Cardiovascular Revascularization Medicine 15 (2014) 86–91
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Cardiovascular Revascularization Medicine
Drug-eluting stents in patients on chronic hemodialysis: Paclitaxel-eluting stents vs. limus-eluting stents Gabriel L. Sardi, Joshua P. Loh, Rebecca Torguson, Ana Laynez-Carnicero, Hironori Kitabata, Zhenyi Xue, Lowell F. Satler, Augusto D. Pichard, Ron Waksman ⁎ Division of Cardiology, MedStar Washington Hospital Center, Washington, DC
a r t i c l e
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Article history: Received 9 January 2014 Accepted 9 January 2014 Keywords: Drug-eluting stents Paclitaxel-eluting stents Limus-eluting stents Hemodialysis Restenosis
a b s t r a c t Background: Patients requiring chronic hemodialysis (HD) are at high risk for restenosis after percutaneous coronary intervention (PCI) with bare metal stents. Outcome data on drug-eluting stent (DES) implantation in HD patients are limited and suggest superiority of paclitaxel-eluting stents (PES) over limus-eluting stents (LES). Methods: In total, 218 consecutive patients were prospectively enrolled. A comparison of post-PCI outcomes up to 2 years was carried out between patients receiving PES (n = 62) and LES (n = 156; SES n = 112, EES n = 44). The primary end point was 2-year major adverse cardiac events [MACE; death, Q-wave myocardial infarction and target lesion revascularization (TLR)]. Results: Baseline characteristics were comparable. The overall prevalence of diabetes mellitus was 71%. On clinical follow-up to 2 years, MACE rates were similar [PES 32/51 (62.7%) vs. LES 77/132 (58.3%), p = 0.59]; however, clinically-driven revascularization occurred more than twice as frequently in LES patients: TLR [PES 4/36 (11.1%) vs. LES 24/93 (25.8%), p = 0.07] and target vessel revascularization [5/37 (13.5%) vs. 33/96 (34.4%), p = 0.02]. Given that overall mortality was nominally higher for PES patients [31/50 (62.0%) vs. 61/ 127 (48.0%), p = 0.09], a competing outcome analysis was implemented for TLR against mortality, which demonstrated that the trend for increased TLR with LES was no longer apparent (p = 0.282). On multivariable adjustment, only diabetes mellitus was independently associated with TLR (use of PES was not). Conclusions: Patients on chronic HD experience high rates of clinically driven TLR despite DES implantation. Use of PES does not demonstrate a significant advantage over LES in this population. © 2014 Published by Elsevier Inc.
1. Introduction Coronary artery disease is highly prevalent in end-stage kidney disease patients requiring chronic hemodialysis (HD); a high-risk population in whom cardiovascular disease is the principle cause of death [1–3], and in whom myocardial infarction (MI) is a much stronger predictor of risk compared to the general population [4–6]. An increased incidence of target lesion restenosis (TLR) has been recognized in HD patients after percutaneous coronary intervention (PCI) with bare metal stents [7]. This can be attributed to the presence of extensive calcification and lesion complexity, a high prevalence of diabetes mellitus (DM) [8,9] and a heightened pro-inflammatory state [10,11]. The use of drug-eluting stents (DES) as a better alternative, is conceivable in patients receiving chronic HD, but this notion is limited by the fact that randomized clinical trials typically exclude such patients, and as a result, DES performance data in this population are very limited. Some observational studies have reported ⁎ Corresponding author at: MedStar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. Tel.: +1 202 877 2812; fax: +1 202 877 2715. E-mail address: [email protected] (R. Waksman). 1553-8389/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.carrev.2014.01.006
lower rates of repeat revascularization with paclitaxel-eluting stents (PES) compared to sirolimus-eluting stents in patients receiving chronic HD [12,13]. However, the mechanism for this presumed PES advantage has not been clarified, and the observation has not been confirmed in a randomized clinical trial. Here we aimed to evaluate the use of various DES types on a relatively large population of patients treated with chronic HD and to specifically assess whether the use of PES in this population carries a significant advantage when compared to other available DES types. 2. Methods Clinical, procedural and follow-up data were prospectively collected for consecutive patients on chronic HD undergoing PCI with stenting from January 2000 to December 2010. Chronic HD was defined as regular dialysis treatment for ≥ 30 days. The TAXUS® PES (Boston Scientific Corporation, Natick, MA) was used, and then compared to sirolimus-eluting (CYPHER®, Cordis Corporation, Bridgewater, NJ) and everolimus-eluting stents [XIENCE® (Abbott Vascular, Santa Clara, CA) or PROMUS® (Boston Scientific, Natick, MA)], herein grouped as limus-eluting stents (LES).
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The institutional review boards of MedStar Washington Hospital Center and MedStar Health Research Institute (Washington, DC) approved this study. Experienced staff at a dedicated data-coordinating center performed all data collection, entry, and analysis. Data regarding baseline clinical and procedural data, together with postprocedure in-patient events, were obtained from hospital chart review. Clinical follow-up at 30 days, 6 months and 1 year was conducted via telephone contact or office visits. Primary source documents for all events were obtained and adjudicated by physicians not involved in the procedures and who were unaware of the objectives of the study. PCI was performed according to guidelines current at procedure time. In all cases, interventional strategy and choice of peri-procedural and discharge medications were at the responsible physician’s discretion. Anticoagulation regimens included either bivalirudin 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure or unfractionated heparin to achieve an activated clotting time of 200–300 s in all patients. All patients received an aspirin loading dose of 325 mg and were prescribed 81–325 mg once daily indefinitely. After a clopidogrel loading dose of 300–600 mg, patients were prescribed 75 mg once daily for ≥ 6 months. The primary end point was defined as major adverse cardiac events (MACE), the composite of all-cause mortality, Q-wave myocardial infarction, and TLR at 2 years’ follow up. The secondary end point was the individual outcome of TLR at 2 years. Academic Research Consortium definitions for stent thrombosis were used [14]. Q-wave myocardial infarction was defined as an elevation of creatine kinase-MB ≥ 3 times the upper normal value in the presence of new pathologic Q waves (N0.4 s) in ≥ 2 contiguous leads of the electrocardiogram. TLR was defined as clinically driven revascularization of the index lesion. PCI angiographic success was defined as a residual stenosis of b 30% with Thrombolysis in Myocardial Infarction grade 3 flow. Clinical success was defined as angiographic success plus the absence of TLR, Q-wave myocardial infarction, or death prior to hospital discharge. Major bleeding was defined using the Thrombolysis in Myocardial Infarction criteria [15]. Vascular complications were defined as the presence of a large hematoma (≥ 5 cm), fistula, or pseudoaneurysm formation, retroperitoneal bleeding, or the need for surgical repair. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Normally distributed continuous variables are presented as mean ± SD. Those not normally distributed are shown
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as median ± interquartile range. Categorical variables are expressed as frequencies and percentages. Baseline characteristics were compared using Student’s t test for parametric variables or the Mann– Whitney U test when not normally distributed. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Two-year outcomes were compared with the log-rank test and are presented by Kaplan–Meier percentages. To test the independent effect of DM and angiographic lesion complexity over TLR at 2 years in patients with end-stage renal disease, a multivariable Cox regression model was constructed with the following variables: History of DM, American College of Cardiology/American Heart Association (ACC/AHA) type C lesion, and use of PES. These variables were chosen based on a value for p b 0.1 on univariable analysis or because they were considered clinically relevant. The proportional hazards assumption was assessed by Kolmogorov-type Supremum test. Only patients with data present for all co-variables were included. A p value b 0.05 was considered statistically significant. To evaluate if death before TLR occurrence confounded the result for this end point, a competing outcome analysis was carried out over the entire cohort. To analyze whether the presence of DM would favor the performance of one type of DES over the other, a subgroup analysis was performed by restricting the population to those with a history of DM. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [16]. 3. Results A total of 218 patients on chronic HD underwent PCI with a DES. Sixty-two patients were treated with a PES, while 156 patients received a LES (SES n = 112, EES n = 44). There were no exclusions. The average age for the entire cohort was 67 years (±11) and the population was predominantly male (57%). Sixty percent of patients were African American. Table 1 outlines the baseline characteristics for both the entire cohort and the DM subgroup. There were no significant baseline clinical differences between the patients treated with either type of stent in the overall cohort and in the DM-restricted population. Overall, the prevalence of DM was 71%, of which 39.2% received insulin. More than 50% of the population had a history of coronary revascularization by either PCI or coronary artery bypass grafting.
Table 1 Baseline characteristics. Entire Cohort
Age (years) Men African–American Current smoker Unstable angina at presentation Myocardial infarction at presentation Cardiogenic shock at presentation History of diabetes mellitus Insulin-treated diabetes mellitus History of hypertension History of dyslipidemia History of myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass surgery History of congestive heart failure Left ventricular ejection fraction Angiotensin-converting enzyme inhibitor Beta blocker Statin
Diabetes Mellitus Restricted
LES (n = 156)
PES (n = 62)
p Value
LES (n = 115)
PES (n = 39)
p Value
66.62 ± 10.67 84 (53.8%) 97 (62.2%) 13 (8.3%) 51 (32.9%) 16 (10.3%) 7 (4.6%) 115 (74.2%) 65 (41.9%) 154 (98.7%) 143 (92.3%) 47 (32.4%) 46 (31.5%) 46 (31.5%) 68 (45.9%) 0.42 ± 0.15 66 (44.6%) 125 (83.9%) 118 (81.9%)
66.97 ± 11.63 40 (64.5%) 33(53.2%) 9 (14.5%) 19 (30.6%) 6 (9.7%) 2 (3.3%) 39 (62.9%) 20 (32.3%) 61 (98.4%) 52 (83.9%) 22 (40.0%) 20 (37.0%) 15 (24.2%) 31 (51.7%) 0.42 ± 0.15 34 (54.8%) 51 (83.6%) 45 (73.8%)
0.83 0.15 0.22 0.17 0.75 0.89 1.00 0.10 0.19 1.00 0.06 0.31 0.46 0.43 0.45 0.98 0.18 0.96 0.19
66.27 ± 10.57 54 (47.0%) 74 (64.3%) 8 (7.0%) 36 (31.6%) 12 (10.5%) 6 (5.2%) 115 (100.0%) 65 (56.5%) 113 (98.3%) 108 (93.9%) 32 (29.9%) 34 (31.2%) 27 (23.5%) 49 (45.4%) 0.44 ± 0.15 49 (45.0%) 89 (81.7%) 89 (82.4%)
66.44 ± 11.00 23 (59.0%) 21(53.8%) 4 (10.3%) 15 (38.5%) 4 (10.3%) 2 (5.3%) 39 (100.0%) 20 (51.3%) 39 (100.0%) 35 (89.7%) 14 (42.4%) 12 (38.7%) 11 (28.2%) 20 (52.6%) 0.43 ± 0.15 22 (56.4%) 33 (84.6%) 26 (68.4%)
0.93 0.20 0.24 0.50 0.43 1.00 1.00 0.57 1.00 0.47 0.18 0.43 0.55 0.44 0.90 0.22 0.81 0.07
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Table 2 Baseline angiographic and procedural characteristics. LES (n = 156) Procedural Characteristics Number of diseased vessels 2.13 ± 0.88 Number of lesions treated 1.83 ± 0.97 Number of implanted stents 1.63 ± 0.88 Pre-intervention lesion 0.85 ± 0.09 stenosis (visual estimation) Post-intervention lesion 0.04 ± 0.13 stenosis (visual estimation) Implanted stent diameter 3.18 ± 1.85 Implanted stent length 19.8 ± 6.45 Intraprocedural bivalirudin use 109 (69.9%) Angiographic Characteristics (Lesion based) Angiographic success 302/311 (97.1%) Left anterior descendent artery PCI 106/315 (33.7%) Left circumflex artery PCI 100/315 (31.7%) Right coronary artery PCI 77/315 (24.4%) Saphenous vein graft PCI 18/315 (5.7%) ACC/AHA Type A lesion 15/300 (5.0%) ACC/AHA Type B1/B2 lesion 182/300 (60.7%) ACC/AHA Type C lesion 103/300 (34.3%) PCI to an ostial lesion 14/312 (4.5%) PCI to a lesion with 14/314 (4.5%) in-stent restenosis IVUS performed during index PCI 179/311 (58.8%) Rotational atherectomy used 9/315 (2.9%) Balloon used for pre-dilatation 118/289 (40.8%) Balloon used for post-dilatation 59/289 (20.4%) Angiographic dissection 2/300 (0.7%) Development of no-reflow 1/299 (0.3%)
Table 4 Long-term outcomes. PES (n = 62)
p Value
2.07 1.63 1.45 0.86
0.94 0.86 0.76 0.08
0.78 0.17 0.16 0.32
0.05 ± 0.14
0.58
2.96 ± 0.47 19.96 ± 9.24 41 (66.1%)
0.19 0.88 0.59
102/104 (98.1%) 44/104 (42.3%) 23/104 (22.1%) 29/104 (27.9%) 7/104 (6.7%) 3/104 (2.9%) 79/104 (76.0%) 22/104 (21.2%) 6/102 (5.9%) 4/104 (3.8%)
0.74 0.11 0.06 0.48 0.70 0.58 0.01 0.01 0.60 1.00
67/103 (65.0%) 6/104 (5.8%) 51/100 (51.0%) 13/100 (13.0%) 0 0
0.18 0.22 0.08 0.10 1.00 1.00
± ± ± ±
PCI, percutaneous coronary intervention; ACC/AHA, American College of Cardiology/ American Heart Association; IVUS, intravascular ultrasound.
Approximately 40% of patients had an acute coronary syndrome at presentation for which PCI was performed; 4% were in cardiogenic shock at presentation. Table 2 shows the angiographic and procedural characteristics for the general population in the two treatment arms, which are largely similar. Statistically significant differences were found with regard to the complexity of lesions based on the ACC/AHA classification, with a higher incidence of type B1/B2 lesions in those treated with PES compared to LES (76.0% vs. 60.2%, p = 0.01), and more type C lesions in patients treated with LES compared to PES (33.9% vs. 21.2%, p = 0.01). Unadjusted in-hospital outcomes are reported in Table 3. Overall there were no significant differences in outcomes between the 2 groups before hospital discharge, but there was a trend toward higher all-cause and cardiovascular mortality in patients treated with LES as compared to PES.
Table 3 In-hospital Outcomes.
Post-procedural myocardial infarctiona In-hospital major adverse cardiac eventsb Death Cardiac death Q-wave myocardial infarction Urgent target lesion revascularization Stent Thrombosis Neurologic event (cerebrovascular accident) Vascular complications Major bleeding Clinical success a
PES (n = 62)
p Value
One-year outcomes Major adverse cardiac eventsa 55 (35.7%) 24 (38.7%) 0.68 Death 42 (27.5%) 21 (33.9%) 0.35 Q-wave myocardial infarction 1 (0.7%) 3 (5.1%) 0.09 Target lesion revascularization 17 (12.4%) 4 (6.8%) 0.24 Target vessel revascularization 23 (16.5%) 4 (6.8%) 0.07 Cumulative definite stent thrombosis 3 (1.9%) 2 (3.2%) 0.62 Two-year outcomes a Major adverse cardiac events 77/132 (58.3%) 32/51 (62.7%) 0.57 Death 61/127 (48.0%) 31/50 (62.0%) 0.09 Q-wave myocardial infarction 1/83 (1.2%) 3/36 (8.3%) 0.08 Target lesion revascularization 24/93 (25.8%) 4/36 (11.1%) 0.06 Target vessel revascularization 33/96 (34.4%) 5/37 (13.5%) 0.02 Cumulative definite stent thrombosis 3/135 (2.2%) 2/52 (3.8%) 0.67 a
Death, Q-wave myocardial infarction, and target lesion revascularization.
Long-term outcomes are presented in Table 4. The composite primary end point of MACE occurred similarly in both study cohorts up to 2 years [PES 32/51 (62.7%), vs. LES 77/132 (58.3%), p = 0.59], (Fig. 1) but the individual components of TLR and death deserve further mention. Although they did not reach statistical significance, TLR rates were doubled in patients treated with LES (PES 6.8% vs. LES 12.4%, p = 0.24 at 1 year, and PES 11.1% vs. LES 25.8%, p = 0.06 at 2 years), (Fig. 2). Target vessel revascularization rates demonstrated similar trends at 1 year (PES 6.8% vs. LES 16.5%, p = 0.07), and reached statistical significance at 2 years (PES 13.5% vs. LES 34.4%, p = 0.02). (Fig. 3). Of further interest, the individual component of death was nominally higher in patients treated with a PES (33.9% vs. LES 27.5%, p = 0.35, at 1 year and PES 62% vs. LES 48%, p = 0.09, at 2 years). Given the opposite trends of these death and revascularization outcomes, we performed a competitive outcome analysis to evaluate whether the occurrence of death confounded the TLR end point. After adjustment, the difference favoring the use of PES in regard to TLR was no longer apparent (adjusted p = 0.37). Multivariable risk adjustment confirmed the lack of an independent association between TLR and PES use (HR 1.49, 95% CI 0.49–4.49, p = 0.480) with the only predictor of TLR at 2 years being a history of DM (HR 8.61, 95%CI 1.15–64.3, p = 0.036). (Table 5). Table 6 presents the long-term outcomes of the DM subgroup. Similar MACE and TLR rates were seen between PES and LES groups up to 2 years, which is consistent with the results of the entire cohort. Multivariable risk adjustment confirmed the lack of an independent association between TLR and the use of a PES (HR 1.36, 95%CI 0.45–4.14, p = 0.590). Insulin requirement or treatment of an angiographically complex index lesion did not demonstrate an independent association with 2-year TLR. (Table 7). 4. Discussion
LES (n = 156)
PES (n = 62)
p Value
27 (17.4%) 9 (5.8%) 7 (4.5%) 4 (2.6%) 2 (1.3%) 0 0 2 (1.3%) 5 (3.2%) 5 (3.2%) 147 (94.2%)
9 (14.5%) 1 (1.6%) 0 0 0 1 (1.7%) 0 1 (1.6%) 3 (4.8%) 3 (4.8%) 61 (98.4%)
0.60 0.29 0.20 0.58 1.00 0.28 1.00 0.69 0.69 0.29
CK-MB elevation to 3× upper limit of normal. In-hospital all-cause death, Q-wave myocardial infarction, urgent target lesion revascularization, urgent coronary artery bypass surgery. b
LES (n = 156)
The primary finding of this study is that in patients receiving chronic HD, implantation of a PES does not appear to confer a particular clinical advantage over the rapamycin analog-eluting stents (SES or EES). In addition, our results support the notion that restenosis after PCI is very prevalent in HD patients, even after DES implantation. Previous reports based on observational data have suggested a revascularization advantage of PES over SES in patients receiving chronic HD [12,13]. This concept is of important clinical significance for the management of a population with a rising prevalence in the US [2]. Currently available DES comparisons in patients receiving chronic HD have predominantly evaluated SES against PES. These retrospective analyses have reported less favorable outcomes for
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Fig. 1. Survival free of MACE. This graph demonstrates the high incidence of adverse events in the evaluated cohort of patients treated with chronic hemodialysis. At two years, more than half the patients experienced a MACE event. In addition, there are no significant differences between PES and LES in regards to this composite outcome. MACE, major adverse cardiac events; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
patients treated with SES, as worsening degrees of renal dysfunction are associated with increasing rates of restenosis [17]; a finding not present in patients treated with a PES [13,18]. Thus, the use of paclitaxel has been favored, especially if DM and renal failure coexist [19]. It has been suggested that PES maintain their anti-restenotic properties in patients with DM, which is one of the most common etiologies of end-stage kidney disease leading to chronic HD [20–22]. Contrary to the theoretical advantages of PES, our results do not
demonstrate a clinically meaningful difference in regards to the incidence of TLR when PES and LES are compared in patients receiving chronic HD. This conclusion is reached after adjustment for baseline angiographic complexity as well as different trends in mortality, and is further confirmed in the subgroup of patients with DM. The frequency of co-morbid conditions and complex angiographic findings encountered in this cohort of HD patients highlights the importance of accounting for baseline differences when evaluating such a high-risk population. Previous studies suggesting a benefit
Fig. 2. Survival free of TLR. This graph shows the unadjusted incidence of TLR on HD patients treated with PES vs. LES. Before adjustment for baseline characteristics, a trend favoring PES implantation is apparent. Notably, this finding is no longer present after adjustment. (See Table 5). TLR, target lesion revascularization; HD, hemodialysis; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
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Fig. 3. Survival free of TVR. This graph shows the unadjusted incidence of TVR on HD patients treated with PES vs. LES. Before adjustment for baseline characteristics, PES appears to be more favorable. TVR, target vessel revascularization; HD, hemodialysis; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
of PES over SES [12,13] have salient baseline clinical and angiographic differences that favored PES, which could explain their conflicting conclusions. The results of the present study correlate well with a small randomized study of patients on HD treated with either SES or PES, which found no angiographic differences up to 8 months of followup [8]. Furthermore, this “real world” study highlights the frequent need for revascularization in patients receiving chronic HD. Clinically-driven TLR rates of 11% at 1 year and 22% at 2 years, as noted in the overall cohort, are two to three-fold higher than the rates reported for DM patients treated with DES, a population already considered to be at high risk [21,23,24]. This supports the concept
Table 5 Multivariable model on two-year target lesion revascularization (TLR).
Implantation of a paclitaxel-eluting stent History of diabetes mellitus ACC/AHA type C index lesion
Hazard Ratio (95% CI*) TLR
p Value
1.49 (0.49–4.49) 8.61 (1.15–64.3) 1.75 (0.73–4.16)
0.480 0.036 0.208
ACC/AHA, American College of Cardiology/American Heart Association.
Table 6 Long-term outcomes on the diabetes mellitus-restricted population. LES (n = 115) One-year outcomes Major adverse cardiac eventsa Death Q-wave myocardial infarction Target lesion revascularization Target vessel revascularization Cumulative definite stent thrombosis Two-year outcomes Major adverse cardiac eventsa Death Q-wave myocardial infarction Target lesion revascularization Target vessel revascularization Cumulative definite stent thrombosis a
PES (n = 39)
p Value
44 31 1 16 19 3
(38.6%) (27.4%) (1.0%) (16.0%) (18.8%) (2.6%)
14 12 2 4 4 2
(35.9%) (30.8%) (5.4%) (10.8%) (10.8%) (5.1%)
0.76 0.69 0.18 0.45 0.26 0.60
60/96 44/91 1/59 22/68 25/70 3/98
(62.5%) (48.4%) (1.7%) (32.4%) (35.7%) (3.1%)
21/32 21/32 2/24 4/25 5/26 2/33
(65.6%) (65.6%) (8.3%) (16.0%) (19.2%) (6.1%)
0.75 0.09 0.20 0.12 0.12 0.60
Death, Q-wave myocardial infarction, and target lesion revascularization.
that HD acts as an additive risk factor for TLR in DM patients [25], and highlights the finding that despite high rates of angiographic success, restenosis continues to be highly prevalent in HD patients, even after DES implantation. This study is strengthened in that it includes a relatively large number of patients in whom outcomes were carefully recorded prospectively; and is one of the largest cohorts specifically comparing DES PCI in patients receiving chronic HD. It is, however, limited by its single-center, retrospective nature, which makes it subject to the known shortcomings of such evaluations. The limited number of events, as well as the relatively high attrition rates encountered in this high-risk population, may have underpowered our ability to detect differences among groups. Moreover, this study encompasses a lengthy period of 10 years, during which management changes have arisen, such as the preferential use of newer-generation DES instead of PES. Despite these limitations, clinical characteristics and basic adjunctive medications were carefully recorded and presented in detail. Although the groups were found to be very similar at baseline, unmeasured confounders may still be present and may potentially influence our results. Finally, older-generation PES (Taxus®) is infrequently used today in the US, but the clinical implications of such a comparison against this stent are of current relevance. Studies in HD patients have evaluated this stent in particular, and newergeneration PES available today are expected to grant the same benefits, as it is still proposed that the use of paclitaxel on a stent is more favorable for patients with DM and for those on chronic HD. In conclusion, patients on chronic HD experience high rates of clinically-driven TLR despite DES implantation, and the use of PES does not confer a significant clinical advantage over rapamycin
Table 7 Multivariable model on two-year target lesion revascularization (TLR) in the diabetes mellitus- restricted population.
Paclitaxel-eluting stent implantation Insulin requiring diabetes mellitus ACC/AHA type C index lesion
Hazard Ratio (95% CI*) TLR
p Value
1.36 (0.45–4.14) 0.68 (0.28–1.64) 1.95 (0.80–4.75)
0.590 0.388 0.142
ACC/AHA, American College of Cardiology/American Heart Association.
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analog-eluting stents (SES and EES). The significant prevalence and impact of coronary artery disease on this growing population necessitate the need for a large randomized trial. References [1] K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1–S266. [2] US Renal Data System, USRDS 2010 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2010. [3] Robert AM, Brown JR, Sidhu MS, Ramanath VS, Devries JT, Jayne JE, et al. Dartmouth Dynamic Registry Investigators. The evaluation of creatinine clearance, estimated glomerular filtration rate and serum creatinine in predicting contrastinduced acute kidney injury among patients undergoing percutaneous coronary intervention. Cardiovasc Revasc Med 2012;13:3–10. [4] Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 1998;339:799–805. [5] Wright RS, Reeder GS, Herzog CA, Albright RC, Williams BA, Dvorak DL, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 2002;137:563–70. [6] Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113–9. [7] Le Feuvre C, Dambrin G, Helft G, Beygui F, Touam M, Grünfeld JP, et al. Clinical outcome following coronary angioplasty in dialysis patients: a case–control study in the era of coronary stenting. Heart 2001;85:556–60. [8] Kamoi D, Ishii H, Takahashi H, Aoyama T, Toriyama T, Tanaka M, et al. Sirolimus- vs. paclitaxel-eluting stent to coronary intervention in dialysis patients. Int J Cardiol 2013;165:533–6. [9] Naidu SS, Selzer F, Jacobs A, Faxon D, Marks DS, Johnston J, et al. Renal insufficiency is an independent predictor of mortality after percutaneous coronary intervention. Am J Cardiol 2003;92:1160–4. [10] Ishii H, Kumada Y, Toriyama T, Aoyama T, Takahashi H, Amano T, et al. Aortic valvular calcification predicts restenosis after implantation of drug-eluting stents in patients on chronic haemodialysis. Nephrol Dial Transplant 2009;24:1562–7. [11] Ishii H, Toriyama T, Aoyama T, Takahashi H, Amano T, Hayashi M, et al. Prognostic values of C-reactive protein levels on clinical outcome after implantation of sirolimuseluting stents in patients on hemodialysis. Circ Cardiovasc Interv 2009;2:513–8. [12] Higashitani M, Mori F, Yamada N, Arashi H, Kojika A, Hoshi H, et al. Efficacy of paclitaxel-eluting stent implantation in hemodialysis patients. Heart Vessels 2011;26:582–9.
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[13] Otsuka M, Toyofuku M, Watanabe N, Motoda C, Kawase T, Takeda R, et al. Clinical usefulness of drug-eluting stents in the treatment of dialysis patients with coronary artery disease. EuroIntervention 2011;6:754–9. [14] Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [15] Coats AJS, Shewan LG. Statement on authorship and publishing ethics in the International Journal of Cardiology. Int J Cardiol 2011;153:239–40. [16] Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1–11. [17] Nakazawa G, Tanabe K, Aoki J, Yamamoto H, Higashikuni Y, Onuma Y, et al. Impact of renal insufficiency on clinical and angiographic outcomes following percutaneous coronary intervention with sirolimus-eluting stents. Catheter Cardiovasc Interv 2007;69:808–14. [18] Halkin A, Mehran R, Casey CW, Gordon P, Matthews R, Wilson BH, et al. Impact of moderate renal insufficiency on restenosis and adverse clinical events after paclitaxel-eluting and bare metal stent implantation: results from the TAXUS-IV Trial. Am Heart J 2005;150:1163–70. [19] Mayor M, Malik AZ, Minor Jr RJ, Deshpande MC, Strauss WE, Maloney TH, et al. One-year outcomes from the TAXUS express stent versus cypher stent. Am Heart J 2009;103:930–6. [20] Rocic P. Differential phosphoinositide 3-kinase signaling: implications for PTCA? Am J Physiol Heart Circ Physiol 2009;297:H1970–1. [21] Stone GW, Kedhi E, Kereiakes DJ, Parise H, Fahy M, Serruys PW, et al. Differential clinical responses to everolimus-eluting and Paclitaxel-eluting coronary stents in patients with and without diabetes mellitus. Circulation 2011;124:893–900. [22] Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med 1995;332:1004–14. [23] Kufner S, de Waha A, Tomai F, Park SW, Lee SW, Lim DS, et al. A meta-analysis of specifically designed randomized trials of sirolimus-eluting versus paclitaxeleluting stents in diabetic patients with coronary artery disease. Am Heart J 2011;162:740–7. [24] Mieres J, Fernandez-Pereira C, Risau G, Solorzano L, Pauletto R, Rodriguez-Granillo AM, et al. One-year outcome of patients with diabetes mellitus after percutaneous coronary intervention with three different revascularization strategies: results from the DiabEtic Argentina Registry (DEAR). Cardiovasc Revasc Med 2012;13: 265–71. [25] Sardi GL, Maluenda G, Torguson R, Xue Z, Suddath WO, Kent KM, et al. Impact of diabetes mellitus on long-term clinical outcomes of patients on chronic hemodialysis after percutaneous coronary intervention. J Interv Cardiol 2012;25:147–55.
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Drug-eluting stents in patients on chronic hemodialysis: Paclitaxel-eluting stents vs. limus-eluting stents Gabriel L. Sardi, Joshua P. Loh, Rebecca Torguson, Ana Laynez-Carnicero, Hironori Kitabata, Zhenyi Xue, Lowell F. Satler, Augusto D. Pichard, Ron Waksman ⁎ Division of Cardiology, MedStar Washington Hospital Center, Washington, DC
a r t i c l e
i n f o
Article history: Received 9 January 2014 Accepted 9 January 2014 Keywords: Drug-eluting stents Paclitaxel-eluting stents Limus-eluting stents Hemodialysis Restenosis
a b s t r a c t Background: Patients requiring chronic hemodialysis (HD) are at high risk for restenosis after percutaneous coronary intervention (PCI) with bare metal stents. Outcome data on drug-eluting stent (DES) implantation in HD patients are limited and suggest superiority of paclitaxel-eluting stents (PES) over limus-eluting stents (LES). Methods: In total, 218 consecutive patients were prospectively enrolled. A comparison of post-PCI outcomes up to 2 years was carried out between patients receiving PES (n = 62) and LES (n = 156; SES n = 112, EES n = 44). The primary end point was 2-year major adverse cardiac events [MACE; death, Q-wave myocardial infarction and target lesion revascularization (TLR)]. Results: Baseline characteristics were comparable. The overall prevalence of diabetes mellitus was 71%. On clinical follow-up to 2 years, MACE rates were similar [PES 32/51 (62.7%) vs. LES 77/132 (58.3%), p = 0.59]; however, clinically-driven revascularization occurred more than twice as frequently in LES patients: TLR [PES 4/36 (11.1%) vs. LES 24/93 (25.8%), p = 0.07] and target vessel revascularization [5/37 (13.5%) vs. 33/96 (34.4%), p = 0.02]. Given that overall mortality was nominally higher for PES patients [31/50 (62.0%) vs. 61/ 127 (48.0%), p = 0.09], a competing outcome analysis was implemented for TLR against mortality, which demonstrated that the trend for increased TLR with LES was no longer apparent (p = 0.282). On multivariable adjustment, only diabetes mellitus was independently associated with TLR (use of PES was not). Conclusions: Patients on chronic HD experience high rates of clinically driven TLR despite DES implantation. Use of PES does not demonstrate a significant advantage over LES in this population. © 2014 Published by Elsevier Inc.
1. Introduction Coronary artery disease is highly prevalent in end-stage kidney disease patients requiring chronic hemodialysis (HD); a high-risk population in whom cardiovascular disease is the principle cause of death [1–3], and in whom myocardial infarction (MI) is a much stronger predictor of risk compared to the general population [4–6]. An increased incidence of target lesion restenosis (TLR) has been recognized in HD patients after percutaneous coronary intervention (PCI) with bare metal stents [7]. This can be attributed to the presence of extensive calcification and lesion complexity, a high prevalence of diabetes mellitus (DM) [8,9] and a heightened pro-inflammatory state [10,11]. The use of drug-eluting stents (DES) as a better alternative, is conceivable in patients receiving chronic HD, but this notion is limited by the fact that randomized clinical trials typically exclude such patients, and as a result, DES performance data in this population are very limited. Some observational studies have reported ⁎ Corresponding author at: MedStar Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. Tel.: +1 202 877 2812; fax: +1 202 877 2715. E-mail address: [email protected] (R. Waksman). 1553-8389/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.carrev.2014.01.006
lower rates of repeat revascularization with paclitaxel-eluting stents (PES) compared to sirolimus-eluting stents in patients receiving chronic HD [12,13]. However, the mechanism for this presumed PES advantage has not been clarified, and the observation has not been confirmed in a randomized clinical trial. Here we aimed to evaluate the use of various DES types on a relatively large population of patients treated with chronic HD and to specifically assess whether the use of PES in this population carries a significant advantage when compared to other available DES types. 2. Methods Clinical, procedural and follow-up data were prospectively collected for consecutive patients on chronic HD undergoing PCI with stenting from January 2000 to December 2010. Chronic HD was defined as regular dialysis treatment for ≥ 30 days. The TAXUS® PES (Boston Scientific Corporation, Natick, MA) was used, and then compared to sirolimus-eluting (CYPHER®, Cordis Corporation, Bridgewater, NJ) and everolimus-eluting stents [XIENCE® (Abbott Vascular, Santa Clara, CA) or PROMUS® (Boston Scientific, Natick, MA)], herein grouped as limus-eluting stents (LES).
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The institutional review boards of MedStar Washington Hospital Center and MedStar Health Research Institute (Washington, DC) approved this study. Experienced staff at a dedicated data-coordinating center performed all data collection, entry, and analysis. Data regarding baseline clinical and procedural data, together with postprocedure in-patient events, were obtained from hospital chart review. Clinical follow-up at 30 days, 6 months and 1 year was conducted via telephone contact or office visits. Primary source documents for all events were obtained and adjudicated by physicians not involved in the procedures and who were unaware of the objectives of the study. PCI was performed according to guidelines current at procedure time. In all cases, interventional strategy and choice of peri-procedural and discharge medications were at the responsible physician’s discretion. Anticoagulation regimens included either bivalirudin 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure or unfractionated heparin to achieve an activated clotting time of 200–300 s in all patients. All patients received an aspirin loading dose of 325 mg and were prescribed 81–325 mg once daily indefinitely. After a clopidogrel loading dose of 300–600 mg, patients were prescribed 75 mg once daily for ≥ 6 months. The primary end point was defined as major adverse cardiac events (MACE), the composite of all-cause mortality, Q-wave myocardial infarction, and TLR at 2 years’ follow up. The secondary end point was the individual outcome of TLR at 2 years. Academic Research Consortium definitions for stent thrombosis were used [14]. Q-wave myocardial infarction was defined as an elevation of creatine kinase-MB ≥ 3 times the upper normal value in the presence of new pathologic Q waves (N0.4 s) in ≥ 2 contiguous leads of the electrocardiogram. TLR was defined as clinically driven revascularization of the index lesion. PCI angiographic success was defined as a residual stenosis of b 30% with Thrombolysis in Myocardial Infarction grade 3 flow. Clinical success was defined as angiographic success plus the absence of TLR, Q-wave myocardial infarction, or death prior to hospital discharge. Major bleeding was defined using the Thrombolysis in Myocardial Infarction criteria [15]. Vascular complications were defined as the presence of a large hematoma (≥ 5 cm), fistula, or pseudoaneurysm formation, retroperitoneal bleeding, or the need for surgical repair. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Normally distributed continuous variables are presented as mean ± SD. Those not normally distributed are shown
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as median ± interquartile range. Categorical variables are expressed as frequencies and percentages. Baseline characteristics were compared using Student’s t test for parametric variables or the Mann– Whitney U test when not normally distributed. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Two-year outcomes were compared with the log-rank test and are presented by Kaplan–Meier percentages. To test the independent effect of DM and angiographic lesion complexity over TLR at 2 years in patients with end-stage renal disease, a multivariable Cox regression model was constructed with the following variables: History of DM, American College of Cardiology/American Heart Association (ACC/AHA) type C lesion, and use of PES. These variables were chosen based on a value for p b 0.1 on univariable analysis or because they were considered clinically relevant. The proportional hazards assumption was assessed by Kolmogorov-type Supremum test. Only patients with data present for all co-variables were included. A p value b 0.05 was considered statistically significant. To evaluate if death before TLR occurrence confounded the result for this end point, a competing outcome analysis was carried out over the entire cohort. To analyze whether the presence of DM would favor the performance of one type of DES over the other, a subgroup analysis was performed by restricting the population to those with a history of DM. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [16]. 3. Results A total of 218 patients on chronic HD underwent PCI with a DES. Sixty-two patients were treated with a PES, while 156 patients received a LES (SES n = 112, EES n = 44). There were no exclusions. The average age for the entire cohort was 67 years (±11) and the population was predominantly male (57%). Sixty percent of patients were African American. Table 1 outlines the baseline characteristics for both the entire cohort and the DM subgroup. There were no significant baseline clinical differences between the patients treated with either type of stent in the overall cohort and in the DM-restricted population. Overall, the prevalence of DM was 71%, of which 39.2% received insulin. More than 50% of the population had a history of coronary revascularization by either PCI or coronary artery bypass grafting.
Table 1 Baseline characteristics. Entire Cohort
Age (years) Men African–American Current smoker Unstable angina at presentation Myocardial infarction at presentation Cardiogenic shock at presentation History of diabetes mellitus Insulin-treated diabetes mellitus History of hypertension History of dyslipidemia History of myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass surgery History of congestive heart failure Left ventricular ejection fraction Angiotensin-converting enzyme inhibitor Beta blocker Statin
Diabetes Mellitus Restricted
LES (n = 156)
PES (n = 62)
p Value
LES (n = 115)
PES (n = 39)
p Value
66.62 ± 10.67 84 (53.8%) 97 (62.2%) 13 (8.3%) 51 (32.9%) 16 (10.3%) 7 (4.6%) 115 (74.2%) 65 (41.9%) 154 (98.7%) 143 (92.3%) 47 (32.4%) 46 (31.5%) 46 (31.5%) 68 (45.9%) 0.42 ± 0.15 66 (44.6%) 125 (83.9%) 118 (81.9%)
66.97 ± 11.63 40 (64.5%) 33(53.2%) 9 (14.5%) 19 (30.6%) 6 (9.7%) 2 (3.3%) 39 (62.9%) 20 (32.3%) 61 (98.4%) 52 (83.9%) 22 (40.0%) 20 (37.0%) 15 (24.2%) 31 (51.7%) 0.42 ± 0.15 34 (54.8%) 51 (83.6%) 45 (73.8%)
0.83 0.15 0.22 0.17 0.75 0.89 1.00 0.10 0.19 1.00 0.06 0.31 0.46 0.43 0.45 0.98 0.18 0.96 0.19
66.27 ± 10.57 54 (47.0%) 74 (64.3%) 8 (7.0%) 36 (31.6%) 12 (10.5%) 6 (5.2%) 115 (100.0%) 65 (56.5%) 113 (98.3%) 108 (93.9%) 32 (29.9%) 34 (31.2%) 27 (23.5%) 49 (45.4%) 0.44 ± 0.15 49 (45.0%) 89 (81.7%) 89 (82.4%)
66.44 ± 11.00 23 (59.0%) 21(53.8%) 4 (10.3%) 15 (38.5%) 4 (10.3%) 2 (5.3%) 39 (100.0%) 20 (51.3%) 39 (100.0%) 35 (89.7%) 14 (42.4%) 12 (38.7%) 11 (28.2%) 20 (52.6%) 0.43 ± 0.15 22 (56.4%) 33 (84.6%) 26 (68.4%)
0.93 0.20 0.24 0.50 0.43 1.00 1.00 0.57 1.00 0.47 0.18 0.43 0.55 0.44 0.90 0.22 0.81 0.07
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Table 2 Baseline angiographic and procedural characteristics. LES (n = 156) Procedural Characteristics Number of diseased vessels 2.13 ± 0.88 Number of lesions treated 1.83 ± 0.97 Number of implanted stents 1.63 ± 0.88 Pre-intervention lesion 0.85 ± 0.09 stenosis (visual estimation) Post-intervention lesion 0.04 ± 0.13 stenosis (visual estimation) Implanted stent diameter 3.18 ± 1.85 Implanted stent length 19.8 ± 6.45 Intraprocedural bivalirudin use 109 (69.9%) Angiographic Characteristics (Lesion based) Angiographic success 302/311 (97.1%) Left anterior descendent artery PCI 106/315 (33.7%) Left circumflex artery PCI 100/315 (31.7%) Right coronary artery PCI 77/315 (24.4%) Saphenous vein graft PCI 18/315 (5.7%) ACC/AHA Type A lesion 15/300 (5.0%) ACC/AHA Type B1/B2 lesion 182/300 (60.7%) ACC/AHA Type C lesion 103/300 (34.3%) PCI to an ostial lesion 14/312 (4.5%) PCI to a lesion with 14/314 (4.5%) in-stent restenosis IVUS performed during index PCI 179/311 (58.8%) Rotational atherectomy used 9/315 (2.9%) Balloon used for pre-dilatation 118/289 (40.8%) Balloon used for post-dilatation 59/289 (20.4%) Angiographic dissection 2/300 (0.7%) Development of no-reflow 1/299 (0.3%)
Table 4 Long-term outcomes. PES (n = 62)
p Value
2.07 1.63 1.45 0.86
0.94 0.86 0.76 0.08
0.78 0.17 0.16 0.32
0.05 ± 0.14
0.58
2.96 ± 0.47 19.96 ± 9.24 41 (66.1%)
0.19 0.88 0.59
102/104 (98.1%) 44/104 (42.3%) 23/104 (22.1%) 29/104 (27.9%) 7/104 (6.7%) 3/104 (2.9%) 79/104 (76.0%) 22/104 (21.2%) 6/102 (5.9%) 4/104 (3.8%)
0.74 0.11 0.06 0.48 0.70 0.58 0.01 0.01 0.60 1.00
67/103 (65.0%) 6/104 (5.8%) 51/100 (51.0%) 13/100 (13.0%) 0 0
0.18 0.22 0.08 0.10 1.00 1.00
± ± ± ±
PCI, percutaneous coronary intervention; ACC/AHA, American College of Cardiology/ American Heart Association; IVUS, intravascular ultrasound.
Approximately 40% of patients had an acute coronary syndrome at presentation for which PCI was performed; 4% were in cardiogenic shock at presentation. Table 2 shows the angiographic and procedural characteristics for the general population in the two treatment arms, which are largely similar. Statistically significant differences were found with regard to the complexity of lesions based on the ACC/AHA classification, with a higher incidence of type B1/B2 lesions in those treated with PES compared to LES (76.0% vs. 60.2%, p = 0.01), and more type C lesions in patients treated with LES compared to PES (33.9% vs. 21.2%, p = 0.01). Unadjusted in-hospital outcomes are reported in Table 3. Overall there were no significant differences in outcomes between the 2 groups before hospital discharge, but there was a trend toward higher all-cause and cardiovascular mortality in patients treated with LES as compared to PES.
Table 3 In-hospital Outcomes.
Post-procedural myocardial infarctiona In-hospital major adverse cardiac eventsb Death Cardiac death Q-wave myocardial infarction Urgent target lesion revascularization Stent Thrombosis Neurologic event (cerebrovascular accident) Vascular complications Major bleeding Clinical success a
PES (n = 62)
p Value
One-year outcomes Major adverse cardiac eventsa 55 (35.7%) 24 (38.7%) 0.68 Death 42 (27.5%) 21 (33.9%) 0.35 Q-wave myocardial infarction 1 (0.7%) 3 (5.1%) 0.09 Target lesion revascularization 17 (12.4%) 4 (6.8%) 0.24 Target vessel revascularization 23 (16.5%) 4 (6.8%) 0.07 Cumulative definite stent thrombosis 3 (1.9%) 2 (3.2%) 0.62 Two-year outcomes a Major adverse cardiac events 77/132 (58.3%) 32/51 (62.7%) 0.57 Death 61/127 (48.0%) 31/50 (62.0%) 0.09 Q-wave myocardial infarction 1/83 (1.2%) 3/36 (8.3%) 0.08 Target lesion revascularization 24/93 (25.8%) 4/36 (11.1%) 0.06 Target vessel revascularization 33/96 (34.4%) 5/37 (13.5%) 0.02 Cumulative definite stent thrombosis 3/135 (2.2%) 2/52 (3.8%) 0.67 a
Death, Q-wave myocardial infarction, and target lesion revascularization.
Long-term outcomes are presented in Table 4. The composite primary end point of MACE occurred similarly in both study cohorts up to 2 years [PES 32/51 (62.7%), vs. LES 77/132 (58.3%), p = 0.59], (Fig. 1) but the individual components of TLR and death deserve further mention. Although they did not reach statistical significance, TLR rates were doubled in patients treated with LES (PES 6.8% vs. LES 12.4%, p = 0.24 at 1 year, and PES 11.1% vs. LES 25.8%, p = 0.06 at 2 years), (Fig. 2). Target vessel revascularization rates demonstrated similar trends at 1 year (PES 6.8% vs. LES 16.5%, p = 0.07), and reached statistical significance at 2 years (PES 13.5% vs. LES 34.4%, p = 0.02). (Fig. 3). Of further interest, the individual component of death was nominally higher in patients treated with a PES (33.9% vs. LES 27.5%, p = 0.35, at 1 year and PES 62% vs. LES 48%, p = 0.09, at 2 years). Given the opposite trends of these death and revascularization outcomes, we performed a competitive outcome analysis to evaluate whether the occurrence of death confounded the TLR end point. After adjustment, the difference favoring the use of PES in regard to TLR was no longer apparent (adjusted p = 0.37). Multivariable risk adjustment confirmed the lack of an independent association between TLR and PES use (HR 1.49, 95% CI 0.49–4.49, p = 0.480) with the only predictor of TLR at 2 years being a history of DM (HR 8.61, 95%CI 1.15–64.3, p = 0.036). (Table 5). Table 6 presents the long-term outcomes of the DM subgroup. Similar MACE and TLR rates were seen between PES and LES groups up to 2 years, which is consistent with the results of the entire cohort. Multivariable risk adjustment confirmed the lack of an independent association between TLR and the use of a PES (HR 1.36, 95%CI 0.45–4.14, p = 0.590). Insulin requirement or treatment of an angiographically complex index lesion did not demonstrate an independent association with 2-year TLR. (Table 7). 4. Discussion
LES (n = 156)
PES (n = 62)
p Value
27 (17.4%) 9 (5.8%) 7 (4.5%) 4 (2.6%) 2 (1.3%) 0 0 2 (1.3%) 5 (3.2%) 5 (3.2%) 147 (94.2%)
9 (14.5%) 1 (1.6%) 0 0 0 1 (1.7%) 0 1 (1.6%) 3 (4.8%) 3 (4.8%) 61 (98.4%)
0.60 0.29 0.20 0.58 1.00 0.28 1.00 0.69 0.69 0.29
CK-MB elevation to 3× upper limit of normal. In-hospital all-cause death, Q-wave myocardial infarction, urgent target lesion revascularization, urgent coronary artery bypass surgery. b
LES (n = 156)
The primary finding of this study is that in patients receiving chronic HD, implantation of a PES does not appear to confer a particular clinical advantage over the rapamycin analog-eluting stents (SES or EES). In addition, our results support the notion that restenosis after PCI is very prevalent in HD patients, even after DES implantation. Previous reports based on observational data have suggested a revascularization advantage of PES over SES in patients receiving chronic HD [12,13]. This concept is of important clinical significance for the management of a population with a rising prevalence in the US [2]. Currently available DES comparisons in patients receiving chronic HD have predominantly evaluated SES against PES. These retrospective analyses have reported less favorable outcomes for
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Fig. 1. Survival free of MACE. This graph demonstrates the high incidence of adverse events in the evaluated cohort of patients treated with chronic hemodialysis. At two years, more than half the patients experienced a MACE event. In addition, there are no significant differences between PES and LES in regards to this composite outcome. MACE, major adverse cardiac events; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
patients treated with SES, as worsening degrees of renal dysfunction are associated with increasing rates of restenosis [17]; a finding not present in patients treated with a PES [13,18]. Thus, the use of paclitaxel has been favored, especially if DM and renal failure coexist [19]. It has been suggested that PES maintain their anti-restenotic properties in patients with DM, which is one of the most common etiologies of end-stage kidney disease leading to chronic HD [20–22]. Contrary to the theoretical advantages of PES, our results do not
demonstrate a clinically meaningful difference in regards to the incidence of TLR when PES and LES are compared in patients receiving chronic HD. This conclusion is reached after adjustment for baseline angiographic complexity as well as different trends in mortality, and is further confirmed in the subgroup of patients with DM. The frequency of co-morbid conditions and complex angiographic findings encountered in this cohort of HD patients highlights the importance of accounting for baseline differences when evaluating such a high-risk population. Previous studies suggesting a benefit
Fig. 2. Survival free of TLR. This graph shows the unadjusted incidence of TLR on HD patients treated with PES vs. LES. Before adjustment for baseline characteristics, a trend favoring PES implantation is apparent. Notably, this finding is no longer present after adjustment. (See Table 5). TLR, target lesion revascularization; HD, hemodialysis; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
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Fig. 3. Survival free of TVR. This graph shows the unadjusted incidence of TVR on HD patients treated with PES vs. LES. Before adjustment for baseline characteristics, PES appears to be more favorable. TVR, target vessel revascularization; HD, hemodialysis; PES, paclitaxel-eluting stent; LES, limus-eluting stent.
of PES over SES [12,13] have salient baseline clinical and angiographic differences that favored PES, which could explain their conflicting conclusions. The results of the present study correlate well with a small randomized study of patients on HD treated with either SES or PES, which found no angiographic differences up to 8 months of followup [8]. Furthermore, this “real world” study highlights the frequent need for revascularization in patients receiving chronic HD. Clinically-driven TLR rates of 11% at 1 year and 22% at 2 years, as noted in the overall cohort, are two to three-fold higher than the rates reported for DM patients treated with DES, a population already considered to be at high risk [21,23,24]. This supports the concept
Table 5 Multivariable model on two-year target lesion revascularization (TLR).
Implantation of a paclitaxel-eluting stent History of diabetes mellitus ACC/AHA type C index lesion
Hazard Ratio (95% CI*) TLR
p Value
1.49 (0.49–4.49) 8.61 (1.15–64.3) 1.75 (0.73–4.16)
0.480 0.036 0.208
ACC/AHA, American College of Cardiology/American Heart Association.
Table 6 Long-term outcomes on the diabetes mellitus-restricted population. LES (n = 115) One-year outcomes Major adverse cardiac eventsa Death Q-wave myocardial infarction Target lesion revascularization Target vessel revascularization Cumulative definite stent thrombosis Two-year outcomes Major adverse cardiac eventsa Death Q-wave myocardial infarction Target lesion revascularization Target vessel revascularization Cumulative definite stent thrombosis a
PES (n = 39)
p Value
44 31 1 16 19 3
(38.6%) (27.4%) (1.0%) (16.0%) (18.8%) (2.6%)
14 12 2 4 4 2
(35.9%) (30.8%) (5.4%) (10.8%) (10.8%) (5.1%)
0.76 0.69 0.18 0.45 0.26 0.60
60/96 44/91 1/59 22/68 25/70 3/98
(62.5%) (48.4%) (1.7%) (32.4%) (35.7%) (3.1%)
21/32 21/32 2/24 4/25 5/26 2/33
(65.6%) (65.6%) (8.3%) (16.0%) (19.2%) (6.1%)
0.75 0.09 0.20 0.12 0.12 0.60
Death, Q-wave myocardial infarction, and target lesion revascularization.
that HD acts as an additive risk factor for TLR in DM patients [25], and highlights the finding that despite high rates of angiographic success, restenosis continues to be highly prevalent in HD patients, even after DES implantation. This study is strengthened in that it includes a relatively large number of patients in whom outcomes were carefully recorded prospectively; and is one of the largest cohorts specifically comparing DES PCI in patients receiving chronic HD. It is, however, limited by its single-center, retrospective nature, which makes it subject to the known shortcomings of such evaluations. The limited number of events, as well as the relatively high attrition rates encountered in this high-risk population, may have underpowered our ability to detect differences among groups. Moreover, this study encompasses a lengthy period of 10 years, during which management changes have arisen, such as the preferential use of newer-generation DES instead of PES. Despite these limitations, clinical characteristics and basic adjunctive medications were carefully recorded and presented in detail. Although the groups were found to be very similar at baseline, unmeasured confounders may still be present and may potentially influence our results. Finally, older-generation PES (Taxus®) is infrequently used today in the US, but the clinical implications of such a comparison against this stent are of current relevance. Studies in HD patients have evaluated this stent in particular, and newergeneration PES available today are expected to grant the same benefits, as it is still proposed that the use of paclitaxel on a stent is more favorable for patients with DM and for those on chronic HD. In conclusion, patients on chronic HD experience high rates of clinically-driven TLR despite DES implantation, and the use of PES does not confer a significant clinical advantage over rapamycin
Table 7 Multivariable model on two-year target lesion revascularization (TLR) in the diabetes mellitus- restricted population.
Paclitaxel-eluting stent implantation Insulin requiring diabetes mellitus ACC/AHA type C index lesion
Hazard Ratio (95% CI*) TLR
p Value
1.36 (0.45–4.14) 0.68 (0.28–1.64) 1.95 (0.80–4.75)
0.590 0.388 0.142
ACC/AHA, American College of Cardiology/American Heart Association.
G.L. Sardi et al. / Cardiovascular Revascularization Medicine 15 (2014) 86–91
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