Sirolimus Eluting Coronary Stent Implantation in Patients On

Advance Publication by J-STAGE Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Sirolimus Eluting Coronary Stent Implantation in Patients on Maintenance Hemodialysis – The OUCH Study (Outcome of Cypher Stent in Hemodialysis Patients) – Yuji Ikari, MD, PhD; Kengo Tanabe, MD, PhD; Yutaka Koyama, MD; Ken Kozuma, MD, PhD; Koichi Sano, MD, PhD; Takaaki Isshiki, MD; Takaaki Katsuki, MD, PhD; Kazuo Kimura, MD; Masahisa Yamane, MD; Nozomu Takahashi, MD; Kiyoshi Hibi, MD; Kotaro Hasegawa, MD; Sugao Ishiwata, MD; Takahiko Kiyooka, MD; Hiroyoshi Yokoi, MD; Yoshiki Uehara, MD; Kazuhiro Hara, MD

Background: Pivotal studies on drug-eluting stents have excluded hemodialysis (HD) patients. No quantitative coronary angiography (QCA) analysis has been reported.

Methods and Results: The OUtcome of Cypher stent in Hemodialysis patients (OUCH) Study is a prospective non-randomized single-arm registry designed to assess the results of sirolimus-eluting stents in HD patients, with follow-up QCA in an independent core laboratory. The primary endpoint was the occurrence of target-vessel failure (TVF) defined as cardiac death, myocardial infarction (MI), and target-vessel revascularization (TVR) at 1 year. A total of 117 patients were enrolled. The TVF rate was 24.9% (2.6% cardiac death, 1.4% MI, 23.9% TVR), and stent thrombosis was documented in 1 patient (0.9%). Coronary calcification was a predictor of TVF. Late lumen loss (LLL) averaged 0.69±0.93 mm. The histogram of LLL showed that a total of 76% of lesions were distributed the same normally as that in normal renal function (average LLL 0.20±0.29 mm), but 24% of lesions were outliers (average LLL 2.07±0.62 mm).

Conclusions: This report describes different clinical and QCA results in HD patients as higher TVF rate, different predictive factors, and different histogram of LLL compared with normal renal function. The different histogram of LLL was the existence of many outliers with the same average and the same deviation, suggesting the loss of sirolimus had an effect on a significant number of HD patients.

Key Words: Chronic kidney disease; Drug eluting stent; Hemodialysis; Prognosis; Quantitative coronary angiography

oronary artery disease has different characteristics in randomized controlled trial in dialysis patients (4D) found no hemodialysis (HD) patients as compared to patients evidence of benefit from statins.2 Coronary artery calcification C with normal renal function. Dialysis patients have is frequent and severe in HD patients.3 All the well-designed extremely poor prognosis, with adjusted all-cause mortality studies on drug-eluting stents (DES) have excluded HD pa- rates 6.7- to 8.5-fold higher than those of their non-dialysis tients probably to avoid heterogeneity in the treated group. counterparts in the general population.1 The cardiovascular These studies have proven that DES is associated with lower mortality rate of dialysis patients is 3- to 6-fold higher than event rates than bare metal stents (BMS) in patients with nor- that from infection.1 Despite clear evidence of statins prevent- mal renal function. Thus, available data of DES in HD patients ing coronary events in patients with normal renal function, the are from single-center retrospective studies. They reported that

Received January 17, 2012; revised manuscript received February 22, 2012; accepted March 28, 2012; released online May 11, 2012 Time for primary review: 33 days Tokai University School of Medicine, Isehara (Y.I.); Mitsui Memorial Hospital, Tokyo (K.T., K. Hara); Iwatsuki Minami Hospital, Saitama (Y.K., K.S.); Teikyo University Hospital, Tokyo (K. Kozuma, T.I.); Jichi Medical University Hospital, Shimotsuke (T. Katsuki, N.T.); Yokohama City University Medical Center, Yokohama (K. Kimura, K. Hibi); Sekishinkai Sayama Hospital, Sayama (M.Y., K. Hasegawa); Toranomon Hospital, Tokyo (S.I.); Tokai University Hachioji Hospital, Hachioji (T. Kiyooka); Kokura Memorial Hospital, Kokura (H.Y.); and The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa (Y.U.), Japan Mailing address: Yuji Ikari, MD, PhD, Department of Cardiovascular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan. E-mail [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-12-0046 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication by J-STAGE IKARI Y et al.

Table 1. Patient Characteristics Troponin I (ng/ml) 0.21±0.65 Creatine kinase (IU/L) 67±55 Patient number 117 Creatine kinase MB subtype (IU/L) 7±6 Male gender (%) 69 Age (years) 65±10 BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL- Height (cm) 160±8 C, low-density lipoprotein cholesterol; CAD, coronary artery Weight (kg) 58±11 disease; DM, diabetes mellitus; PCI, percutaneous coronary BMI (kg/m2) 22.3±3.3 intervention; CABG, coronary artery bypass graft surgery; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin recep- Hypertension (%) 91 tor blocker. SBP (mmHg) 149±24 DBP (mmHg) 76±14 Dyslipidemia (%) 43 sirolimus-eluting stent (SES) implantation was associated with Total cholesterol (mg/dl) 177±40 lower TLR rates than BMS implantation.4–7 However, several HDL-C (mg/dl) 44±14 reports showed completely opposite results, with SES failing LDL-C (mg/dl) 109±61 to reduce rates of any events such as TLR, mortality, or major Triglyceride (mg/dl) 162±78 adverse cardiac events compared with BMS.8–11 Furthermore, Current smoking (%) 11 to our knowledge, no quantitative coronary angiography (QCA) Peripheral artery disease (%) 29 analysis has been reported for DES in HD patients. In view of Cerebrovascular disease (%) 3 the uncertain value of DES in HD patients to date, we con- Family history of CAD (%) 15 ducted this prospective non-randomized multicenter trial of DM (%) 70 SES implantation using QCA carried out in an independent Reason of renal failure core laboratory. Diabetic nephropathy (%) 66 Non-diabetic nephropathy (%) 34 Methods Duration of hemodialysis (years) 5.8±5.7 Study Design and Patient Population Diagnosis The OUCH Study (OUtcome of Cypher stent in Hemodialy- Stable angina (%) 47 sis) is a prospective multicenter registry study targeting the Unstable angina (%) 8 outcome of sirolimus-eluting coronary stent implantation in Asymptomatic ischemia (%) 45 patients undergoing maintenance HD. Inclusion criteria were Previous myocardial infarction (%) 15 end-stage renal disease requiring HD, age ≥21 years, and elec- Previous PCI (%) 31 tive percutaneous coronary intervention (PCI) with SES. Ex- Previous CABG (%) 11 clusion criteria were a history of surviving an episode of sud- Number of diseased vessels den death, cardiogenic shock, emergency PCI, ST-segment elevation myocardial infarction (MI), intolerance to antiplate- 1 (%) 62 let drugs, coronary stenting within 6 months, in-stent resteno- 2 (%) 25 sis following DES implantation, MI within 30 days, severe 3 (%) 13 valvular heart disease, critical limb ischemia, patients waiting Non-protected left main disease (%) 8 for renal transplantation, and total occlusion of the target ves- Aortic valve stenosis (%) 15 sel. All patients received information about the inclusion and Mitral valve regurgitation (%) 38 exclusion criteria for the study, and gave written informed Ejection fraction (%) 57±12 consent. Ejection fraction <50% (%) 21 All PCI procedures were carried out at the discretion of the Baseline medication operator and with the objective of achieving optimal results, Aspirin (%) 97 although in elective situations the use of SES (Cypher Bx Ticlopidine (%) 50 Velocity) was mandatory. BMS could be used only to facili- tate bail-out in cases where SES caused edge dissection. Use Clopidogrel (%) 38 of other DES was prohibited; however, rotablator could be Cilostazol (%) 10 used when necessary. Use of intravascular ultrasound (IVUS) Statin (%) 27 to confirm optimal stent expansion was encouraged. ACEI (%) 11 Follow-up was started from the date of the PCI. Planned ARB (%) 49 staged PCI procedures were not considered as adverse events. β-blocker (%) 28 The “target lesion” was defined at the time of the initial PCI. Insulin (%) 21 Follow-up clinical data were collected at 1, 8, and 12 months, Sulphonyl urea (%) 5 and follow-up coronary angiography was performed in 83% Sevelamer (%) 25 of patients at 8 months. All patients received antiplatelet agents, Calcium carbonate (%) 62 both aspirin 80–200 mg/day and a thienopyridine derivative Baseline blood data (clopidogrel 75 mg or ticlopidine 200 mg daily). Maintenance HD was performed 3 times a week using a high performance Hemoglobin (g/dl) 10.6±1.6 membrane. Calcium (mg/dl) 8.2±2.1 Phosphate (mg/dl) 4.9±3.6 Data Management and Definitions B-type natriuretic peptide (pg/ml) 654±922 Data were collected and submitted from the participating sites (Table 1 continued the next column.) using case record forms and study codes to protect subject Advance Publication by J-STAGE OUCH: SES for HD patients

identity. A private independent contract research organization, Table 2. Lesion Characteristics and Coronary Intervention Japan Cardiocore (Tokyo, Japan), was retained to serve as the Procedures administrator of the study. Number of lesions 139 In the presence of Thrombosis In Myocardial Infarction Target vessels (TIMI) grade 3 flow, angiographic success was defined as the achievement of a minimum stenosis diameter reduction to LMCA (%) 6.5 <50%. Overall procedural success was defined as presence of LAD (%) 43.2 angiographic success plus absence of a major complication, LCX (%) 23.7 and procedural failure as either lack of angiographic success RCA (%) 26.6 or occurrence of a major complication. ACC/AHA classification All the angiographic data were transmitted to the indepen- A (%) 2.2 dent core laboratory (Japan Cardiocore) and assessed by ex- B1 (%) 15.1 perts blinded to patient data. QCA was carried out in the core B2 (%) 50.4 laboratory using CAAS 5.4 (Pie Medical Imaging, Maastricht, C (%) 32.3 The Netherlands). TIMI flow The primary endpoint of the study was occurrence of target- TIMI 0 (%) 1.4 vessel failure (TVF), defined as cardiac death, MI in the target vessel, and the requirement for target-vessel revascularization TIMI 1 (%) 2.2 (TVR) within the first year after PCI. Major adverse cardiac TIMI 2 (%) 4.4 event was defined as death, MI, repeat PCI, or coronary artery TIMI 3 (%) 92.0 bypass graft surgery. Deaths were classified as cardiac or non- Lesion type cardiac. Sudden death as a result of an unknown cause was Discrete (%) 35.2 classified as a cardiac death. Repeat PCI was categorized as Tubular (%) 36.0 target lesion, target vessel, or non-TVR according to whether Diffuse (%) 28.8 the index lesion or artery was involved. Stent thrombosis was Angiographic calcification categorized as definite, probable, or possible according to the None/mild (%) 43.2 ARC definition.12 Moderate (%) 23.0 Severe (%) 33.8 Statistical Analysis The primary endpoint was TVF at 12 months. In previous re- Lesion tortuosity ports, HD patients had a 52% mortality rate at 2.3 years of None/mild (%) 93.5 follow-up,13 and 0.4 acute MI per person-year.14 Patients in Moderate (%) 5.8 this study were supposed to have worse prognosis than normal Severe (%) 0.7 HD patients because of the co-existence of coronary artery Eccentric lesion (%) 62.6 disease. In non-dialysis patients, the TVF of SES at 1 year was Thrombus (%) 0 reported as approximately 10%.15–18 Because of the much high- Dissection (%) 0.7 er incidence of complications in HD patients, the target case Haziness (%) 10.8 number for this registry was set at 120 for 12 months of fol- Ulceration (%) 2.9 low-up, which was deemed sufficient to make valid observa- Aneurysm (%) 0.7 tions on the primary endpoint. Irregular lesion surface (%) 44.6 Continuous variables were expressed as mean ± SD and were compared with the Student’s unpaired t test. Categorical vari- Lesion bending >45 degree (%) 5.0 ables were expressed as counts and percentages, and the chi- Ostial lesion (%) 11.5 squared test was used for comparison. Cumulative 1-year ad- De novo lesion (%) 100 verse event rates were estimated according to the Kaplan-Meier In stent restenosis (%) 0 method and compared by the log-rank test. Stepwise logistic Vein grafts (%) 0 analysis was performed to detect predictors of groups. All Chronic total occlusion (%) 1.4 analyses were performed with the SAS 9.2 system. Rotational atherectomy (%) 28 This trial is registered with UMIN as number UMIN Bifurcation 42 (30.2%) 000001155. Side branch protection with guidewire 37 1 stent/2 stents 37/6 Results Culotte 2 Baseline and Procedural Characteristics Crush 2 A total of 120 patients who fulfilled the inclusion criteria were T-stent 2 enrolled between June 2007 and May 2009. After an initial Final kissing balloon technique 23 successful PCI, consent was withdrawn by 3 patients, and thus TIMI, Thrombosis In Myocardial Infarction. 117 individuals completed the study. A total of 139 target lesions were present in these 117 patients. Clinical follow-up was available in 100% of patients at 12 months and angiographic follow-up was available in 113 lesions (83%) at 8 was present in 38%; and non-protected left main disease in months. 8%. The mean ejection fraction was 57%; and 21% of patients Overall, the mean age of patients was 65 years; 69% were had an ejection fraction <50%. Baseline blood tests showed a male, 91% had hypertension; and 70% had diabetes (Table 1). mean B-type natriuretic peptide concentration of 654 pg/ml The average duration of HD was 5.8 years. Multivessel disease (normal <18.4 pg/ml) and troponin I level of 0.21 ng/ml (nor- Advance Publication by J-STAGE IKARI Y et al.

Table 3. Results of Sub-Segmental Quantitative Coronary Angiographic Analysis (n=115) Proximal edge In-stent Distal edge In-segment (n=91) (n=113) (n=113) analysis (n=113) Reference diameter Pre-procedure (mm) NA NA NA 2.72±0.63 Post-procedure (mm) 3.15±0.55 2.89±0.60 2.70±0.59 2.80±0.63 8 m follow-up (mm) 3.02±0.58 2.78±0.59 2.55±0.62 2.74±0.61 Minimal lumen diameter Pre-procedure (mm) NA NA NA 0.84±0.38 Post-procedure (mm) 2.73±0.58 2.59±0.54 2.30±0.55 2.25±0.50 8 m follow-up (mm) 2.36±0.86 1.89±0.96 2.06±0.79 1.69±0.85 % diameter stenosis Pre-procedure (%) NA NA NA 69.1±12.9 Post-procedure (%) 13.2±11.3 10.3±7.4 14.8±9.6 18.9±9.4 8 m follow-up (%) 22.3±23.0 32.2±31.4 20.6±24.9 37.8±29.5 Late loss (mm) 0.37±0.79 0.69±0.93 0.24±0.81 0.56±0.89 Restenosis 9 (9.9%) 30 (26.1%) 10 (8.7%) 34 (29.6%)

Figure. Histogram of in-stent late loss. The figure shows a normal distribution between late loss of –0.50 mm and 1.0 mm. In contrast, a total of 24% is outliers with late loss more than 1.0 mm.

mal <0.04 ng/ml). used in 6 patients (2 Culotte, 2 crush, and 2 T stents). Lesion characteristics and coronary intervention procedures are shown in Table 2. American Heart Association (AHA)/ QCA Data ACC type B2/C lesions were present in 82.7%, and angio- Data from QCA performed in an independent core laboratory graphically severe calcification was found in 33.8%. Rota- are shown in Table 3. Average in-stent late loss was 0.69± tional atherectomy was employed in 28% of patients, and bi- 0.93 mm. The histogram of in-stent late loss is shown in Figure. furcation lesions were present in 42 (30.2%). To treat these A total of 76% of lesions were located less than 1 mm. Distri- lesions, 1 stent was used in 37 patients, whereas 2 stents were bution of these lesions is similar to the reported pattern follow- Advance Publication by J-STAGE OUCH: SES for HD patients

ing SES implantation in normal renal function (Figure S1,S2). Table 4. Clinical Follow-up Data at 1 Year Twenty-four percent of lesions were outliers located more than 1 mm. Number of patients 117 Death 11 (9.4%) Clinical Follow-up Data Cardiac death 3 (2.6%) The mortality rate at 1 year was 9.4%, with 2.6% cardiac and Non-cardiac death 8 (6.8%) 6.8% non-cardiac deaths (Table 4). MI was observed in 1.4% Myocardial infarction 2 (1.4%) of patients, and repeat revascularization was carried out in Stroke 4 (2.7%) 31.2% (28.2% PCI and 5.1% coronary artery bypass graft) TLR 26 (22.2%) including 22.2% with TLR, 1.7% with non-target lesion TVR, Non-TL TVR 2 (1.7%) and 7.5% with non-TVR. Definite/probable stent thrombosis Non-TVR 11 (7.5%) was present in 0.9% of patients according to the ARC defini- Stent thrombosis 1 (0.9%) tion. Admission as a result of heart failure was seen in 6.8%. Admission due to heart failure 8 (6.8%) TVF, the primary endpoint, was present in 24.9% of patients. Predictive factors of TVF were analyzed in Table 5. Severe TVF 29 (24.9%) coronary calcification and use of rotational atherectomy had TLR, target-lesion revascularization; TVR, target-vessel revascu- a high TVF rate. Patients with TVF were younger and had larization; TVF, target-vessel failure. lower low-density lipoprotein (LDL) cholesterol level. Diabe- tes, AHA/ACC type B2/C lesion, or stent length did not show significant correlation with TVF. Factors that are relevant to the in-stent late loss distribution are shown in Table 6. Group 2 were younger but had longer dura- Factors Relating to the Bimodal In-Stent Late Loss tion of HD, lower total cholesterol level, and more severe Distribution angiographic calcification. Due to severe calcification, fre- Using 1 mm as the cut-off value of late lumen loss based on quent rotational atherectomy and difficulty with IVUS catheter the previous reports about late loss histogram,16,19–21 we di- passage were observed. Interestingly, the following factors did vided the 113 lesions into Group 1 (normal distribution, n=86) not show significant difference: frequency of AHA/ACC type and Group 2 (outliers, n=27). The average late loss in Group C lesions, diabetic nephropathy, multivessel disease, or base- 1 was 0.20±0.29 mm and that in Group 2 was 2.07±0.62 mm. line phosphate level.

Table 5. Analysis of Factors Relating With TVF at 1 Year TVF (+) TVF (–) P value Univariate analysis of categorical factors Angiographic calcification 0.0326 None/mild 13% 87% Moderate 31% 69% Severe 37% 63% Use of rotational atherectomy (+) 45% 55% 0.0036 Use of rotational atherectomy (–) 19% 81% Sevelamer hydrochloride (+) 14% 86% 0.0739 Sevelamer hydrochloride (–) 31% 69% Univariate analysis of numerical factors Age 61±9 66±10 0.0076 Height (cm) 164±9 159±8 0.0090 Weight (kg) 62±11 56±11 0.0201 Total cholesterol (mg/dl) 161±26 182±42 0.0423 LDL-C (mg/dl) 84±26 117±67 0.0167 Duration of hemodialysis (months) 87±70 62±66 0.1012 Quantitative coronary angiography data Late loss in stent (mm) 1.57±0.94 0.24±0.46 <0.0001 Late loss in segment (mm) 1.40±0.80 0.14±0.51 <0.0001 Acute gain (mm) 1.91±0.63 1.69±0.51 0.0916 Late loss index 0.85±0.48 0.16±0.38 <0.0001 Factors without significant correlation DM (–) 23% 77% 0.5601 DM (+) 28% 72% AHA/ACC type A/B1 lesion 24% 76% 0.7644 AHA/ACC type B2/C lesion 27% 73% Total stent length (mm) 27±11 24±9 0.1278 TVF, target-vessel failure; LDL-C, low-density lipoprotein cholesterol; AHA, American Heart Association; DM, diabetes mellitus. Advance Publication by J-STAGE IKARI Y et al.

Table 6. Factors Relating With Late Loss Distribution Pattern Group 1: normal Group 2: P value distribution outliers Quantitative coronary angiography data Late loss in stent (mm) 0.20±0.29 2.07±0.62 <0.0001 Late loss in segment (mm) 0.13±0.41 1.78±0.59 <0.0001 Acute gain (mm) 1.68±0.50 1.89±0.70 0.1618 TVF 10% 85% <0.0001 Univariate analysis of categorical factors Use of rotational atherectomy 21% 41% 0.0398 Impossibility of IVUS catheter passage 4% 18% 0.0320 Coronary calcification None/mild 50% 26% 0.0358 Moderate 23% 22% Severe 27% 52% Univariate analysis of numerical factors Age 66±11 60±7 0.0016 Total cholesterol (mg/dl) 184±42 160±32 0.0459 LDL-C (mg/dl) 115±67 89±34 0.0820 Duration of hemodialysis (months) 60±59 97±66 0.0120 Total stent length (mm) 25±14 34±17 0.0276 Max troponin I in hospital 3.60±7.25 1.40±1.48 0.0182 Max CK level in hospital (IU/L) 143±247 77±79 0.0391 Max CK MB level in hospital (IU/L) 20±35 11±8 0.0482 TVF, target-vessel failure; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; CK, creatine kinase.

Risk factors such as diabetes, stent length, or AHA/ACC type Table 7. Multivariate Stepwise Logistic Regression Analysis Relating With the Late Loss Group B2/C lesions did not show significant correlation with TVF. However, coronary calcification and use of rotational atherec- Factors OR 95% CI P value tomy as a result of calcification were predictors of TVF. Inter- Angiographic calcification estingly, patients with TVF were younger and had lower LDL Severe vs. none/mild 13.13 1.85–92.96 0.0426 cholesterol level. These observations are novel and might be Moderate vs. non/mild 6.00 0.89–40.15 0.529 specific in HD patients. Mean in-stent late loss following SES implantation in normal renal function was 0.01 mm in RAVEL,29 0.17 mm in SIR- Multivariate stepwise logistic regression analysis identified IUS,30 0.12 mm in C-SIRIUS,31 and 0.20 mm in E-SIRIUS,32 angiographic calcification as the exclusive factor that distin- further validating the striking difference with that in HD pa- guished Group 1 from Group 2 (Table 7). tients (0.69±0.93 mm). Histograms of late loss after SES implantation reported by Cosgrave et al,19 Sabate et al,20 Kandzari et al,16 and Mauri et al21 showed a clear normal distribution Discussion (Figure S1). One can speculate late loss distribution is differ- In the OUCH Study, TVF 1 year following SES implantation ent in HD patients because of the worse clinical outcome.33–35 was 24.9%, and average in-stent late loss at 8 months was Although late loss should be distributed evenly normally in 0.69±0.93 mm in patients undergoing maintenance HD. To HD patients, there were several hypotheses to explain it: (1) our knowledge this is the first prospective report of TVF and higher average with the same deviation; (2) the same average in-stent late loss following DES implantation in HD patients. with the wider deviation; (3) both higher and wide deviation; In previous reports, TVF 1 year following SES implantation and (4) existence of outliers with the same average and the in normal renal function was 9.8% in SIRIUS,15 11.5% in same deviation. The present study showed that the answer is ENDEAVOR III,16 10.9% in ASCOT/TOSCA-4,17 and 9.3% the latter: the existence of many outliers with the same aver- in J-PMS studies,18 indicating that TVF following SES im- age and the same deviation (Figure S2). The group of 76% plantation was in the 10% range. Accordingly, the figure of distributed normally in the OUCH Study had average TVF of 24.9% for TVF in the OUCH Study clearly shows that HD 9.2% and late loss of 0.20 mm, figures similar to those in pa- patients had greater risk than that of patients with normal renal tients with normal renal function.18,15,30–32 These data suggest function. The high TVF rate supports the results of previous that there are 2 groups of HD patients. In 1 group, SES ap- large registry studies showing that HD was a predictor of pears to limit intimal hyperplasia in a manner similar to that death, MI,18 the requirement for TLR,22–25 late stent thrombo- in the setting of normal renal function. In the other group, sis,26 and other major adverse cardiac events27,28 following this beneficial effect is lacking. Coronary calcification was the SES implantation. strong predictor for the outliers. Also these patients were young- Predictors of TVF in HD patients were clearly different er with longer duration of HD and lower cholesterol level. from these with normal renal function as shown in Table 5. The variable results of SES in previous studies for HD pa- Advance Publication by J-STAGE OUCH: SES for HD patients tients might be a direct result of the selection bias from the R, et al. Sirolimus-eluting stents vs bare metal stents for coronary significant number of outliers. This result raises important ques- intervention in Japanese patients with renal failure on hemodialysis. tions; 1) what is the underlying mechanism underlying lack or Circ J 2008; 72: 56 – 60. 11. Ichimoto E, Kobayashi Y, Iijima Y, Kuroda N, Kohno Y, Komuro I. minimized of sirolimus effects in a significant number of HD Long-term clinical outcomes after sirolimus-eluting stent implanta- patients? and 2) is it possible to determine the response against tion in dialysis patients. Int Heart J 2010; 51: 92 – 97. sirolimus before SES implantation? Further studies are neces- 12. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, sary to clarify these HD specific problems on DES. et al. Clinical end points in coronary stent trials: A case for standard- ized definitions.Circulation 2007; 115: 2344 – 2351. There are several limitations in this study. This was a pro- 13. deFilippi C, Wasserman S, Rosanio S, Tiblier E, Sperger H, Tocchi spective but non-randomized study. The case number was M, et al. Cardiac troponin T and C-reactive protein for predicting limited to 117. However, previous studies reporting the out- prognosis, coronary atherosclerosis, and cardiomyopathy in patients comes of SES implantation in treating HD patients have in- undergoing long-term hemodialysis. JAMA 2003; 290: 353 – 359. 4–10,36 14. Iseki K, Fukiyama K. Long-term prognosis and incidence of acute cluded fewer than 100 cases, and the meta-analysis men- myocardial infarction in patients on chronic hemodialysis: The Okinawa tioned above included only 279 DES cases from 5 studies.37 Dialysis Study Group. Am J Kidney Dis 2000; 36: 820 – 825. The current study might be one of the largest prospective stud- 15. Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald ies thus far reported that targets HD patients receiving SES PJ, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: A randomized trial of a sirolimus-eluting stent versus a standard stent treatment. Furthermore, this is also the first report of QCA in patients at high risk for coronary restenosis. Circulation 2004; using DES in HD patients. 109: 634 – 640. In conclusion, the TVF rate of 24.9% following SES im- 16. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, plantation in HD patients was higher than that in the setting of Ball MW, et al. Comparison of zotarolimus-eluting and sirolimus- normal renal function with a TVF rate of approximately eluting stents in patients with native coronary artery disease: A ran- 15–18 domized controlled trial. J Am Coll Cardiol 2006; 48: 2440 – 2447. 10%. The interesting distribution of late loss in HD pa- 17. Kandzari DE, Rao SV, Moses JW, Dzavik V, Strauss BH, Kutryk tients appears to be a novel finding, and might explain the MJ, et al. Clinical and angiographic outcomes with sirolimus-eluting extreme variations in outcomes observed by others. Further stents in total coronary occlusions: The ACROSS/TOSCA-4 (Ap- studies are necessary to understand the mechanism underlying proaches to Chronic Occlusions With Sirolimus-Eluting Stents/Total Occlusion Study of Coronary Arteries-4) trial. JACC Cardiovasc lack of sirolimus effects in significant numbers of HD pa- Interv 2009; 2: 97 – 106. tients. 18. Ikari Y, Kotani J, Kozuma K, Kyo E, Nakamura M, Yokoi H. 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