Original Contribution
Impact of Drug-Eluting Stents on Outcomes of Patients with
End-Stage Renal Disease Undergoing Percutaneous Coronary Revasculari
September 2006
Several randomized trials have demonstrated the efficacy of drug-eluting stents (DES) in reducing restenosis and the need for target vessel revascularization (TVR) in comparison to bare metal stents (BMS).1-3 Patient and lesion subsets examined in most trials were highly selected and thus not representative of the “real-world” patients undergoing coronary artery stent placement. However, several published series and registries have shown that the benefits of DES in reducing restenosis could be extended to several higher-risk patient subsets.4-7
Patients with end-stage renal disease (ESRD) on long-term dialysis have an accelerated process of atherosclerosis with very high rates of morbidity and mortality from coronary artery disease.8,9 In addition, both the risk of in-stent restenosis and the need for repeat revascularization are particularly high in this patient population.10 Since ESRD patients were excluded from randomized trials testing DES, it remains unclear whether DES have an advantage over BMS in this patient subset. The aim of this study was to compare clinical outcomes when DES, rather than BMS, were used for percutaneous revascularization in patients with ESRD.
Methods
Study population. We analyzed the characteristics and outcomes of 89 consecutive patients with ESRD who underwent coronary stenting at our institution and 9 regional VA medical centers between January 2002 and August 2004. All the patients had established ESRD and were already on renal replacement therapy (hemodialysis or peritoneal dialysis) before percutaneous coronary intervention (PCI). A total of 1,250 patients with ESRD were identified in the electronic patient databases of the participating hospitals. Of those, 346 patients underwent cardiac catheterization, including 89 patients who successfully underwent PCI with placement of a coronary stent: either a DES or a BMS. In every study patient, only 1 type of stent (DES or BMS) was used. Patients included in the analysis had clinical follow up >/=9 months after the index PCI.
Procedural and angiographic analysis. All interventions were performed according to standard techniques, and the final strategy (device selection and anticoagulation regimen) was left to the discretion of the individual operators. The number of diseased coronary arteries was defined as the number of major coronary arteries with luminal diameter stenosis >/=70%. Procedural success was defined as angiographic success (residual stenosis In-hospital outcome and clinical follow up. Baseline demographics, procedural details and clinical outcomes were obtained from review of the medical records, clinic visits and procedural reports. Subsequent clinical follow up was performed by review of office or emergency room visits and hospital admissions that appeared in the electronic medical records of the individual patients. Source documents from hospital admissions, clinical diagnoses, laboratory values, and cardiac procedures were systematically reviewed to adjudicate adverse events.
Study endpoints. The primary endpoint was target vessel revascularization (TVR) within 9 months of the index coronary stenting procedure. TVR was defined as surgical or repeat percutaneous revascularization to treat any lesion located in the primary vessel treated during the index procedure. The secondary endpoint was the composite of death, myocardial infarction (MI), and TVR within 9 months. An MI was defined, per the joint ACC/ESC consensus document, as elevation of troponin-I above the institutional normal value.11Statistical analysis. Demographic, clinical, angiographic and procedural characteristics were summarized for and compared across the DES and BMS patient groups. Continuous characteristics were analyzed using the unrestricted-variances two-sample t-test, while dichotomous characteristics were analyzed using Fisher’s exact test. Logistic regression models were employed to compare clinical outcomes of DES patients to those of BMS patients. For each endpoint, we fit both a logistic regression model with only stent type as a predictor (univariate analysis), and a logistic regression model with stent type, average stent size, average stent length, age, left ventricular ejection fraction, diabetes, previous myocardial infarction (MI), number of diseased vessels, previous coronary artery bypass graft surgery (CABG), peripheral vascular disease (PVD) and vessels treated as predictors (multivariate analysis). Odds ratio (OR) estimates, 95% confidence intervals (CI), and p-values were obtained from the logistic regression models. A (two-sided) p-value (SAS Institute, Cary, North Carolina).
Results
Demographic and clinical characteristics (Table 1). Of the 89 patients included in the study, 24 received DES and 65 received BMS. DES patients tended to be younger than BMS patients (58 vs. 64 years; p = 0.072). Otherwise, demographic and clinical characteristics of DES and BMS patients were similar. In particular, the percentages of patients with diabetes (71% vs. 83%; p = 0.239) and those with previous CABG (17% vs. 29%; p = 0.284) were similar.
Angiographic and procedural characteristics (Table 2). The target vessels and percentages of patients with multivessel disease were similar in both groups. Since several patients had multiple stents implanted, comparisons were based on the average stent length and average stent diameter for each patient. DES patients received longer stents than BMS patients (20.4 mm vs. 17.3 mm; p = 0.006). In addition, the average stent diameter was smaller in the DES group (2.9 mm vs. 3.1 mm; p = 0.008). The procedural success rate and anticoagulation regimens did not differ between the two groups, with one exception: in accordance with manufacturer recommendations, post-procedure dual antiplatelet therapy was used for a longer duration in the DES group (typically >/= 6 months) than in the BMS group (100% vs. 18% for > 30 days of clopidogrel; p Clinical outcomes (Figure 1). The primary endpoint of TVR within 9 months occurred in 1 of the 24 DES patients (4%) and 17 of the 65 BMS patients (26%). The unadjusted OR (odds favoring the endpoint for a DES patient divided by odds favoring the endpoint for a BMS patient) was 0.12 (95% CI 0.015–0.98; p = 0.048). The adjusted OR was 0.07 (95% CI 0.006–0.844; p = 0.036). Thus, both univariate and multivariate analyses make a significant distinction in favor of DES.
The secondary (composite) endpoint was reached by 8 (33%) patients in the DES group and 39 (60%) of the BMS patients. The unadjusted and adjusted OR were 0.33 (95% CI 0.13–0.89; p = 0.029) and 0.11 (95% CI 0.022–0.513; p = 0.005), respectively. Six (25%) of the DES patients and 22 (34%) of the BMS patients died within 9 months. Two (8%) patients in the DES group and 3 (5%) patients in the BMS group were diagnosed with a MI. By definition, the diagnosis of MI was made based on an abnormal serum level of troponin according to the local laboratory values and cutoffs. Abnormal troponin levels were demonstrated on serial blood draws. In all cases, electrocardiographic changes and/or CK-MB elevation were present, supporting the diagnosis of MI.
Table 3 summarizes the results of the multivariate models fit to identify important predictors of the primary and secondary endpoints. In addition to the favorable impact of DES in reducing TVR and the composite of major adverse events, other variables found to be important in predicting adverse clinical outcomes included history of prior MI (p = 0.033 for TVR), history of previous CABG (p = 0.006 for the composite endpoint), and worsening left ventricular ejection fraction (p = 0.004 for the composite endpoint).
Discussion
In this analysis, we found DES to be effective in reducing 9-month TVR and the composite of death, MI and TVR in patients with ESRD undergoing PCI. However, mortality during this relatively short follow-up period remained strikingly high in this patient population, irrespective of the type of stent used for PCI. To our knowledge, this is the only study comparing outcomes of ESRD patients on chronic renal replacement therapy receiving DES versus those receiving BMS.
ESRD patients on dialysis are at particularly high risk of developing vascular disease, and those with established cardiovascular disease have worse outcomes and higher mortality than patients with normal renal function.12 Several pathophysiologic mechanisms to explain this increased risk have been suggested; most are related to the higher prevalence of traditional risk factors (most importantly diabetes and hypertension) among ESRD patients, but some of the increased risk may be related to the presence of “nontraditional” conditions specific to this patient population (anemia, arteriovenous fistula, left ventricular hypertrophy, increased oxidative stress, hyperhomocysteinemia, etc.).12–15 There is evidence that ESRD is also associated with an enhanced inflammatory state that contributes to the development of atherosclerosis in various arterial beds.12,15–18
Traditionally, the restenosis rate and the need for TVR have been much higher among ESRD patients undergoing PCI than in other patient populations. This has been true for balloon angioplasty as well as for BMS placement.19–23 There have been no data on the impact of DES in ESRD patients on dialysis, though a recent study by Lemos and colleagues observed improved outcomes with DES over conventional stents for patients with renal impairment.24 The improvement in outcomes was limited to a reduction in TVR, without a corresponding decrease in mortality. Patients on dialysis were excluded from that analysis, and the average creatinine clearance in the renal impairment arm was approximately 50 ml/min (i.e., mild or moderate kidney dysfunction). In another report by the same group concerning 10 patients with ESRD followed for 1 year, the feasibility of sirolimus-eluting stent use was established.25 That report did not compare DES and BMS with regard to outcomes. Our study extends the observations of both reports to demonstrate a significant benefit to dialysis patients from DES in comparison to BMS. Although the sample size was small, the incidence of TVR in the DES group was similar to that reported in randomized trials performed on highly selected and relatively low-risk patient populations.2,3
This study confirms historic data demonstrating high mortality rates among patients with ESRD, irrespective of the revascularization method. Although a numeric but statistically insignificant reduction in 9-month mortality was observed in favor of the DES group, the significant difference in the composite endpoint of death, MI and TVR was clearly driven by the 84% reduction in TVR. Similarly, large reductions in TVR have been noted in both the randomized trials and the large, retrospective studies comparing DES to BMS.2,3,6,7Study limitations. This is a retrospective study, and the limitations inherent in this type of study are well established, particularly the inability to avoid disparities in baseline characteristics that may influence the development of adverse events. The small numbers of patients and events did not allow a more detailed analysis of other potential predictors of adverse outcomes. In such small samples, subgroup analysis is usually not helpful and may portray chance findings as true associations. Angiographic characteristics of the target lesions were not available for review. However, our modeling incorporated the main clinical characteristics believed to affect the risks of TVR and other adverse outcomes following PCI. An important, but nonetheless unavoidable, limitation is the significant difference between the two study arms regarding the duration of clopidogrel use and its potential effect on the development of ischemic events.
Conclusions
In contemporary practice, patients with ESRD remain at particularly high risk for ischemic events following percutaneous coronary revascularization. Consistent with prospective trial data among patients with preserved renal function, we have observed the use of DES in ESRD patients on chronic dialysis to be associated with a markedly lower need for TVR and markedly fewer major adverse events. The reduction in the composite of major adverse events was primarily driven by the reduction in TVR. Given the consistency of benefit with DES, all patients with ESRD undergoing percutaneous coronary revascularization should preferentially receive a DES rather than a BMS.
References
1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
2. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
3. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231.
4. Ge L, Iakovou I, Sangiorgi GM, et al. Treatment of saphenous vein graft lesions with drug-eluting stents: Immediate and midterm outcome. J Am Coll Cardiol2005;45:989–994.
5. Werner GS, Krack A, Schwarz G, et al. Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents. J Am Coll Cardiol 2004;44:2301–2306.
6. Ong AT, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel- versus sirolimus-eluting stents for coronary artery disease in an unselected population: one-year results of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry. J Am Coll Cardiol 2005;45:1135–1141.
7. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world”: the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation 2004;109:190–195.
8. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697–701.
9. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296–1305.
10. Azar RR, Prpic R, Ho KK, et al. Impact of end-stage renal disease on clinical and angiographic outcomes after coronary stenting. Am J Cardiol 2000;86:485–489.
11. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined — A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959–969.
12. Shlipak MG, Fried LF, Crump C, et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107:87–92.
13. Muntner P, Hamm LL, Kusek JW, et al. The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease. Ann Intern Med 2004;140:9–17.
14. Galle J. Oxidative stress in chronic renal failure. Nephrol Dial Transplant 2001;16:2135–137.
15. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000;356:147–52.
16. Luke RG. Chronic renal failure — A vasculopathic state. N Engl J Med 1998;339:841–843.
17. London GM, Marchais SJ, Guerin AP, et al. Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 2002;17:1713–1724.
18. Suliman ME, Stenvinkel P, Qureshi AR, et al. Hyperhomocysteinemia in relation to plasma free amino acids, biomarkers of inflammation and mortality in patients with chronic kidney disease starting dialysis therapy. Am J Kidney Dis 2004;44:455–465.
19. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113–1119.
20. Ahmed WH, Shubrooks SJ, Gibson CM, et al. Complications and long-term outcome after percutaneous coronary angioplasty in chronic hemodialysis patients. Am Heart J 1994;128:252–255.
21. Le Feuvre C, Dambrin G, Helft G, et al. Clinical outcome following coronary angioplasty in dialysis patients: A case-control study in the era of coronary stenting. Heart 2001;85:556–560.
22. Marso SP, Gimple LW, Philbrick JT, DiMarco JP. Effectiveness of percutaneous coronary interventions to prevent recurrent coronary events in patients on chronic hemodialysis. Am J Cardiol 1998;82:378–380.
23. Szczech LA, Best PJ, Crowley E, et al. Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 2002;105:2253–2258.
24. Lemos PA, Arampatzis CA, Hoye A, et al. Impact of baseline renal function on mortality after percutaneous coronary intervention with sirolimus-eluting stents or bare metal stents. Am J Cardiol 2005;95:167–172.
25. Daemen J, Lemos P, Aoki J, et al. Treatment of coronary artery disease in dialysis patients with sirolimus-eluting stents: 1-year clinical follow-up of a consecutive series of cases. J Invasive Cardiol 2004;16:685–687.
