Comparison of Percutaneous Coronary Intervention with Medication in the Treatment of Coronary Artery Disease in Hemodialysis Patients : Journal of the American Society of Nephrology

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Clinical Dialysis

Comparison of Percutaneous Coronary Intervention with Medication in the Treatment of Coronary Artery Disease in Hemodialysis Patients

Yasuda, Kaoru*,‡; Kasuga, Hirotake*; Aoyama, Toru; Takahashi, Hiroshi; Toriyama, Takanobu; Kawade, Yasumasa*; Iwashima, Shigejiro*; Yamada, Shigeki*; Kawahara, Hirohisa*; Maruyama, Shoichi; Yuzawa, Yukio; Ishii, Hideki§; Murohara, Toyoaki§; Matsuo, Seiichi

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Journal of the American Society of Nephrology 17(8):p 2322-2332, August 2006. | DOI: 10.1681/ASN.2005090958
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Abstract

Since Lindner et al. (1) reported that the incidence of ischemic heart disease was approximately 10 times higher in hemodialysis (HD) patients than in the general (non-HD) population, research has been directed at solving this problem. Uremia-related risk factors (e.g., hemodynamic overload, abnormal calcium metabolism) in addition to the traditional risk factors accelerate arteriosclerosis in HD patients (2), resulting in a 20 to 35 times higher cardiovascular mortality rate among HD patients than that in the non-HD population (3,4). In Japan as well, cardiac disease is the leading cause of death among HD patients, accounting for 30% of all-cause deaths (5). Percutaneous coronary intervention (PCI) has become a well-established procedure for the coronary revascularization in HD patients with coronary artery disease (CAD). However, previous research has indicated that the initial success after PCI was comparable for HD patients and non-HD patients but that the re-stenosis rate was higher and the survival rate was lower in HD patients than in non-HD patients (68). Conversely, many studies have been performed among non-HD patients with CAD to compare the therapeutic effects of PCI with those of medical treatment, and most of them have demonstrated that PCI significantly relieves the symptoms of angina and/or improves the exercise tolerance compared with medical therapy only (913). The study by Mark et al. (12) revealed that PCI was superior to medication alone particularly for CAD patients with two-vessel disease, whereas little difference was observed in the survival rate between the two therapies when applied to patients with single-vessel disease. Concerning the prognosis of CAD among patients with severe renal dysfunction, Keeley et al. (14) conducted a prospective study that showed that PCI improved long-term survival among patients with severe renal dysfunction (estimated GFR <60 ml/min per 1.73 m2) and acute coronary syndrome. However, there are no relevant up-to-date data comparing medical treatment and PCI for patients who are on HD. The aim of this study was to clarify whether PCI improves the prognosis of HD patients with CAD compared with medical treatment only.

Materials and Methods

Patients

In the Nagoya Kyoritsu Hospital and its affiliated clinics, an echocardiogram and a treadmill exercise test are performed at least once a year by all patients who are on maintenance HD. Between 1996 and January 1998, 893 outpatients who had no history of PCI or coronary artery bypass graft (CABG) and were undergoing maintenance HD at the Nagoya Kyoritsu Hospital and the Ama Kyoritsu Clinic (three times a week) were screened by echocardiogram and treadmill exercise tests. Of 893 patients, 303 showed asynergic wall-motion abnormality on the echocardiogram, 143 showed ST depression >1 mV on the treadmill exercise test, and 159 showed clinical symptoms greater than the Canadian Cardiovascular Society classification II. A total of 349 patients who showed at least one of these abnormalities were considered to be at high risk for coronary heart disease. Of these 349 patients, 317 chose to undergo an initial coronary angiogram (CAG) on their written informed consent. On CAG, 167 patients showed coronary artery stenosis defined as a luminal narrowing of ≥75% (stenosis group) and 150 patients did not (nonstenosis group). Among the nonstenosis group, 28 (23.0%) patients showed luminal narrowing of 50%, 76 (62.3%) patients showed 25% narrowing, and 18 (14.7%) patients showed 0%. Patients who had been treated previously for congestive heart failure, myocardial infarction, or ventricular arrhythmia and patients who had undergone valvular surgery or CABG were excluded. Patients with left main trunk disease diagnosed by CAG also were excluded. Consequently, 259 HD patients (122 without stenosis and 137 with stenosis) were enrolled in this study. Patients in the stenosis group were informed of the benefits and risks of PCI, and the decisions were made jointly with the physicians. Eighty-eight patients chose PCI and were classified as the PCI group. In this group, the procedure was performed using standard techniques within 2 wk after the initial CAG. Forty-nine patients who chose medical treatment only were classified as the medication group. The study was performed according to the guidelines of the Declaration of Helsinki, and all subjective patients gave their informed consent to participate in this study, which was approved by the local ethics committee.

Protocols

Clinical follow-up was conducted until December 2002. Patients were treated adequately with regular HD treatment three times a week, and a standard electrocardiogram and chest x-ray were taken every month. In addition, an echocardiogram and a treadmill exercise test were performed at least once per a year in the nonstenosis group and at least once every 6 mo in the medication and the PCI groups. Coronary angiogram also was performed once every year in the medication and the PCI groups. When the patients in any group showed abnormal findings in the routine tests or symptoms of CAD during the follow-up period, CAG was performed adequately and promptly. When re-stenosis (luminal narrowing of ≥50% at a target lesion) occurred in patients in the PCI group, a second PCI was performed. When de novo stenosis (luminal narrowing of ≥75%) occurred in any patient in any group, PCI was recommended and performed on their informed consent. When the patients underwent CABG, they were excluded as dropout cases. The primary end point was cardiac death as a result of congestive heart failure, myocardial infarction, and fatal arrhythmia and also including sudden death with unknown origin. The secondary end point was all-cause death.

Statistical Analyses

Statistical analysis was performed using Stat View 5.0 (SAS Institute, Cary, NC). The cumulative survival rates in each group were estimated by the Kaplan-Meier method, and the differences in survival rates between groups were evaluated by log-rank (Mantle-Cox) method. For comparison of the baseline data among multiple groups, ANOVA and Fisher protected least significant difference method for quantitative variables and χ2 test for categorical variables were used. A t test was used for comparison of quantitative data between two groups. Odds ratios (OR) and confidence intervals (CI) were calculated for each factor by a Cox univariate analysis, and prognostic factors to predict cardiac and all-cause death were determined. All of the prognostic variables with P < 0.25 were entered into a Cox multivariable analysis to determine independent predictors.

The stenosis group was evaluated further in subanalyses by classifying its members as having single-vessel disease defined as >75% stenosis of the lumen diameter in one major epicardial coronary artery (medication n = 22; PCI n = 23) or multivessel disease in which there were stenotic lesions in two or three major epicardial coronary arteries (medication n = 26; PCI n = 63). Next, a propensity-matched analysis was performed to minimize the selection bias (15). Using a multivariable logistic regression model, each patient was assigned a propensity score that reflected the probability that he or she would receive PCI. Covariates in the model included gender, age, left ventricular ejection fraction (LVEF), multivessel disease, left anterior descending artery stenosis, and unstable angina. The c statistic (the area under the receiver operating characteristic curve) was 0.747, showing the adequacy of the model. Patients in the medication group and those in the PCI group were matched 1:1, to a single-digit, on the basis of the estimated propensity score for receiving PCI. Using data from these propensity-matched groups, the cumulative survival rates in each group were estimated and OR were determined for cardiac and all-cause death.

Data were expressed as the mean value ± SD. Differences were considered significant at P < 0.05.

Results

Patients

The mean duration of follow-up was 39 mo (SD 19). During the follow-up period (39 ± 19 mo), 50 of 88 patients in the PCI group developed coronary artery stenosis, and all of them underwent PCI (28 target lesion and 22 de novo lesion). Nine of 49 patients in the medication group developed de novo stenosis, and three of 122 patients in the nonstenosis group developed de novo stenosis. Then, two patients in the nonstenosis group and two patients in the PCI group underwent CABG. One patient in the nonstenosis group and one patient in the medication group underwent PCI. They were excluded as dropout cases. Therefore, the number of the patients was 119 in the nonstenosis group, 86 in the PCI group, and 48 in the medication group (Figure 1).

Baseline Characteristics

Gender; age; duration of HD; hypertension; smoking; blood chemistry; and the history of cerebrovascular disease, peripheral arterial disease, and left ventricular hypertrophy (LVH) were comparable among the three groups (Table 1). The incidence of diabetes was significantly more frequent in the medication and the PCI groups than in the nonstenosis group and was comparable between the medication and the PCI groups. Frequency of unstable angina pectoris was statistically higher in the PCI group. LVEF was significantly lower in the PCI group than in the nonstenosis group but was not different from that in the medication group. Multivessel disease was significantly more frequent in the PCI group than in the medication group. Nicorandil, nitrites, and aspirin/antiplatelets were prescribed more frequently to the PCI and the medication groups than to the nonstenosis group. However, medication that was prescribed to the PCI and the medication groups was not statistically different.

Prognosis

Main Analysis.

In PCI group, the initial procedure was performed successfully in all cases, and 55 (63.9%) patients underwent stent implantation. During the follow-up period, 93 patients (31 in the nonstenosis, 29 in the medication, and 33 in the PCI group) died, and 47 patients died of cardiac diseases (14, 19, and 14, respectively; Table 2). Forty-nine (57.0%) patients in the PCI group (25 of 55 patients who initially underwent coronary stent implantation and 24 of 31 who initially underwent angioplasty alone) experienced coronary re-stenosis. All 49 patients underwent repeated PCI (mean times 2.3 ± 1.9 times; mean interval 8 ± 8 mo). Twenty-nine of 49 patients with re-stenosis underwent coronary stent placement, and the other 20 underwent angioplasty alone. Among the three groups, the 5-yr cardiac survival rate was significantly lower in the medication group (41.6%) than in the nonstenosis group (84.5%; P < 0.0001) or the PCI group (77.1%; P = 0.0006) but was comparable in the nonstenosis group and the PCI group (Figure 2). The 5-yr all-cause survival rate was the lowest in the medication group (19.3%) followed by the PCI group (48.4%; P = 0.004) and the nonstenosis group (64.3%; P < 0.0001). The difference in all-cause survival between in the PCI and nonstenosis groups was significant (P = 0.019; Figure 3).

Results of OR for cardiac and all-cause death by Cox univariate analysis are presented in Table 3. PCI was associated with cardiac survival (OR 0.28; 95% confidence interval [CI] 0.14 to 0.58; P = 0.0006). Other predictors for cardiac death were age (OR 1.04; 95% CI 1.01 to 1.08; P = 0.0071), peripheral arterial disease (OR 4.57; 95% CI 1.09 to 19.14; P = 0.037), hematocrit (OR 1.42; 95% CI 1.05 to 1.93; P = 0.022), serum albumin levels (OR 0.41; 95% CI 0.28 to 0.59; P = 0.017), and total cholesterol level (OR 1.02; 95% CI 1.00 to 1.05; P = 0.041). As for all-cause death, PCI (OR 0.51; 95% CI 0.31 to 0.85; P = 0.0095), age (OR 1.02; 95% CI 1.00 to 1.05; P = 0.034), peripheral arterial disease (OR 3.18; 95% CI 1.35 to 7.47; P = 0.0079), serum creatinine levels (OR 0.78; 95% CI 0.62 to 0.98; P = 0.033), serum albumin levels (OR 0.52; 95% CI 0.39 to 0.68; P = 0.016), and LVEF <0.40 (OR 1.79; 95% CI 1.05 to 3.22; P = 0.042) were significant predictors.

A Cox stepwise multivariate analysis showed that PCI (OR 0.16; 95% CI 0.09 to 0.29; P = 0.0018), age (OR 1.09; 95% CI 1.05 to 1.12; P = 0.0049), and serum albumin levels (OR 0.16; 95% CI 0.09 to 0.27; P = 0.0005) were independent predictors of cardiac death. As for all-cause death, PCI (OR 0.24; 95% CI 0.16 to 0.37; P = 0.0008), age (OR 1.10; 95% CI 1.07 to 1.13; P = 0.0001), and serum albumin levels (OR 0.21; 95% CI 0.15 to 0.30; P = 0.0007) were independent predictors (Table 4).

Subgroup Analysis.

With reference to a number of coronary lesions, we divided the patients into two groups: Single-vessel disease and multivessel disease. Among patients with single-vessel disease, baseline characteristics were not different between the medication (n = 22) and the PCI (n = 23) groups. Among patients with multivessel disease, the PCI group (n = 63) had lower hematocrit levels and more frequent episodes of unstable angina compared with the medication group (n = 26; Table 5). All of the other baseline characteristics examined were comparable between the two groups. These results suggested that the PCI group may have had a higher baseline risk for CAD. Among patients with single-vessel disease, the 5-yr cardiac survival rate was significantly higher in the PCI group (89.4%) than in the medication group (51.3%; P = 0.043), whereas the 5-yr survival rate, notwithstanding cause of death, was not significantly different between these two groups (47.0 versus 21.4%; P = 0.089). Among patients with multivessel disease, the 5-yr both cardiac and all-cause survival rates were significantly higher in the PCI group than in the medication group (75.0 versus 34.1% [P = 0.0007] and 48.4 versus 21.8% [P = 0.022]; Table 6).

A Cox stepwise multivariable analysis showed that among patients with single-vessel disease, only PCI was an independent predictor of cardiac death (OR 0.17; 95% CI 08 to 0.39; P = 0.034) and that age (OR 1.06; 95% CI 1.04 to 1.08; P = 0.0005) and peripheral artery disease (OR 3.78; 95% CI 2.07 to 6.93; P = 0.027) were independent predictors of all-cause death. In patients with multivessel disease, PCI was an independent predictor of cardiac death (OR 0.15; 95% CI 0.09 to 0.27; P = 0.0008) as well as all-cause death (OR 0.39; 95% CI 0.24 to 0.63; P = 0.048). Age and LVEF <0.40 also were independent predictors of cardiac death (OR 1.09; 95% CI 1.06 to 1.12, P = 0.0006; and OR 4.76; 95% CI, 1.24 to 9.5, P = 0.026, respectively; Table 7).

Propensity-Matched Patients Analysis.

Thirty-nine patients from each of the medication and the PCI groups were matched according to the estimated propensity scores. The baseline data of the two groups are shown in Table 8. The propensity scores in these matched groups were 0.59 ± 0.20 in the medication group and 0.62 ± 0.17 in the PCI group (P = 0.39). The analysis revealed that the 5-yr cardiac survival rate was significantly lower in the medication group (51.4%) than in the PCI group (81.3%; P = 0.030). The 5-yr all-cause survival rate also was lower in the medication group (23.4%) than in the PCI group (54.3%; P = 0.041; Table 9).

Results of a Cox multivariable analysis showed that PCI (OR 0.15; 95% CI 0.06 to 0.31; P = 0.012) and LVEF <0.4 (OR 3.32; 95% CI 1.91 to 12.12; P = 0.012) were independent predictors of cardiac death. As for all-cause death, PCI (OR 0.29; 95% CI 0.17 to 0.47; P = 0.011), age (OR 1.04; 95% CI 1.02 to 1.11; P = 0.040) and LVEF <0.4 (OR 2.91; 95% CI 1.28 to 6.61; P = 0.017) were independent predictors (Table 10).

Discussion

Our results revealed that both survival rates for cardiac and all-cause death were significantly higher in the PCI group than in the medication group. Furthermore, cardiac mortality was comparable between the PCI and the nonstenosis groups. A Cox multivariable analysis revealed that PCI was an independent predictor of cardiac and all-cause survival. Moreover, similar results were obtained after the PCI and the medication groups were adjusted with propensity scores. To our knowledge, this is the first prospective cohort study to compare the effects of PCI on the prognosis in HD patients with those of the medical therapy alone.

In the general population with CAD, many randomized, controlled studies have been performed to compare the therapeutic effects of PCI with those of medical therapy (913). Parisi et al. (9) reported that the relief of angina and the improvement of exercise tolerance were significantly greater in patients who underwent PCI than in those who were treated with medical therapy only. Nonetheless, they also reported that PCI did not significantly improve the survival rate of the patients who had CAD with single-vessel disease compared with medical therapy. Hueb et al. (10) and the Second Randomized Intervention Treatment of Angina (RITA-2) trial participants (11) reported similar results in patients with single left anterior descending artery stenosis. Furthermore, Mark et al. (12) reported that there was no cardiac survival advantage at 5 yr after PCI over medical treatment among patients with single-vessel disease but that PCI was associated with higher cardiac survival rate than medical treatment among patients with two-vessel disease, and CABG was associated with a higher survival rate than PCI treatment among patients with three-vessel disease. Consequently, medical treatment was considered to be a reasonable strategy for single-vessel disease in non-HD patients with CAD, whereas interventional therapies (PCI or CABG) were considered to be reasonable strategies for multivessel disease in non-HD patients with CAD (13). In contrast, our results revealed for the first time that PCI showed a cardiac survival advantage over medical therapy regardless of the number of diseased vessels among the HD patients with CAD. These results suggest that PCI should be the initial therapeutic strategy for CAD among HD patients even when they have single-vessel disease.

The high prevalence of ischemic heart disease in HD patients has been a widely known problem (14). Uremia-related risk factors in addition to the traditional risk factors accelerate arteriosclerosis in HD patients (2); therefore, cardiovascular mortality was much higher among HD patients compared with the general population (3,4). Parfrey et al. (16) described that continuous hemodynamic overload state is the most important risk factor that inevitably causes LVH and that LVH predisposes to ischemic symptoms by reducing coronary reserve. Furthermore, they reported that LVH that is complicated by CAD easily causes severe LV dysfunction such as cardiac failure or death. In fact, 70% of the patients in our study had LVH, and cardiac failure has always been the leading cause of death in HD patients in Japan (5). On the basis of these unique clinical backgrounds of HD patients, angioplasty might be needed even for the mildest form of CAD, such as single-vessel disease, among patients who are on maintenance HD.

High incidence of re-stenosis in target lesions remains the major problem among HD patients who undergo PCI. Many studies have revealed that re-stenosis rate was obviously higher in HD patients than in the general population despite the comparable initial success rate (68,17). Because of the high re-stenosis rate that is caused by severe calcified and diffuse coronary lesion, some authors have not recommended PCI for HD patients with CAD (17,18). Although in our study as well repeated PCI was performed in as many as 57% of patients (32% with re-stenosis at the original target lesion and 25% with de novo stenosis) and the average times of PCI were 2.3 ± 1.9, the improvement of the prognosis clearly was achieved by PCI. One Japanese group (19) reported that they performed repeated PCI (average 2.2 times) on dialysis patients with diabetes and showed that the 5-yr survival rate among these patients did not differ from that of dialysis patients without diabetes. They also described that repeated PCI is the most important predictor for prognosis in the result of the multivariable analysis, including all of the other risk factors. The most important finding in their study was that multiple PCI reduce the long-term mortality of HD patients with diabetes to levels similar to those among HD patients without diabetes. Another Japanese group showed that diabetes was not a predictor of survival outcome among HD patients who had CABG, PCI, or both (20). They stated that complete revascularization may have improved the long-term survival among patients both with and without diabetes. In our study, there were significantly more patients with diabetes among the groups with stenosis (the PCI and the medication groups) as compared with the nonstenosis group. However, diabetes was not a risk factor for cardiac or overall death when analysis was done on the PCI and the medication groups. We assume a similar reason for this result: Effective revascularization allowed patients with diabetes a good prognosis, comparable to that of patients without diabetes. We are currently conducting another study to prove this hypothesis.

Many reports show that the prognosis after PCI was a lot worse in HD patients than in non-HD patients. Le Feuvre et al. (6) reported that although the initial success rate, the in-hospital mortality, and the incidence of cardiac infarction were not different between HD patients after PCI compared with non-HD patients after PCI, 1-yr cardiac mortality was as high as 11% among HD patients compared with 2% in non-HD patient. Other reports described that 1-yr mortality was 10 to 15% in HD patients with CAD (7,8). Furthermore, Foley et al. (21) reported that 14, 19, and 31% of patients with ESRD already had CAD, angina, and cardiac failure when they started HD therapy, respectively. It was confirmed recently that ESRD itself is the major risk factor for CAD. At the same time, it also has been regarded that it is extremely difficult to obtain a good prognosis in such a unique population as dialysis patients. In our study, all-cause survival rate at 24 mo was 74.2% in the PCI group, which was a lot higher than that in the United States, 48%, as reported by Herzog et al. (22). One likely reason for this discrepancy is that the general prognosis of HD patients in Japan is better than that in the United States (23). Another possible explanation is that aggressive screening tests that were performed in our study resulted in a better prognosis. In the Nagoya Kyoritsu Hospital and its affiliated clinics, we have built up a unique system for the earlier detection of CAD and specific risk reduction management. Serial cardiac screening tests such as echocardiogram and treadmill exercise tests are performed repeatedly in all of the HD patients from the point of the initiation of dialysis therapy, and long-term electrocardiography (Holter recording) is performed as needed. When the patients in any group showed abnormal findings in the routine tests or symptoms of CAD during the follow-up period, CAG was performed adequately and promptly. We found that this system actually has resulted in a great improvement of the prognosis (24). Further studies are ongoing to prove the effectiveness of our system.

Concerning the medication that was given to patients with CAD in our study, we prescribed β blockers to only a small number of patients. Instead, we gave calcium blockers to a larger number of patients. The situation in Japan may be different from that in the United States, where β blockers are given to most patients with CAD. It is known that Japanese generally tend to have coronary vasospastic angina (25). Calcium channel blockers prevent coronary vasospasm whereas β blockers exacerbate it, so we used calcium channel blockers more often than β blockers.

We note the limitations of our study. The patients were not randomly assigned to groups; rather, they chose PCI or medical therapy jointly with physicians on the basis of their informed consent. All patients had similar clinical backgrounds except for a higher incidence of unstable angina and multivessel disease in the PCI group. These data suggested that the PCI group had a disadvantage compared with the medication group at baseline. Therefore, it is not likely that patients who chose PCI had special features that would be advantageous for a better prognosis. Furthermore, a Cox multivariable analysis showed that among various factors, PCI was the strongest independent predictor for cardiac prognosis. Nonetheless, the selection bias could not be excluded. To compare better the effect on outcomes of PCI or medication alone, we used the propensity score approach, allowing adjustment for treatment selection bias. We then obtained similar results among propensity-matched patients. PCI brought about better cardiac and all-cause survival compared with medication only, and PCI turned out to be a potent independent predictor of better cardiac and overall survival. Because we could match the propensity scores of each pair only to a single digit, small differences may remain. However, they likely would affect only the magnitude (rather than the direction) of our findings. Nonetheless, randomized, controlled studies would be needed to exclude selection bias fully and to confirm our findings further.

Conclusion

Among HD patients with CAD, the cardiac survival rate was significantly higher in the PCI group than in the medication group regardless of the number of diseased vessels, and it was not significantly different from that in the nonstenosis group. All-cause survival rate was significantly higher in the PCI group compared with the medication group. These results suggest that dialysis patients who have higher risk for CAD have the necessity to undergo PCI more aggressively than previously considered.

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Figure 1:
Flow diagram of study population. TMT (+), ST depression >1 mV on treadmill test; CCS, Canadian Cardiovascular Society; CHF, congestive heart failure; MI, myocardial infarction; VA, ventricular arrhythmia (>Lown IVb); VS, valve surgery; LMT, left main trunk disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
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Figure 2:
Kaplan-Meier analysis of cardiac survival among the three groups after coronary angiogram. *P < 0.0001 versus medication; **P = 0.0006 versus medication.
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Figure 3:
Kaplan-Meier analysis of all-cause survival among the three groups after coronary angiogram. *P < 0.0001 versus medication; *P = 0.019 versus PCI; **P = 0.004 versus medication.
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Table 1:
Clinical characteristics at baseline a
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Table 2:
Prognosis during follow-up perioda
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Table 3:
OR for cardiac and all-cause death by Cox univariate analysis in HD patients with coronary stenosisa
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Table 4:
OR for cardiac and all-cause death by a Cox multivariable analysis in HD patients with coronary stenosisa
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Table 5:
Clinical characteristics at baseline in HD patients with coronary stenosis
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Table 6:
Cardiac and all-cause survival rate in patients with single- and multivessel disease
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Table 7:
OR for cardiac and all-cause death by stepwise Cox multivariate analysis in HD patients with single- and multivessel disease
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Table 8:
Clinical characteristics at baseline in propensity-matched patients with coronary stenosis
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Table 9:
Cardiac and all-cause survival rate (%) in propensity-matched patients with coronary stenosis
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Table 10:
OR for cardiac and all-cause death by a Cox multivariable analysis in propensity-matched patients with coronary stenosis

This study was supported partly by a research grant for Research on Human Genome, Tissue Engineering Food Biotechnology from the Ministry of Health, Labor and Welfare (H17-regeneration-010; awarded to S. Matsuo.).

Published online ahead of print. Publication date available at www.jasn.org.

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