent thrombosis rates associated with DES.
In a large, real-world patient population undergoing PCI and stenting, use of DES in patients with DM was associated with significant reductions in the risks of death, MI, and repeat revascularization procedures at long-term follow-up. Longer-term follow-up is needed to determine whether a similar safety profile is maintained.
We wish to acknowledge Paul Dreyer, PhD, of the Massachusetts Department of Public Health and the members of the Mass-DAC PCI Data Adjudication Committee for their assistance: Kurt Barringhaus, MD; Clifford J. Berger, MD; David Cohen, MD; Angela Corey, RN; Jean Crossman, RN; Daniel Fisher, MD; Joseph Garasic, MD; Jean-Pierre Geagea, MD; Gregory Giugliano, MD; Kalon Ho, MD; Alice Jacobs, MD; James Kirshenbaum, MD; Josh Krasnow, MD; Anthony Marks, MD; Theo E. Meyer, MD, PhD; Kathy Minahan, RN; Zoran Nedelijkovic, MD; Barbara Oxley, RN; Thomas C. Piemonte, MD; Kenneth Rosenfield, MD; Pinak B. Shah, MD; Samuel J. Shubrooks, Jr, MD; James Waters, MD; and Bonnie Weiner, MD.
Source of Funding
This study was funded by the Massachusetts Department of Public Health contract 620022A4PRE (Dr Normand, A. Lovett, T.S. Silbaugh, K. Zelevinsky, and R.E. Wolf).
Dr Mauri has received honoraria from Abbott Vascular, Boston Scientific, Cordis, and Medtronic Vascular. The other authors report no conflicts.
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Patients with diabetes mellitus are at high risk for restenosis, myocardial infarction, and cardiac mortality after coronary stenting. In randomized comparisons, drug-eluting stents (DES) have reduced restenosis relative to bare-metal stents (BMS); however, data on the long-term outcomes of DES in diabetes mellitus are conflicting. This population-based study prospectively collected clinical and procedural data on all diabetic patients who underwent percutaneous coronary intervention with stents from April 1, 2003, through September 30, 2004, at all nonfederal hospitals in Massachusetts. The aim of the study was to evaluate the long-term safety of DES versus BMS specifically in patients with diabetes mellitus from a contemporary US population. Rates of mortality, myocardial infarction, and repeat revascularization procedures were ascertained over the 3 years after stent placement. Propensity-score–matched analysis was performed to compare DES- and BMS-treated patients because the choice of stent was not randomly assigned. Diabetes mellitus was present in 5051 patients (29% of the overall population) treated with DES or BMS during the study. Sixty-six percent of patients with diabetes mellitus received DES compared with 34% who received BMS. In the 1:1–matched DES versus BMS patients, the risk-adjusted mortality, myocardial infarction, and target vessel revascularization rates at 3 years were lower in the diabetic patients treated with DES compared with BMS. The results of this large population-based study suggest that DES are safe and effective in patients with diabetes mellitus undergoing percutaneous coronary intervention with stenting in long-term follow-up.
The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.820159/DC1.
Guest Editor for this article was Eric R. Bates, MD.