Independent predictors of restenosis after percutaneous coronary revascularization in haemodialysis patients

Hiroki Hase1,, Masato Nakamura2, Nobuhiko Joki1, Taro Tsunoda2, Ryoichi Nakamura1, Tomokatsu Saijyo1, Masaki Morishita3 and Tetsu Yamaguchi1,2

1 Third Department of Internal Medicine, Division of Nephrology, 2 Third Department of Internal Medicine, Division of Cardiology and 3 Division of Clinical Engineering, Ohashi Hospital, Toho University School of Medicine, Tokyo, Japan



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Percutaneous balloon angioplasty has become a well-established and routine procedure for coronary revascularization of haemodialysis patients with coronary artery disease. However, the incidence of restenosis after balloon angioplasty is significantly higher in haemodialysis patients than in the general population. We performed a retrospective study comparing balloon angioplasty with coronary stenting in haemodialysis patients. We evaluated the long-term clinical and angiographic outcome after successful percutaneous coronary revascularization in haemodialysis patients.

Methods. A total of 103 consecutive haemodialysis patients (123 lesions) underwent procedurally and clinically successful percutaneous revascularization. Patients were treated with three different strategies: (i) balloon angioplasty in 55 patients (69 lesions); (ii) coronary stenting with balloon angioplasty in 23 patients (25 lesions); and (iii) coronary stenting with rotational atherectomy in 25 patients (29 lesions) who had severely calcified stenotic coronaries.

Results. The rates of in-hospital mortality were similar in the three groups. The 1-year incidence of overall events and major adverse cardiac events (MACE) were significantly higher in the balloon group than in the stent with/without rotational atherectomy groups (75% vs 36 and 28%, P<0.01; 71% vs 32 and 28%, P<0.01). Use of coronary stenting (relative risk=0.006, P<0.001) and the presence of calcified coronary lesion (relative risk=68.2, P<0.001) were independent predictors of the 1-year MACE-free survival after percutaneous revascularization. The 3-year MACE-free survival rate was significantly lower in the balloon group than in the stent with/without rotational atherectomy groups (11% vs 33 and 47%, P<0.005 and P<0.001).

Conclusions. This study shows that coronary stenting reduces the incidence of MACE in haemodialysis patients with/without calcified coronary lesions. Moreover, coronary stenting reduces the restenosis rate of both complex and restenotic lesions, and rotational atherectomy prior to coronary stenting reduces the restenosis rate of the severely calcified coronary lesions. These results suggest that coronary stenting with/without rotational atherectomy has led to an improved long-term outcome in the haemodialysis patients with coronary artery disease.

Keywords: balloon angioplasty; cardiac event; haemodialysis; rotational atherectomy; stent



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Cardiac events, especially those related to coronary artery disease, remain the leading cause of mortality among patients with chronic renal disease. During the 20 years since Gruntzig et al. [1] introduced conventional balloon angioplasty into clinical practice, it has become a well-established and routine procedure for coronary revascularization in haemodialysis patients with coronary artery disease. However, the incidence of restenosis after balloon angioplasty is significantly higher in haemodialysis patients than in the general population [28].

Recently, it has been reported that coronary stenting reduces restenosis rates [9], and that rotational atherectomy followed by stenting is a useful interventional treatment for revascularization of severely calcified stenotic coronary lesions [10]. Coronary lesions in haemodialysis patients are often moderately or severely calcified due to a calcium–phosphate balance disorder [11,12]. Although percutaneous revascularization using coronary stenting might be expected to reduce coronary restenosis in haemodialysis, there have been few reports evaluating the effect of coronary stenting in such patients [13,14].

Until 1992, all haemodialysis patients were treated with balloon angioplasty in our institution. In 1993, coronary stenting became available, and the decision to stent was based on vessel size, lesion morphology, and the absence of clinical contraindications. Starting in 1997, we used the rotational atherectomy in patients with severely calcified coronary lesions. Here, we performed a retrospective study comparing balloon angioplasty with coronary stenting in haemodialysis patients with coronary artery disease. We also evaluated the clinical and angiographic predictors of the cumulative incidence of major adverse cardiac events (MACE), including cardiac death, non-fatal acute myocardial infarction, coronary artery bypass surgery, and repeated percutaneous revascularization in these patients.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient population
Between April 1993 and December 1999, 56 consecutive haemodialysis patients (64 stenotic native coronary arteries) were revascularized by coronary stent placement in our institute. Eight patients (14%) were excluded from this study because of age less than 50 or greater than 75 years. Thus, 48 patients with procedurally and clinically successful coronary stenting of 54 coronary lesions were eligible for this study. Fifty-five haemodialysis patients (69 lesions) without previous coronary artery bypass surgery, who had undergone balloon angioplasty during the same period at our institute, were selected as the control group after matching for age. The 24 patients who had severely calcified stenotic coronary lesions underwent plaque debulking by rotational atherectomy prior to coronary stenting. All patients selected percutaneous revascularization over bypass surgery after giving informed consent. The cause of renal failure was diabetes mellitus in 49% of the balloon group and 58% of the stent group, chronic glomerulonephritis in 49% of the balloon group and 40% of the stent group, and hypertension in 2% of the balloon group and 2% of the stent group. Moderate lesion calcification was defined as the presence of mobile luminal opacities seen under fluoroscopy and demonstrated to correlate with cardiac motion. Severe calcification was defined as dense radio-opacification on both sides of the arterial lumen, generally not correlated with cardiac motion. The global left ventricular ejection fraction was evaluated by the echocardiogram rather than radiographic ventriculogram to decrease the volume of contrast media used.

Percutaneous coronary revascularization
Selection of device or strategy was mostly dependent on the morphologic characteristics of the target lesion and a history of target lesion restenosis. Balloon angioplasty was performed using standard techniques. All patients received aspirin (162 mg daily) starting 3 days before the procedure. Heparin (100 IU/kg) was administered just before the procedure. Stent implantation also was performed using standard techniques. Rotational atherectomy was performed with the Rotablator system (Boston Scientific, Natick, MA, USA) and the decision to perform adjunctive balloon angioplasty was left to the operator. Treatment with ticlopidine (200 mg daily) was started immediately after the stent placement and was continued for at least 4 weeks. All patients received long-term aspirin (81–162 mg daily) in the follow-up period.

Lesion morphology was classified according to the AHA/ACC Classification Task Force. Lesion treatment was considered to be successful when there was a greater than 20% gain in luminal diameter. Reference and minimal luminal diameter, and lesion length were determined by use of a quantitative coronary angiographic measurement system.

Angiography and clinical follow-up
During the study period, we routinely attempted to obtain a follow-up coronary angiography 6–12 months after the initial procedure to evaluate the presence of restenosis, regardless of symptomatic status. Angiography was performed earlier if clinically indicated. Non-invasive examinations, including myocardial scintigraphy, echocardiography, and exercise electrocardiography, were performed at regular intervals after the initial follow-up angiography because diabetic and haemodialysis patients commonly do not have typical symptoms of myocardial ischaemia. Patients who died without repeat coronary angiography within 12 months were excluded from angiographic data analysis. Restenosis was defined angiographically as a luminal narrowing of 50% at a previously dilated site. Following hospital discharge, patients were either seen at our hospital or contacted by telephone for follow-up. Follow-up was successful in all patients. The primary end-point of the study was incidence of the MACE and non-cardiac death during the 40 months after successful percutaneous revascularization before December 2000.

Statistical analysis
Statistical analysis was performed with a commercially available software program (StatView 5.0, SAS Institute, Cary, NC, USA). Data are expressed as the mean value±SD. The {chi}2 test or Fisher's exact test for categorical variables and Student's t-test for continuous variables were used to evaluate differences between measured values. P values <0.05 were considered statistically significant. Univariate logistic analysis was used to select the clinical and angiographic predictors of MACE after percutaneous revascularization. Independent predictors of the MACE were determined by using a multivariate stepwise logistic regression model. The relative risk ratios and 95% confidence intervals are presented in tabular form for the final multivariate model. The MACE-free survival rates and the overall survival rates in the three groups were determined by the Kaplan–Meier method.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics
The study cohort was comprised of 103 haemodialysis patients who underwent percutaneous coronary intervention in a total of 123 vessels. The mean follow-up period was 17±16 months with a range of 1–60 months. The baseline clinical characteristics of the haemodialysis patients who underwent successful percutaneous revascularization are shown in Table 1Go. There were no statistically significant differences among the three patient groups with regard to age, gender, smoking, hypertension, history of cardiovascular disease, duration of haemodialysis treatment, left ventricular ejection fraction, underlying coronary disease, or prior percutaneous revascularization. The incidence of diabetes mellitus was significantly higher in the group who underwent stent with rotational atherectomy than in the balloon group. The haematocrit and the biochemical data of the study population are shown in Table 2Go. There were no statistically significant differences among the three groups with respect to the haematocrit, serum urea–nitrogen, creatinine, total protein, total cholesterol, high-density lipoprotein, calcium, phosphate, calcium–phosphate product, or parathyroid hormone concentration. The haemoglobin A1c levels were higher in the stent with rotational atherectomy group than in the balloon group.


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Table 1. Demographic and clinical characteristics

 

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Table 2. Hematologic data and serum chemistries

 

Angiographic and procedural characteristics
The angiographic characteristics of the study groups are shown in Table 3Go. Although the incidence of multivessel disease and the target vessels for percutaneous revascularization did not differ among the three groups, the incidence of calcified lesions, especially severely calcified lesions was significantly higher in the stent with rotational atherectomy group than in the balloon group. Compared with the balloon group, the stent with rotational atherectomy group was more likely to have revascularization performed on AHA/ACC type C lesions. The pre-procedure quantitative coronary angiographic analysis showed that the lesion length was significantly longer in the stent with rotational atherectomy group than in the balloon group. The minimal luminal diameter obtained as a result of the revascularization was significantly larger in the stent groups than in the balloon group.


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Table 3. Angiographic characteristics

 
In the diabetic subgroup, the frequency of AHA/ACC type B2 and C lesions was higher (100% vs 58%, P<0.05) in the stent with balloon group than in the balloon only group. The incidence of severely calcified lesion was significantly higher in the stent with rotational atherectomy group than in the balloon group. Lesion length was significantly longer in the stent with/without rotational atherectomy group than in the balloon group.

Long-term results of percutaneous coronary intervention
The 1-year clinical and angiographic outcomes of the three groups are shown in Table 4Go. The in-hospital mortality rates and the duration of in-hospital stay were similar in the three groups. Six patients (11%) in the balloon group, one patient (5%) in the stent with balloon group, and four patients (16%) in the stent with rotational atherectomy group died within 1 year after discharge. None of the deceased patients had undergone their first follow-up angiography before death. During the 1-year follow-up, there were higher incidences of overall events and MACE in the balloon group than in the coronary stent groups. However, the incidences of cardiac death and non-cardiac death were not significantly different among the three groups. The incidence of target lesion restenosis was significantly higher in the balloon group than in the stent groups.


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Table 4. One-year clinical outcome

 
In the diabetic subgroup, there were higher incidences of over all events and MACE in the balloon group than in the stent with rotational atherectomy group. The incidence of target lesion restenosis and repeated intervention were significantly lower in the stent with rotational atherectomy group than in the balloon only group.

As shown in Table 5Go, the incidence of MACE within 1 year after percutaneous revascularization was predicted independently by two variables. Coronary stenting was the variable that was most closely associated with a decreased risk of MACE, and the presence of moderate to severely calcified coronary lesions was the variable that was most closely associated with an increased risk of MACE after percutaneous revascularization based on stepwise logistic regression analysis.


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Table 5. One-year predictors of MACE (n=100)

 
In all haemodialysis patients, 3-year MACE-free and overall survival rates were 26% and 68%. There was a significantly better 3-year MACE-free survival rate in the stent with/without rotational atherectomy groups than in the balloon group (33 and 47% vs 11%, P<0.005 and P<0.001). There were no statistically significant differences among the three patient groups with regard to 3-year overall survival rate.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Based on these data, 3-year MACE-free survival rate (24%) and overall survival rate (68%) were lower than the results of a previous study [15]. The lower survival rates are likely due to a higher percentage of haemodialysis patients in our population. The cumulative incidence of MACE was significantly higher in patients treated with balloon angioplasty than in those treated with coronary stenting. The majority of MACE after percutaneous revascularization was attributable to accelerated restenosis of treated lesions.

Haemodialysis patients have a high cardiac morbidity and mortality, mainly due to coronary artery disease [16,17]. As a result, haemodialysis patients frequently require percutaneous revascularization. However, the long-term results after balloon angioplasty have been disappointing in these patients, mainly because of accelerated restenosis. A restenosis rate of 47–81% after successful balloon angioplasty has been reported in haemodialysis patients, which is significantly higher than for the general population [28]. The incidence of MACE depends on the rate of restenosis. The high rate of target lesion restenosis decreased the MACE-free survival rates after balloon angioplasty.

The increase in the minimal luminal diameter as a result of percutaneous revascularization was greater in patients treated with coronary stenting than in patients treated with balloon angioplasty [9,10]. The minimal luminal diameter after balloon angioplasty has generally been found to be smaller in haemodialysis patients than in the general population, because of coronary artery calcification [11]. However, coronary stenting decreased the prevalence of MACE and target lesion restenosis in haemodialysis patients in this study. The ‘repeat coronary revascularization rate’ at 1-year after coronary stenting has been reported to be between 33% and 37% in haemodialysis patients [13,14]. In our study, the incidence of MACE 1-year after revascularization was 28% in the coronary stent with balloon group. The lower rate of MACE is probably due to a decreased incidence of severely calcified lesions in our population.

Until 1997, there were no effective percutaneous revascularization devices for treating complex coronary lesions with severe calcification. In this study, haemodialysis patients who had severely calcified and complex stenotic coronary lesions underwent plaque debulking by rotational atherectomy prior to coronary stenting. Although they were high-risk patients, the incidence of MACE was significantly lower than in those patients treated by balloon angioplasty. These results suggest that the larger minimal luminal diameter created by coronary stenting for less calcified lesions, or rotational atherectomy use prior to stenting for severely calcified lesions, tends to prevent early restenosis because of decreased elastic recoil and/or coronary remodeling in those patients. Rotational atherectomy may favour homogeneous dilatation, production of a circular intima-lumen interface in calcified coronary lesions, an increase in luminal size, and a decrease in plaque-plus-media area [10].

Coronary artery calcification occurs more frequently in young adults with end-stage renal disease than in either normal subjects of the same age and gender or older adults with normal renal function [19]. The duration of treatment with dialysis was substantially longer in the patients with coronary artery calcification than in those without calcification [20]. The mechanism responsible for vascular calcification in patients with chronic renal failure remains uncertain, and the relationship between arterial-wall calcification and the atherosclerotic or restenotic process is not fully understood [21]. Patients with calcification had higher serum phosphorus concentrations and a higher serum calcium–phosphorus ion product. Furthermore, their daily intake of calcium-containing phosphate-binding agents was nearly twice as great as in patients without calcification. Therefore, long-term exposure to the abnormalities in minimal metabolism that characterize chronic renal failure and the treatment of these abnormalities appear to contribute to the development of coronary artery calcification in patients with end-stage renal disease [20].

Our study has several potential limitations. First, this study was retrospective and the number of patients was small. Therefore, the quality of the data does not allow us to draw conclusions with the same confidence as would be derived from a large-scale prospective trial. Second, the cost of the coronary stenting and rotational atherectomy was not calculated. Consequently, it is difficult to determine whether there is a cost-effective MACE-free survival advantage for performing coronary stenting with/without rotational atherectomy in haemodialysis patients.

This study shows that coronary stenting reduces the incidence of MACE in haemodialysis patients with/without calcified coronary lesions. Moreover, coronary stenting reduces the restenosis rate of both complex and restenotic lesions, and rotational atherectomy prior to coronary stenting reduces the restenosis rate of the severely calcified coronary lesions. These results suggest that coronary stenting with/without rotational atherectomy has led to an improved long-term outcome in the haemodialysis patients with coronary artery disease.



   Acknowledgments
 
We would like to thank Drs Raisuke Ijima, Masanori Shiba, and Masamichi Wada for quantitative coronary angiographic analysis.



   Notes
 
Correspondence and offprint requests to: Hiroki Hase, MD, Third Department of Internal Medicine, Toho University Ohashi Hospital, Ohashi 2176, Meguro-ku, Tokyo 153-8515, Japan. E-mail: hiroki{at}oha.toho\|[hyphen]\|u.ac.jp Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 2.12.00
Revision received 10. 7.01.