Major Adverse Cardiac Events in Patients With Moderate to Severe Renal Insufficiency Treated With First-Generation Drug-Eluting Stents
Article Outline
No data are available comparing the long-term outcome of sirolimus-eluting stents (SESs) versus paclitaxel-eluting stents (PESs) in patients with moderate to severe renal insufficiency. The incidence of major adverse cardiac events (MACE), including death, myocardial infarction, and target vessel revascularization, during long-term follow-up were studied in patients with a glomerular filtration rate of <60 ml/min/1.73 m2, as measured by the Modification of Diet in Renal Disease (MDRD) study equation, who also underwent percutaneous coronary intervention with drug-eluting stents. Of 428 patients studied, PESs were placed in 287 patients and SESs in 141 patients. Stepwise Cox regression analyses were performed to identify significant independent risk factors for MACE. At 47 ± 19 months of follow-up, MACE had occurred in 49 (17%) of 287 patients in the PES group (mean age 71 ± 11 years, 55% men) and in 31 (22%) of 141 patients in the SES group (mean age 71 ± 12 years, 53% men). No significant difference was found in the MACE rate between the PES and SES groups. This persisted even after controlling for stent length, lesion complexity, and other co-morbidities. Also, all-cause mortality was not significantly different between the PES and SES groups (7.1% vs 8.5%, respectively). In conclusion, during long-term follow-up of patients with moderate to severe renal insufficiency, the rates of MACE and all-cause mortality were similar in the PES and SES groups.
Coronary artery disease is the predominant cause of mortality in patients with chronic kidney disease (CKD).1, 2, 3 Previous studies have demonstrated a greater incidence of major adverse cardiac events (MACE) in patients with CKD after percutaneous coronary interventions.4 Randomized trials have shown that drug-eluting stents (DESs) substantially reduce MACE primarily by decreasing in-stent restenosis5, 6; however, most of these studies excluded patients with CKD. In the present study, we compared sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) with regard to long-term MACE in patients with a glomerular filtration rate of <60 ml/min/1.73 m2.
Methods
We retrospectively studied 428 consecutive patients with moderate to severe renal insufficiency from January 2003 to December 2005, who had undergone single-vessel percutaneous coronary intervention with a DES at our institution. Moderate to severe renal insufficiency was defined as a glomerular filtration rate of <60 mL/min/1.73 m2. All patients with acute renal failure, requiring dialysis, or with a renal transplant were excluded from the present study. The glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) study equation within 24 hours of percutaneous coronary intervention.
Of 428 patients, PESs were used in 287 patients and SESs in 141 patients. The angiographic and procedural success rates were similar in the SES- and PES-treated patients. Also, the in-hospital outcomes were not different between the SES- and PES-treated patients.
We collected data on demographics and the baseline characteristics of age, gender, race, body mass index, hypertension, diabetes mellitus, dyslipidemia, current smoking, and current medications. Diabetes mellitus was defined as a previous diagnosis, the use of diet or antidiabetic medicines, or a fasting venous blood glucose level of ≥126 mg/dl on 2 occasions in previously untreated patients. Patients who had received medications for hypertension or those with a systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg and not taking concurrent antihypertensive therapy were classified as having hypertension. Hypertension in patients with diabetes was defined as a systolic blood pressure of ≥130 mm Hg or a diastolic blood pressure of ≥80 mm Hg. Dyslipidemia was defined as a serum total cholesterol level of ≥200 mg/dl, low-density lipoprotein cholesterol level of ≥100 mg/dl, high-density lipoprotein level of ≤40 mg/dl, triglycerides of ≥150 mg/dl, or if the patient was taking any lipid-lowering drugs. Patients who had smoked within the previous 1 year of entry into the study were deemed current smokers.
We also collected data on the angiographic and procedural variables, including the number of coronary arteries with ≥50% stenosis, the vessel stented (left anterior descending, left circumflex, right coronary artery, vein graft, or arterial graft), the lesion complexity (A, B, or C), length of the stented segment, target vessel diameter, and use of glycoprotein IIb/IIIa inhibitors during the procedure.
The primary outcome of interest was MACE, which was a composite of death, nonfatal myocardial infarction, and target vessel revascularization. The primary outcome MACE was compared in the PES and SES groups. We also studied death, myocardial infarction, and target vessel revascularization individually. The mean duration of follow-up was 49 ± 21 months in the SES group and 46 ± 18 months in the PES group. Follow-up data were obtained for all 428 patients in the study by frequent office visits to the cardiologist and from the Social Security Death Index.
All statistical analyses were performed using a Statistical Analysis Systems, version 9, software package (SAS Institute, Cary, North Carolina). Descriptive statistics included the mean and SD for continuous measurements and proportions for categorical ones. We applied 2-sample t tests and chi-square tests to test the equality of the means and proportions between the PES and SES groups. The association between DES and the MACE was tested using logistic regression models, controlling for other covariates at each step. Purposeful selection methods were used during that process to evaluate the significance and confounding effects of the covariates. The covariates considered for the final model for the outcome of interest included the variables of age, gender, race, stent length, target vessel diameter, indications for percutaneous coronary intervention, coronary artery disease burden, lesion complexity, previous coronary artery bypass surgery, smoking, hypertension, diabetes, dyslipidemia, body mass index, and use of drugs, including aspirin, clopidogrel, thrombolytics, glycoprotein IIb/IIIa inhibitors, β blockers, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The goodness of fit of the models was evaluated using the Pearson goodness of fit statistic and c statistic (area under the receiver operating characteristic curve). All associations less than the α level of 0.05 were considered significant.
Results
Table 1 lists the demographics and baseline characteristics in the SES and PES groups. The baseline characteristics and lesion characteristics were similar in both groups. As listed in Table 1, the antiplatelet drugs aspirin and clopidogrel were taken by 99% to 100% of all patients. β Blockers were taken by 94% of patients and statins by 97% to 98% of patients. Glycoprotein IIb/IIIa inhibitors were used by 6% to 8% of the patients.
Table 1. Demographics and baseline patient characteristics
| Variable | SES (n = 141) | PES (n = 287) | p Value |
|---|---|---|---|
| Age (years) | 71 ±12 | 71±11 | 0.53 |
| Gender | |||
| Men | 75(53%) | 157(55%) | |
| Women | 66(47%) | 130(45%) | 0.84 |
| Race | |||
| White | 121(86%) | 249(87%) | |
| Nonwhite | 20(14%) | 38(13%) | 0.77 |
| Indication | |||
| Unstable angina pectoris | 62(44%) | 129(45%) | 0.92 |
| Positive stress test | 44(31%) | 104(36%) | 0.33 |
| Acute myocardial infarction | 35(25%) | 54(19%) | 0.097 |
| Body mass index (kg/m2) | 28±6 | 29±6 | 0.62 |
| Body mass index ≥30 kg/m2 | 50(35%) | 100(35%) | 0.91 |
| Glomerular filtration rate (ml/min/1.73 m2) | 45±14 | 46±13 | 0.43 |
| Hypertension | 135(96%) | 265(92%) | 0.22 |
| Diabetes mellitus | 69(49%) | 130(45%) | 0.61 |
| Dyslipidemia⁎ | 136(96%) | 280(98%) | 0.54 |
| Smoker | 41(29%) | 73(25%) | 0.42 |
| Aspirin use | 139(99%) | 285(99%) | 0.60 |
| Clopidogrel use | 141(100%) | 286(100%) | 1.0 |
| β-Blocker use | 133(94%) | 271(94%) | 1.0 |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use | 57(40%) | 120(42%) | 0.83 |
| Statin use | 136(96%) | 280(98%) | 0.54 |
| Glycoprotein IIb/IIIa inhibitor use | 9(6%) | 22(8%) | 0.70 |
| Thrombolytic use | 17(12%) | 29(10%) | 0.62 |
| Previous coronary bypass | 30(21%) | 64(22%) | 0.90 |
| No. of coronary arteries involved | |||
| 1 | 44(31%) | 102(36%) | 0.39 |
| 2 | 50(35%) | 100(35%) | 0.91 |
| 3 | 47(33%) | 85(30%) | 0.44 |
| Complexity of stented lesion | |||
| A | 74(52%) | 143(50%) | 0.61 |
| B | 46(33%) | 108(38%) | 0.34 |
| C | 21(15%) | 36(13%) | 0.55 |
| Left ventricular ejection fraction | |||
| >50% | 78(55%) | 166(58%) | 0.68 |
| <30% | 5(4%) | 17(6%) | 0.36 |
| 30–50% | 58(41%) | 104(36%) | 0.34 |
| Stented coronary artery | |||
| Left anterior descending | 62(44%) | 114(40%) | 0.41 |
| Left circumflex | 32(23%) | 78(27%) | 0.35 |
| Right | 35(25%) | 84(30%) | 0.36 |
| Vein graft | 12(9%) | 11(4%) | 0.07 |
| Length of stented segment (mm) | 25±11 | 25±15 | 0.98 |
| Target vessel diameter (mm) | 3±0.4 | 3±0.4 | 0.63 |
| Follow-up duration (months) | 49±21 | 46±18 | 0.22 |
⁎Defined as serum cholesterol ≥200 mg/dl, serum low-density lipoprotein cholesterol ≥100 mg/dl, serum high-density lipoprotein cholesterol <40 mg/dl, or serum triglycerides >150 mg/dl. |
Table 2 lists the incidence of MACE in the 2 groups. MACE occurred in 49 (17%) of 287 patients in the PES group and in 31 (22%) of 141 patients in the SES group. No significant difference was found in the incidence of MACE between the PES and SES groups.
Table 2. Incidence of major adverse cardiac events (MACE) at follow-up
| Variable | SES (n = 141) | PES (n = 287) | p Value |
|---|---|---|---|
| Major adverse cardiac events⁎ | 31(22%) | 49(17%) | 0.24 |
| Death | 12(9%) | 21(7%) | 0.70 |
| Myocardial infarction | 9(6%) | 16(6%) | 0.83 |
| Target vessel revascularization | 14(10%) | 24(8%) | 0.59 |
⁎Composite end point of myocardial infarction, death, and target vessel revascularization. |
Stepwise Cox regression analyses showed that the type of DES was not associated with a greater incidence of MACE. Table 3 lists the variables associated with a greater incidence of MACE. These included diabetes mellitus, target vessel diameter, and type C lesions. Figure 1 illustrates the Kaplan-Meier curves for the hazard ratios for 4 years in the PES and SES groups. No significant difference was found in these curves during the 4 years.
Table 3. Cox regression analysis to identify significant independent prognostic covariates for major adverse cardiac events (MACE)
| Variable | Parameter Estimate | SE | p Value | Hazard Ratio | 95% CI |
|---|---|---|---|---|---|
| Smoking | 0.428 | 0.246 | 0.082 | 1.534 | 0.947–2.484 |
| Diabetes mellitus | 0.869 | 0.242 | <0.001 | 2.384 | 1.484–3.827 |
| Stent length >30 mm | −0.086 | 0.247 | 0.727 | 0.917 | 0.565–1.488 |
| Stent width <3 mm | −0.137 | 0.279 | 0.622 | 0.872 | 0.505–1.505 |
| Triple vessel disease | −0.523 | 0.259 | 0.044 | 0.593 | 0.357–0.985 |
| Stent type (sirolimus-eluting stent vs paclitaxel-eluting stent) | 0.142 | 0.233 | 0.541 | 1.153 | 0.730–1.821 |
| Lesion complexity C | 1.478 | 0.249 | <0.001 | 4.382 | 2.687–7.146 |
| Severe Chronic kidney disease (glomerular filtration rate <30 ml/min/1.73 m2) | 0.455 | 0.290 | 0.117 | 1.576 | 0.892–2.784 |
Figure 1.
Kaplan-Meier survival curves for hazard ratios during 4 years in PES and SES groups.
Discussion
CKD is associated with abnormal calcium metabolism leading to complex, often diffuse, and moderate or severe calcification of the coronary arteries.7, 8 It is also associated with endothelial dysfunction9 and pronounced neointimal hyperplasia after coronary stenting, leading to more in-stent restenosis. Patients with CKD also have a greater prevalence of other risk factors for atherosclerosis, including hypertension, diabetes mellitus, hypercoagulability, lipid abnormalities with hypertriglyceridemia and decreased high-density lipoprotein, elevated C-reactive protein levels, and hyperhomocysteinemia. The management of coronary artery disease in a patient with CKD is a difficult clinical challenge. A dearth of data is available on the outcome of stents in patients with renal insufficiency, because many trials have excluded this group of patients.
Evidence has shown that DESs compared with bare metal stents might improve the outcomes in patients with CKD, particularly in patients with end-stage renal disease requiring hemodialysis.10, 11 In a retrospective study10 comparing 76 patients with CKD treated with SESs and 153 patients treated with bare metal stents, SESs were associated with a lower incidence of target vessel revascularization at 6 months (7.1% vs 22.1; p = 0.02). No significant differences in MACE and all-cause mortality were observed. In that study, chronic renal insufficiency was defined by a creatinine of ≥2 mg/dl. Also, 39% of patients in the SES group and 41% in the bare metal stent group required dialysis. In another retrospective study from Japan11 that included patients with end-stage renal disease who required dialysis, 54 patients underwent percutaneous coronary intervention using SESs and 54 using bare metal stents. At 9 months of follow-up, no significant difference was found in the incidence of death, myocardial infarction, or target vessel revascularization. However, the angiographic in-stent restenosis rate was lower in patients treated with SESs than in those treated with bare metal stents (22% vs 40%; p = 0.048). However, to the best of our knowledge, no data are available comparing 2 widely used DESs (PESs and SESs) in patients with moderate to severe chronic renal insufficiency. Recently, studies have been published showing that one DES might be better than the other in patients with diabetes mellitus, which is an inflammatory milieu.12, 13 Such data are lacking in patients with moderate to severe CKD. We had hypothesized that a cytotoxic drug-coated stent (PES) might result in better long-term outcomes than a cytostatic drug-coated stent (SES) in CKD.
In the present study, we did not find any significant difference in the long-term outcomes using PESs or SESs in patients with CKD. Our results have demonstrated that in patients with CKD, PESs and SESs are associated with similar long-term outcomes. These results might have been because of a type 2 error. This was a limitation of our data analysis.
Although this was a retrospective study, our results calls for randomized controlled trials comparing various DESs in patients with CKD.
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PII: S0002-9149(09)02402-3
doi:10.1016/j.amjcard.2009.09.031
Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.
