Favourable long-term outcome by repeated percutaneous coronary revascularization in diabetic haemodialysis patients

Hiroki Hase1,, Nobuhiko Joki1, Masato Nakamura2, Taro Tsunoda2, Yuri Tanaka1, Masayuki Fukazawa1, Yasunori Takahashi3, Yoshihiko Imamura3, Ryoichi Nakamura4 and Tetsu Yamaguchi1,2

1 Third Department of Internal Medicine, Division of Nephrology and 2 Division of Cardiology, Ohashi Hospital, Toho University School of Medicine, 3 Division of Dialysis Center, Nissan Tamagawa Hospital and 4 Komazawa Renal Clinic, Tokyo, Japan



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Diabetic haemodialysis patients have a high prevalence of coronary events and very high mortality rates. Percutaneous coronary intervention has become a well-established and routine procedure for coronary revascularization. This study investigated the long-term outcome of multiple repeated interventions in diabetic haemodialysis patients with coronary artery disease.

Methods. A retrospective study compared 37 type II diabetic haemodialysis patients with coronary artery disease and 26 non-diabetic patients matched for age, angiographic morphology, and devices of percutaneous intervention. All patients had undergone successful percutaneous intervention prior to enrolment. Percutaneous interventions were repeated in the event of restenosis or the development of a de novo lesion.

Results. Diabetic and non-diabetic patients were similar in terms of the number of follow-up angiograms (2.3±1.6 vs 2.4±1.5/patient) and interventions (2.2±1.4 vs 2.2±1.5/patient), incidence of target lesion revascularization (85 vs 82%), and number of de novo lesions (15 vs 17%). The cumulative survival rates after the initial percutaneous intervention were similar in the groups (42% vs 31% at 80 months). Cardiac death occurred in 33% of diabetic patients and 42% of non-diabetic patients. Repeated intervention (regression coefficient=16.0, P<0.001) and a lower left ventricular ejection fraction (regression coefficient=-12.9, P=0.047) were determined for the important clinical factors associated with the survival duration after initial coronary intervention.

Conclusions. Multiple repeated percutaneous interventions reduce the long-term mortality of diabetic and non-diabetic haemodialysis patients with coronary artery disease similarly. Multiple repeated percutaneous coronary interventions are a viable option for controlling myocardial ischaemia and improving the long-term outcome in high-risk diabetic haemodialysis patients.

Keywords: coronary artery disease; diabetes mellitus; haemodialysis; repeated intervention; survival



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients with diabetes mellitus make up an increasingly large percentage of the population with coronary artery disease and renal failure. Percutaneous coronary intervention has become a well-established and routine procedure for revascularization in diabetic [14] and haemodialysis patients [57] with coronary artery disease. However, following balloon angioplasty in diabetic and haemodialysis patients, the rates of restenosis are higher than in the general population. Although coronary stenting decreases the rate of restenosis and improves the clinical outcome in those patients, restenosis remains problematic [7], and multiple repeated interventions are often required. Additionally, survival after percutaneous coronary intervention is shorter in diabetic patients and haemodialysis patients than in the general population of patients with coronary artery disease [1,4,7]. The efficacy of multiple repeated percutaneous coronary interventions on the long-term outcome in haemodialysis patients, particularly in diabetic haemodialysis patients, remains controversial. This study examined the long-term outcome of multiple repeated percutaneous coronary interventions in diabetic haemodialysis patients and compares it with those of non-diabetic haemodialysis patients.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient population
Between April 1993 and December 1999, 67 type II diabetic haemodialysis patients with 83 stenotic native coronary arteries were revascularized by percutaneous coronary intervention in our institute. Excluded were patients with a history of revascularization (28 patients, 42%) and patients who suffered any major adverse cardiac event during first 30 days after the procedure, such as death, myocardial infarction, or need for repeated revascularization (two patients, 3.0%). Thus, 37 patients with successful initial percutaneous coronary revascularization of 51 coronary lesions were enroled in this study. Twenty-six non-diabetic haemodialysis patients without previous coronary artery bypass grafting, who had undergone initial percutaneous coronary intervention during the same period at our institute, were randomly selected as controls, after matching for age, type of coronary disease, angiographic morphology, and method of revascularization. In non-diabetic patients, renal failure had resulted from glomerulonephritis in 23 patients, polycystic disease in two patients, and hypertensive nephrosclerosis in one patient. The global left ventricular ejection fraction was evaluated by echocardiography to minimize infusion volume of contrast medium.

An oral hypoglycaemic agent or insulin at same point had treated all diabetic haemodialysis patients, and all had diabetic retinopathy at the time of the initial procedure. Diabetes mellitus was managed by diet alone in 20 patients (54%), oral hypoglycaemic therapy in 12 (32%), and insulin in five (14%) upon enrolment in the study.

Percutaneous coronary intervention
The patients were informed of the risks and benefits of percutaneous coronary intervention and gave their written consent to participation. Selection of device or strategy was mostly dependent on the morphologic characteristics of the target lesion, including lesion length, reference vessel diameter, minimal luminal diameter, or lesion calcification. 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. From 1997, we used rotational atherectomy prior to coronary stenting in patients with severely calcified coronary lesions. Treatment with ticlopidine 200 mg daily was started immediately after the stent placement, and was continued for at least 4 weeks. All patients were maintained on aspirin 81–162 mg daily.

Lesion morphology was classified according AHA/ACC Classification Task Force. Lesion treatment was considered to be successful when there was a >20% gain in luminal diameter. Reference and minimal luminal diameter, and lesion length were determined by use of the automated edge-detection system CMS (Medis Medical Imaging System). Three experienced interventional cardiologists performed the quantitative coronary angiographic analyses independently.

Angiographic and clinical follow-up
During the study period, we routinely attempted to obtain a follow-up coronary angiogram 6–12 months after successful revascularization, regardless of symptomatic status; angiography was performed earlier if indicated. Patients who died without a repeat coronary angiogram within 12 months were censored from the angiographic follow-up data. Restenosis was defined angiographically as a luminal narrowing of >=50% at a treated site. Coronary bypass surgery was performed for new significant left main trunk disease (>=75% stenosis), when it was technically difficult to the repeat percutaneous intervention, or when it was the patient's choice. Following hospital discharge, patients were either seen at our hospital by our staff or contacted by telephone for follow-up. Follow-up was successful in all patients. All patients underwent haemodialysis treatment for 3 h immediately after the procedure or angiography. The primary end point of the study was death 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 for categorical variables and Student's t-tests for continuous variables were used to evaluate differences between measured values. P values <0.05 were considered statistically significant. The cumulative survival rates in the two groups were determined by the Kaplan–Meier method. A stepwise regression analysis model was used to evaluate the clinical factors associated with the survival duration after initial percutaneous intervention.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics
The clinical profiles of diabetic and non-diabetic haemodialysis patients who received their initial percutaneous coronary intervention were compared (Table 1Go). The two groups were similar in terms of gender, age, smoking history, hypertension, history of cardiovascular disease, left ventricular ejection fraction, and type of coronary artery disease. The duration from the initiation of haemodialysis treatment to initial percutaneous coronary intervention was significantly shorter in the diabetic group than in the non-diabetic group. The two groups were similar in terms of haematocrit, serum urea-nitrogen, creatinine, total protein, total cholesterol, high-density lipoprotein cholesterol, and calcium and phosphate concentration (Table 2Go). The calcium–phosphate product also was similar in the two groups. The haemoglobin A1c levels were higher in the diabetic than in the non-diabetic group.


View this table:
[in this window]
[in a new window]
 
Table 1. Baseline clinical characteristics

 

View this table:
[in this window]
[in a new window]
 
Table 2. Haematocrit and blood chemistry

 

Angiographic characteristics (Table 3Go)
The incidence of multivessel disease, the target vessels for the percutaneous intervention, and the incidence of moderate to severely calcified lesions did not differ between groups. The devices used in the initial percutaneous coronary intervention also were similar in the two groups. The lesion types divided by AHA/ACC classification also were similar in the two groups. In the quantitative coronary angiographic analysis, the pre-procedural reference diameter, minimal luminal diameter and lesion length, and the post-procedural minimal luminal diameter also were similar in the two groups.


View this table:
[in this window]
[in a new window]
 
Table 3. Angiographic characteristics

 

Results of percutaneous coronary intervention (Table 4Go)
The incidence of repeated follow-up angiograms and revascularization, target lesion restenosis, de novo lesions, and mortality were similar in the two groups. However, six diabetic and three non-diabetic patients did not undergo the first follow-up angiogram; five diabetic patients died, and one diabetic and three non-diabetic patients did not consent to angiography. In the diabetic group, two patients had an acute myocardial infarction, two patients suffered sudden death, one patient developed congestive heart failure without chest pain, and one patient had pneumonia. In the non-diabetic group, two patients had an acute myocardial infarction, and one patient had a cerebral bleed. Based on the result of the follow-up angiogram, 22 diabetic and 14 non-diabetic patients underwent a second successful percutaneous intervention. Subsequently, a third successful percutaneous intervention was performed in 13 diabetic and 11 non-diabetic patients, a fourth for seven diabetic and five non-diabetic patients, a fifth for two diabetic and two non-diabetic patients, and a sixth for two diabetic patients. Coronary bypass surgery was performed in two diabetic and two non-diabetic patients after the initial percutaneous intervention and in two diabetic patients and one non-diabetic patient after the second to fourth percutaneous interventions. Coronary bypass surgery was done for a de novo left main trunk lesion in five cases because of an inability to perform repeated percutaneous intervention in two cases. Four patients who underwent coronary artery bypass surgery died during this study period.


View this table:
[in this window]
[in a new window]
 
Table 4. Results of revascularization

 

Long-term survival
The cumulative survival rates 80 months after the initial percutaneous interventions were 42% in the diabetic group and 31% in the non-diabetic group. This difference is not significant (Figure 1Go).



View larger version (23K):
[in this window]
[in a new window]
 
Fig. 1. Comparison of the cumulative survival rates after initial percutaneous coronary intervention in diabetic and non-diabetic haemodialysis patients. The cumulative survival rates were similar.

 
The survival duration after initial percutaneous intervention was associated with two variables. Repeated percutaneous intervention was the variable most closely associated with prolonging survival duration, and a lower left ventricular ejection fraction was the variable most closely associated with reducing survival duration after initial percutaneous intervention based on stepwise regression analysis (Table 5Go).


View this table:
[in this window]
[in a new window]
 
Table 5. Relationships between clinical parameters of initial intervention and survival duration by regression analysis (n=32)

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study is the first to compare the long-term outcome of multiple repeated percutaneous coronary interventions in diabetic and non-diabetic haemodialysis patients. The incidences of myocardial infarction and congestive heart failure due to coronary artery disease have been reported to be higher in diabetic than non-diabetic haemodialysis patients [8]. In the past decade, percutaneous coronary intervention has become a well-established and routine procedure for coronary revascularization in haemodialysis patients. However, repeated coronary revascularization is often necessary in haemodialysis patients because the prevalence of restenosis is high [17].

Contrary to what might be expected, there was no significant difference in the incidence of follow-up angiograms, the incidence of repeated percutaneous interventions, target lesion restenosis, or de novo lesions between diabetic and non-diabetic patients. It has been reported that the restenosis rates and overall mortality rates after single balloon angioplasty and coronary stenting are higher in diabetic than non-diabetic patients without renal disease [1,2,4]. Furthermore, Abizaid et al. [9] and Schofer et al. [10] found that the restenosis rate and the incidence of cardiac event after coronary stenting are higher in insulin-treated patients with diabetes mellitus than in non-insulin-treated diabetic patients. According to current concepts, elastic recoil, vascular remodelling, and/or mural thrombus formation may lead to early restenosis after balloon angioplasty. In addition to these factors, smooth muscle cell activation and synthesis of extracellular matrix have been postulated as causative factors in late post-balloon angioplasty restenosis. In diabetic coronary vessels, the pro-thrombogenic milieu may contribute to the increased incidence of restenosis after percutaneous coronary intervention [11,12]. On the other hand, Aronson et al. [13] noted that the degree of neointimal hyperplasia appears to be greater as a consequence of stimulation by growth factors on vascular smooth muscle cells. These phenomena may contribute to a higher rate of restenosis after percutaneous intervention in diabetic patients. Abnormalities of platelet function, including hyperaggregability and decreased responsiveness to prostacyclin, have also been reported in haemodialysis patients [1416]. Furthermore, plasma coagulation systems are activated by contact with haemodialysis [17]. However, neither experimental nor clinical studies have demonstrated differences in the abnormalities of coagulation system between diabetic and non-diabetic haemodialysis patients. In fact, a few reports found that the rate of restenosis and the survival rate after single coronary revascularization depended on the procedure, rather than the presence or absence of diabetes mellitus status in haemodialysis patients [5,7].

This study also demonstrated that diabetes mellitus does not affect the restenosis rate after single intervention, or long-term outcome of multiple repeated interventions in haemodialysis patients. These results may depend on well-extended minimal luminal diameter after percutaneous intervention. We have used aggressively, coronary stenting with/without rotational atherectomy to gain a well-extended minimal luminal diameter [3,18]. However, the concentrations of haemoglobin A1c in our diabetic patients were relatively low, and insulin-treated patients were only 14%. It may be that these well-controlled metabolisms affect improving a long-term outcome in our diabetic patients.

It has been reported that the recurrence rate does not increase despite the performance of multiple repeated percutaneous interventions for restenosis [19]. That study suggests that repeated percutaneous intervention is a reasonable treatment strategy for restenosis. Repeated percutaneous intervention is generally performed in patients with signs of myocardial ischaemia due to restenosis or who develop de novo lesions. In diabetic haemodialysis patients, follow-up coronary angiogram, especially within 6–12 months after successful revascularization, is recommended regardless of symptom status. At the very best, non-invasive examinations, such as myocardial scintigraphy, echocardiography, or exercise electrocardiograhy, should been done, because diabetic patients commonly do not have typical symptoms of myocardial ischaemia [20]. Any coronary lesion should be treated as appropriate to the clinical situation.

Our study has several potential limitations. First, the costs of the multiple repeated coronary angiograms and percutaneous interventions were not calculated. Consequently, it is difficult to demonstrate a cost-effective survival advantage for performing routine angiography in diabetic haemodialysis patients. Secondly, 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.

In conclusion, multiple repeated percutaneous interventions reduce the long-term mortality of diabetic and non-diabetic haemodialysis patients with coronary artery disease similarly. Multiple repeated percutaneous coronary interventions are a viable option for controlling myocardial ischaemia and improving a long-term outcome in high-risk diabetic haemodialysis patients.



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



   Notes
 
Correspondence and offprint requests to: Hiroki Hase, Third Department of Internal Medicine, Toho University Ohashi Hospital, Ohashi 2-17-6, Meguro-Ku, Tokyo 153-8515, Japan. Email: hiroki{at}oha.toho\|[hyphen]\|u.ac.jp. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Stein B, Weintraub WS, Gebhart SP et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation1995; 91: 979–989[Abstract/Free Full Text]
  2. Asakura Y, Suzuki M, Nonogi H et al. Restenosis after percutaneous transluminal coronary angioplasty in patients with non-insulin-dependent diabetes mellitus (NIDDM). J Cardiovasc Risk1998; 5: 331–334[Medline]
  3. Van Belle E, Bauters C, Hubert E et al. Restenosis rates in diabetic patients: a comparison of coronary stenting and balloon angioplasty in native coronary vessels. Circulation1997; 96: 1454–1460[Abstract/Free Full Text]
  4. Elezi S, Kastrati A, Pache J et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol1998; 32: 1866–1873[ISI][Medline]
  5. Rinehart AL, Herzog CA, Collins AJ et al. A comparison of coronary angioplasty and coronary artery bypass grafting outcomes in chronic dialysis patients. Am J Kidney Dis1995; 25: 281–290[ISI][Medline]
  6. Schoebel FC, Gradaus F, Ivens K et al. Restenosis after elective coronary balloon angioplasty in patients with end stage renal disease: a case-control study using quantitative coronary angiography. Heart1997; 78: 337–342[Abstract/Free Full Text]
  7. Azar RR, Prpic R, Ho KK et al. Impact of end-stage renal disease on clinical and angiographic outcomes after coronary stenting. Am J Cardiol2000; 86: 485–489[ISI][Medline]
  8. Parfrey PS, Foley RN, Harnett JD et al. Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int1996; 49: 1428–1434[ISI][Medline]
  9. Abizaid A, Kornowski R, Mintz GS et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol1998; 32: 584–589[ISI][Medline]
  10. Schofer J, Schluter M, Rau T et al. Influence of treatment modality on angiographic outcome after coronary stenting in diabetic patients: a controlled study. J Am Coll Cardiol2000; 35: 1554–1559[ISI][Medline]
  11. MacRury SM, Lowe GD. Blood rheology in diabetes mellitus. Diabet Med1990; 7: 285–291[ISI][Medline]
  12. Davi G, Catalano I, Averna M et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med1990; 322: 1769–1774[Abstract]
  13. Aronson D, Bloomgarden Z, Rayfield EJ. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol1996; 27: 528–535[ISI][Medline]
  14. Kristensen SD, Knudsen F, Nielsen AH, Ring T. Decreased platelet sensitivity to prostacyclin (epoprostenol) during hemodialysis. Clin Nephrol1984; 21: 230–234[ISI][Medline]
  15. Viener A, Aviram M, Better OS, Brook JG. Enhanced in vitro platelet aggregation in hemodialysis patients. Nephron1986; 43: 139–143[ISI][Medline]
  16. Sabo RS, Bartoli F, Apitz-Castro R. In vivo platelet hyperreactivity, another risk factor for patients under continuous ambulatory peritoneal dialysis. Nephron1988; 49: 228–230[ISI][Medline]
  17. Notohamiprodjo M, Andrassy K, Bommer J, Ritz E. Dialysis membranes and coagulation system. Blood Purif1986; 4: 130–141[Medline]
  18. Hase H, Nakamura M, Joki N et al. Independent predictors of restenosis after percutaneous coronary revascularization in hemodialysis patients. Nephrol Dial Transplant2001; 16: 2372–2377 (Dec)[Abstract/Free Full Text]
  19. Dimas AP, Grigera F, Arora RR et al. Repeat coronary angioplasty as treatment for restenosis. J Am Coll Cardiol1992; 19: 1310–1314[ISI][Medline]
  20. Joki N, Hase H, Nakamura R, Yamaguchi T. Onset of coronary artery disease prior to initiation of haemodialysis in patients with end-stage renal disease. Nephrol Dial Transplant1997; 12: 718–723[Abstract]
Received for publication: 4. 4.01
Revision received 5. 9.01.