Whether drug-eluting stents are effective and safe in patients with moderate renal insufficiency (RI) is unknown. We performed a pooled analysis of data from 3 blinded randomized trials of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs; SIRIUS, C-SIRIUS, E-SIRIUS) that included 1,510 patients. Clinical and angiographic outcomes were stratified by the presence of RI defined by creatinine clearance calculated by the Cockcroft-Gault formula (normal ≥90, mild 60 to 89, moderate <60 ml/min). Patients with baseline creatinine >3.0 mg/dl were excluded from these trials. Baseline mild RI was present in 517 patients (34.7%, mean creatinine clearance 75.7 ml/min) and moderate RI in 228 patients (15.3%, mean creatinine clearance 47.2 ml/min). Treatment with SESs resulted in lower rates of 8-month angiographic restenosis rates in patients with RI (mild RI 6.7% vs 42.6%, p <0.001; moderate RI 9.7% vs 39.7%, p <0.001) and without baseline RI (7.7% vs 37.2%, p <0.001). One-year target vessel revascularization rates were similarly decreased with SESs in patients with (mild RI 4.7% vs 24.2%, p <0.001; moderate RI 5.5% vs 26.9%, p <0.001) and without (8.1% vs 22.4%, p <0.001) RI, and this benefit was maintained at 5 years. Compared to patients with normal or mild RI, patients with moderate RI had higher rates of overall mortality and cardiac death at 1 year and 5 years (death 2.6% vs 0.6%, p <0.01, and 17.5% vs 6.3%, p <0.01, at 1 year and 5 years, respectively; cardiac death 1.3% vs 0.2%, p = 0.05, and 6.6% vs 3.4%, p = 0.04, at 1 year and 5 years, respectively). However, there was no differential effect of SESs versus BMSs on any safety end point. In conclusion, patients with moderate RI have a nearly threefold increase in 5-year mortality after percutaneous coronary intervention compared to patients without RI. The effectiveness of SESs in decreasing restenosis compared to BMSs in patients with moderate RI was preserved and rates of death and myocardial infarction were not adversely affected.
Between 5% to 10% of the overall population and >20% of patients undergoing coronary angiography have significant renal dysfunction with stage ≥3 chronic kidney disease (CKD). Improved understanding of the relative merits of drug-eluting stents and bare metal stents (BMSs) in patients with and without CKD would help optimize the delivery of care to this important population. We therefore performed a pooled analysis of 5-year data from 3 randomized trials comparing the use of BMSs to sirolimus-eluting stents (SESs) to better understand and define the outcomes of patients with renal insufficiency (RI) after percutaneous coronary intervention (PCI) and to compare the relative efficacy and safety of SESs to BMSs in patients with and without RI.
Methods
Patient-level data were pooled for 3 randomized, controlled, double-blind trials evaluating the SES (Cypher, Cordis/Johnson and Johnson, Miami Lakes, Florida) compared to the equivalent BMS (Bx Velocity, Cordis/Johnson and Johnson). The trial cohort of 1,510 patients included those enrolled in the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of De Novo Native Coronary Artery Lesions (SIRIUS in the United States, NCT00232765 ; C-SIRIUS in Canada, NCT00381420 ; and E-SIRIUS in Europe, NCT00235144 ). Details of these trials have been previously reported. Briefly, each trial enrolled subjects with de novo stenoses >50% with a length of 15 to 30 mm (SIRIUS) or 15 to 32 mm (C- and E-SIRIUS) in length in a native vessel with diameter of 2.5 to 3.5 mm (SIRIUS) or 3.0 mm (C- and E-SIRIUS). Subjects with totally occluded, heavily calcified, bifurcated, ostial, unprotected left main, or heavily calcified lesions were excluded, as were subjects with recent or evolving myocardial infarction and those with lesions containing thrombus. Subjects with serum creatinine >3.0 mg/dl were excluded from all 3 original trials. Standard percutaneous techniques were used for stent implantation. Loading doses of clopidogrel were administered before the procedure, and patients were discharged on dual antiplatelet therapy with aspirin (indefinitely) and clopidogrel for 2 months (E- and C-SIRIUS) or 3 months (SIRIUS).
Angiographic data were collected at baseline and protocol-driven follow-up angiography was planned in all patients in 2 trials (E-SIRIUS and C-SIRIUS) or a subset of patients in the third trial (SIRIUS) 8 months after randomization. Angiographic data were analyzed off-line using quantitative coronary angiography (Cardiology Medis System, Leiden, The Netherlands). The same angiographic core laboratory (Brigham and Women’s Hospital, Boston, Massachusetts) was used to adjudicate standard angiographic parameters in all trials. Follow-up for adverse clinical events was carried out for 5 years in all trials. All events were adjudicated by a single blinded clinical events committee using standardized definitions.
Baseline serum creatinine before angiography was collected on a standardized case-report form. Because information on race was not routinely collected, creatinine clearance was calculated by the Cockcroft-Gault formula, corrected for gender, and was considered normal if ≥90 ml/min. Missing information precluded estimation of creatinine clearance in 18 patients, and these patients were excluded from further analysis. Patients were stratified into 3 groups in accordance with guidelines for staging CKD based on glomerular filtration rate advocated by the National Kidney Foundation : group 1, normal renal function/stage 1 CKD (creatinine clearance ≥90 ml/min); group 2, mild renal insufficiency/stage 2 CKD (creatinine clearance 60 to 89 ml/min), and group 3, moderate to severe renal insufficiency/stage 3 to 4 CKD (creatinine clearance <60 ml/min).
The primary clinical end point was all-cause death. Secondary end points included cardiac death, ischemia-driven target vessel revascularization, myocardial infarction, and stent thrombosis. The clinical end-point definitions have been described previously. Briefly, target vessel revascularization was defined as surgical or percutaneous revascularization of the target vessel. Binary restenosis was defined as ≥50% luminal diameter stenosis in the target lesions. Stent thrombosis was defined as definite or probable stent thrombosis according to criteria of the Academic Research Consortium. Definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or pathologic evidence of stent thrombosis or occlusion. Probable stent thrombosis was adjudicated when an unexplained death occurred within 30 days of the index procedure and in cases of acute myocardial infarction involving the target vessel in which angiogram was unavailable.
Continuous variables are reported as mean ± SD or median and interquartile range, if not normally distributed, and compared using 2-sample t test for normally distributed data or Wilcoxon rank-sum test (Mann-Whitney U test), if highly skewed. Categorical variables are reported as percentages and chi-square test used for comparison. Kaplan-Meier plots were constructed to graphically assess event-free survival for clinical end points, and log-rank statistic was used to assess for unadjusted differences in survival. After confirming that proportional hazards assumptions were met, multivariable Cox proportional hazards models were used to identify independent predictors of clinical events. Covariates identified as significant on univariate analysis and a priori potential confounders were included in the model. In these models, renal function was examined as a binary variable (presence or absence of moderate RI defined as creatinine clearance <60 or ≥60 ml/min). In addition to stent type, renal function, and an interaction term of stent type and renal function, the other variables considered in the multivariable model were age, gender, weight, smoking, hypertension, hyperlipidemia, diabetes mellitus, previous coronary artery bypass surgery, previous myocardial infarction, congestive heart failure, glycoprotein IIb/IIIa use, number of stents, preprocedure reference vessel diameter, and left ventricular function. All statistical tests are 2-sided and a p value <0.05 was considered statistically significant. All analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina).
Results
Of the 1,510 randomized patients in the 3 SIRIUS trials, 99.5% (1,492) had data available on renal function for the calculation of creatinine clearance. Mild RI was present in 517 patients (34.7%) and moderate RI was present in 228 patients (15.3%, of these 15 patients had creatinine clearance <30 ml/min). Prevalence of impaired renal function was similar in the drug-eluting stent and BMS groups (normal renal function in 51.5% vs 48.6%, p = 0.44; mild RI in 33.9% vs 35.4%, p = 0.77; moderate RI 14.6% vs 16.0%, p = 0.79).
Baseline clinical and angiographic characteristics of patients stratified by renal function are listed in Table 1 . Patients with mild or moderate RI were more likely to be older, women, have hypertension, or a history of congestive heart failure or coronary artery bypass graft surgery than patients with normal renal function.
| Creatinine Clearance (ml/min) | p Value | ||||
|---|---|---|---|---|---|
| Group 1 ≥90 | Group 2 60–89 | Group 3 <60 | 3-Way Trend | Groups 1 + 2 vs 3 | |
| (n = 747) | (n = 517) | (n = 228) | |||
| Creatinine clearance (ml/min), mean ± SD | 124.0 ± 34.7 | 75.7 ± 8.2 | 47.2 ± 9.6 | <0.01 | <0.01 |
| Clinical characteristics | |||||
| Age (years) | 56.4 ± 9.3 | 65.4 ± 8.6 | 73.6 ± 8.3 | <0.01 | <0.01 |
| Men | 80.7% | 70.0% | 42.1% | <0.01 | <0.01 |
| Indication for percutaneous coronary intervention | |||||
| Stable angina | 43.0% | 46.8% | 47.2% | 0.19 | 0.54 |
| Unstable angina | 50.1% | 44.2% | 45.7% | 0.11 | 0.64 |
| Angina at rest | 19.2% | 17.7% | 19.8% | 0.94 | 0.69 |
| Angina after myocardial infarction | 6.1% | 5.9% | 5.1% | 0.61 | 0.74 |
| Smoking history | 32.1% | 24.0% | 11.8% | <0.01 | <0.01 |
| Hypertension | 63.4% | 65.1% | 74.4% | <0.01 | <0.01 |
| Hyperlipidemia | 76.6% | 75.4% | 65.9% | <0.01 | <0.01 |
| Diabetes mellitus | 28.0% | 20.0% | 29.8% | 0.47 | 0.12 |
| Previous percutaneous revascularization | 23.3% | 23.1% | 20.6% | 0.46 | 0.44 |
| Previous coronary artery bypass surgery | 6.7% | 9.5% | 11.0% | 0.02 | 0.12 |
| Previous myocardial infarction | 32.5% | 36.5% | 33.9% | 0.39 | 1.00 |
| Congestive heart failure | 3.5% | 5.1% | 12.5% | <0.01 | <0.01 |
| Angiographic and procedural characteristics | |||||
| Target coronary artery | 0.11 | 0.22 | |||
| Left main | 0.3% | 0.8% | 0% | ||
| Left anterior descending | 46.8% | 42.3% | 51.5% | ||
| Left circumflex | 24.9% | 23.9% | 21.1% | ||
| Right | 28.0% | 33.0% | 26.9% | ||
| Number of diseased vessels | 1.01 ± 0.1 | 1.00 ± 0 | 1.00 ± 0 | 0.25 | 0.30 |
| Reference vessel diameter (mm) | 2.76 ± 0.47 | 2.71 ± 0.43 | 2.66 ± 0.44 | <0.01 | <0.01 |
| Preprocedure lesion length (mm) | 14.5 ± 5.8 | 14.5 ± 5.9 | 14.5 ± 6.0 | 0.97 | 0.93 |
| Preprocedure diameter stenosis (%) | 65.9 ± 11.8 | 65.8 ± 12.1 | 64.6 ± 12.2 | 0.32 | 0.13 |
| American College of Cardiology/American Heart Association lesion type | 0.08 | 0.35 | |||
| A | 5.6 | 8.3 | 9.7 | ||
| B1 | 36.7 | 34.4 | 31.7 | ||
| B2 | 34.2 | 33.8 | 34.8 | ||
| C | 23.5 | 23.5 | 23.8 | ||
| Left ventricular ejection fraction (%), mean ± SD | 56.4 ± 10.1 | 58.0 ± 11.7 | 57.7 ± 12.0 | 0.02 | 0.41 |
| Glycoprotein IIb/IIIa antagonist used | 54.4 | 42.7 | 48.2 | <0.01 | 0.72 |
| Number of stents, mean ± SD | 1.46 ± 0.7 | 1.49 ± 0.7 | 1.42 ± 0.6 | 0.71 | 0.68 |
| Total stent length (mm), mean ± SD | 23.15 ± 9.1 | 23.62 ± 9.5 | 22.99 ± 7.7 | 0.57 | 0.54 |
| Postprocedure within-stent percent stenosis, mean ± SD | 5.78 ± 8.1 | 6.38 ± 8.5 | 6.12 ± 8.7 | 0.44 | 0.88 |
| Postprocedure in-lesion minimum lumen diameter (mm), mean ± SD | 2.36 ± 0.5 | 2.30 ± 0.5 | 2.24 ± 0.4 | <0.01 | <0.01 |
In-hospital adverse outcomes were infrequent and independent of renal function ( Table 2 ). All-cause mortality and cardiac mortality were more frequent in patients with moderate RI compared to those with normal or mild RI at 1 year and 5 years ( Figure 1 , Table 2 ). Rates of myocardial infarction ( Figure 2 ), target vessel revascularization, or stent thrombosis were similar in patients with or without renal insufficiency.
| Creatinine Clearance (ml/min) | p Value | ||||
|---|---|---|---|---|---|
| Group 1 ≥90 | Group 2 60–89 | Group 3 <60 | 3-Way Trend | Groups 1 + 2 vs 3 | |
| (n = 747) | (n = 517) | (n = 228) | |||
| In-hospital events | |||||
| Death | 1 (0.1%) | 0 | 0 | 0.37 | 1.00 |
| Cardiac death | 1 (0.1%) | 0 | 0 | 0.37 | 1.00 |
| Myocardial infarction | 13 (1.7%) | 7 (1.4%) | 6 (2.6%) | 0.58 | 0.27 |
| Target vessel revascularization | 1 (0.1%) | 1 (0.2%) | 0 | 0.77 | 1.00 |
| Stent thrombosis ⁎ | 0 | 1 (0.2%) | 0 | 0.64 | 1.00 |
| 1-Year events | |||||
| Death | 4 (0.5%) | 3 (0.6%) | 6 (2.6%) | 0.01 | <0.01 |
| Cardiac death | 2 (0.3%) | 1 (0.2%) | 3 (1.3%) | 0.08 | 0.05 |
| Myocardial infarction | 27 (3.6%) | 18 (3.5%) | 12 (5.3%) | 0.37 | 0.26 |
| Target vessel revascularization | 112 (15.0%) | 76 (14.7%) | 38 (16.7%) | 0.65 | 0.48 |
| Stent thrombosis ⁎ | 4 (0.5%) | 8 (1.5%) | 2 (0.9%) | 0.29 | 1.00 |
| 5-Year events | |||||
| Death | 42 (5.6%) | 37 (7.2%) | 40 (17.5%) | <0.01 | <0.01 |
| Cardiac death | 26 (3.5%) | 17 (3.3%) | 15 (6.6%) | 0.09 | 0.04 |
| Myocardial infarction | 58 (7.8%) | 30 (5.8%) | 16 (7.0%) | 0.42 | 1.00 |
| Target vessel revascularization | 178 (23.8%) | 112 (21.7%) | 53 (23.2) | 0.63 | 0.93 |
| Stent thrombosis ⁎ | 12 (1.6%) | 14 (2.7%) | 2 (0.9%) | 0.95 | 0.30 |
⁎ Definite and probable stent thrombosis according to the Academic Research Consortium.
Angiographic restenosis rates at 8 months were lower in patients treated with SESs compared to BMSs across strata of renal function ( Table 3 ) and there were no differences in the amount of in-segment or in-stent late loss (p for 3-way trend = 0.81and 0.58, respectively) or rate of in-segment or in-stent binary restenosis (p for 3-way trend = 0.31and 0.08, respectively) in patients with or without renal insufficiency.
| Creatinine Clearance (ml/min) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| ≥90 | 60–89 | <60 | |||||||
| SES | BMS | p Value | SES | BMS | p Value | SES | BMS | p Value | |
| (n = 272) | (n = 269) | (n = 195) | (n = 209) | (n = 72) | (n = 78) | ||||
| Minimum lumen diameter, in-lesion (mm) | 2.12 ± 0.57 | 1.53 ± 0.70 | <0.001 | 2.11 ± 0.53 | 1.44 ± 0.68 | <0.001 | 1.99 ± 0.64 | 1.50 ± 0.75 | <0.001 |
| Minimum lumen diameter, in stent (mm) | 2.46 ± 0.54 | 1.62 ± 0.78 | <0.001 | 2.41 ± 0.51 | 1.48 ± 0.72 | <0.001 | 2.32 ± 0.69 | 1.56 ± 0.81 | <0.001 |
| Late loss, in-lesion (mm) | 0.24 ± 0.46 | 0.80 ± 0.66 | <0.001 | 0.17 ± 0.38 | 0.87 ± 0.65 | <0.001 | 0.24 ± 0.55 | 0.71 ± 0.62 | <0.001 |
| Late loss, in stent (mm) | 0.18 ± 0.42 | 0.99 ± 0.70 | <0.001 | 0.15 ± 0.36 | 1.08 ± 0.65 | <0.001 | 0.23 ± 0.57 | 0.95 ± 0.66 | <0.001 |
| Binary restenosis, in lesion (%) | 7.7% | 37.2% | <0.001 | 6.7% | 42.6% | <0.001 | 9.7% | 39.7% | <0.001 |
| Binary restenosis, in stent (%) | 2.6% | 34.9% | <0.001 | 2.6% | 42.1% | <0.001 | 6.9% | 39.7% | <0.001 |
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