Abstract
Background and objectives: Peripheral artery disease (PAD) is common in patients on hemodialysis (HD). Recently, cilostazol has been reported to reduce target lesion revascularization (TLR) after percutaneous transluminal angioplasty (PTA) for PAD in the general population. This study aimed to clarify the effects of cilostazol administration on long-term patency after PTA in HD patients.
Design, setting, participants, & measurements: Three-hundred seventy-two consecutive lesions in 193 HD patients successfully undergoing PTA were enrolled in the study and divided into two groups: patients receiving 100 mg cilostazol twice daily in conjunction with standard therapy (130 lesions in 71 patients) and those not administered cilostazol (242 lesions in 122 patients). Effects of cilostazol on preventing restenosis after PTA in these patients were investigated.
Results: Kaplan-Meier analysis demonstrated the 5-yr patency rate was significantly higher in the cilostazol group than in the control group [52.4 versus 32.9%, hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.39 to 0.77, P = 0.0005]. Cox multivariate analysis revealed that administration of cilostazol was an independent predictor of preventing restenosis (HR 0.56, 95% CI 0.36 to 0.87, P = 0.010). In 102 lesions matched after propensity score analysis, cilostazol had a beneficial effect on preventing restenosis (58.4 versus 34.7%, HR 0.47, 95% CI 0.30 to 0.75, P = 0.0017) and was an independent predictor of preventing restenosis (HR 0.50; 95% CI 0.26 to 0.87, P = 0.014) after multivariate Cox analysis.
Conclusions: Cilostazol administration improves long-term patency after PTA in HD patients with PAD.
Accelerated atherosclerosis is a major risk for long-term survivors receiving maintenance HD (1,2). Furthermore, cardiovascular disease is a leading cause of morbidity and mortality in patients with renal disease receiving HD (1–5). It has been reported that PAD is commonly seen in patients on HD (6). In this day and age, PTA has become a common therapeutic standard for PAD in non-HD patients (7,8), and PTA is reported to be effective in patients on HD (9). However, vascular calcification and diffuse lesions may make the PTA procedure difficult to perform (10).
On the other hand, it has been reported that cilostazol, which has antiplatelet action and vasodilatory effects, significantly reduces the risk of restenosis after percutaneous coronary intervention (PCI) in many patients (11–15). Furthermore, chronic cilostazol treatment prevents TLR after PTA of the femoropopliteal artery in the general population (16). However, it is unclear whether this extends to high-risk individuals, such as those receiving HD. In the study presented here, we compared clinical events after PTA in a series of patients on chronic maintenance HD with and without an additional treatment of cilostazol.
Materials and Methods
Subjects and Methods
Study Population.
Between January 1999 and December 2004, 372 consecutive lesions of 193 HD patients with end-stage renal failure underwent their successful PTA for PAD at Nagoya Kyoritsu Hospital. In advance, we excluded patients with age >80 yr and unsuccessful PTA. The study population was stratified by status of treatment with cilostazol: 130 lesions of 71 patients who received oral 100-mg doses of cilostazol twice daily and 242 lesions of 122 patients who were not administered cilostazol.
Protocol.
All patients had significant PAD and underwent elective PTA for peripheral artery stenosis at iliac and/or femoropopliteal significant obstructions. The procedures were performed through the ipsilateral femoral artery with an antegrade approach, and in case of obstructions close to the ipsilateral access site, approach was made from the ipsilateral access site. PTA was performed after intra-arterial injection of 5000 IU of heparin. Lesions were treated with the use of standard PTA techniques. If necessary, treatment with stenting was used. A successful procedure was defined as a final stenosis luminal diameter <30% without angiographical visual arterial dissection and no in-hospital complications, including death or necessity for additional surgical procedure. Other protocols were similar for the two groups. For all patients, aspirin (100–162 mg/d) was administered orally. Follow-up examinations using Doppler ultrasound scanning and clinical observations were conducted 3 mo post-PTA and every 6 mo thereafter. If patients had abnormal Doppler waveform or worsened clinical symptoms according to Fontaine classification criteria, lowered ankle brachial pressure index (ABPI), or worsened ulcer and/or gangrene, arteriography was performed.
Restenosis, defined as angiographic luminal diameter >50%, was the primary endpoint. The secondary endpoints were amputation due to lower extremity ischemia and all-cause mortality. These data were obtained from hospital charts and telephone interviews with patients by trained reviewers who were blinded to the drug assignment.
In the study presented here, no patients were lost to follow-up. The hospital's ethics committee approved the study protocol.
Definitions
We used the TransAtlantic Inter-Society Consensus (TASC) classification as published (17). Critical limb ischemia was also defined according to the TASC criteria (17). Diabetes was diagnosed if patients had a previous or current diagnosis of diabetes, if abnormal results from the oral glucose tolerance test were found, or if hemoglobin A1c (HbA1c) levels of ≥6.5% were found after admission.
Statistical Analyses
Statistical analyses were performed using SAS 6.10 (SAS Institute) software. Continuous variables were assessed as mean ± SD values and were compared using the t test. Differences in the endpoint between the groups were examined with the Kaplan-Meier method and compared using the log-rank test. HR and CI were calculated for each factor by a Cox univariate analysis. Furthermore, Cox multivariable regression analysis was used to determine predictors for the endpoint. Factors with P < 0.05 on the univariate analysis were entered into the multivariable Cox regression model. To minimize the selection bias for cilostazol administration, a propensity-matched analysis was performed. First, to obtain the propensity score, the multivariate logistic regression analysis using the model including cilostazol administration as a dependent variable, and gender, age, and presence of diabetes, critical limb ischemia, TASC type C or D, femoropopliteal lesion and stenting as independent variables was performed. Second, the propensity score in individual cases were calculated using the obtained logistic model. The area under the receiving operating characteristics curve was 0.69. Thereafter, the propensity score was matched 1:1 with two-digits. Differences were considered significant at the 5% level (P < 0.05).
Results
The mean duration of follow-up was 28 ± 24 mo. In the cilostazol group, the drug was well tolerated. Although some patients experienced adverse events such as headache, no patient withdrew from treatment with cilostazol.
The baseline characteristics of the patients are listed in Table 1. Significant differences were seen in incidence of diabetes, stent use, and treatment with sarpogrelate. However, there were no significant differences between the two groups in terms of age, sex, or other risk factors.
Table 1.
Characteristics of patients and lesions
| Variable | Cilostazol (n = 130) | Control (n = 242) | P value |
|---|---|---|---|
| Number of patients | 71 | 122 | |
| Men (%) | 64.8 | 59.0 | 0.42 |
| Age (yr) | 65 ± 10 | 65 ± 10 | 0.74 |
| Duration of HD (years) | 5.5 ± 6.6 | 4.9 ± 5.2 | 0.49 |
| Diabetes (%) | 49.3 | 66.4 | 0.019 |
| Hypertension (%) | 56.3 | 67.2 | 0.13 |
| Hyperlipidemia (%) | 21.2 | 29.5 | 0.20 |
| Smoking (%) | 21.2 | 25.4 | 0.50 |
| Coronary artery disease (%) | 45.1 | 47.5 | 0.77 |
| Past history of stroke (%) | 7.0 | 9.0 | 0.63 |
| Indication for PTA (%) | 0.96 | ||
| Intermittent claudication | 52.4 | 50.7 | |
| Rest pain | 23.8 | 25.4 | |
| Ulcer/gangrene | 23.8 | 23.9 | |
| Preoperative ABPI | 0.64 ± 0.25 | 0.66 ± 0.38 | 0.80 |
| Lesion location (%) | |||
| Iliac | 28.5 | 25.2 | 0.50 |
| Femoropopliteal | 71.5 | 74.8 | |
| TASC classification (%) | 0.62 | ||
| Type A + B | 57.7 | 60.3 | |
| Type C + D | 42.3 | 39.7 | |
| Stent use (%) | 59.2 | 43.8 | 0.0045 |
| Medication (%) | |||
| ACE inhibitors | 18.3 | 27.9 | 0.14 |
| A-II receptor blockers | 29.6 | 29.5 | 0.99 |
| β-blockers | 16.9 | 14.8 | 0.69 |
| Calcium antagonists | 67.6 | 64.7 | 0.68 |
| Statins | 12.7 | 16.4 | 0.48 |
| Warfarin | 8.5 | 9.0 | 0.89 |
| Ticlopidine | 40.8 | 45.9 | 0.49 |
| Sarpogrelate | 4.2 | 35.8 | <0.0001 |
HD, hemodialysis; ABPI, ankle brachial pressure index; TASC, TransAtlantic Inter-Society Consensus; ACE, angiotensin-converting enzyme; A-II, angiotensin II.
Figure 1 shows Kaplan-Meier curves for the primary endpoint: restenosis >50% by angiography. The event-free rate from restenosis for 5 yr was significantly higher in the cilostazol group than in the control group (52.4 versus 32.9%, HR 0.55, 95% CI 0.39 to 0.77, P = 0.0005). Multivariable analysis was performed to determine the effects of cilostazol. Even after adjusting for other risk factors at baseline, the beneficial effect of cilostazol treatment remained significant and independent (HR 0.56, 95% CI 0.36 to 0.87, P = 0.010, Table 2).
Figure 1.
Kaplan-Meier curves for the primary endpoint: The 5-yr event-free rate from restenosis for 5 yr was 52.4% in the cilostazol group and 32.9% in the control group [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.39 to 0.77, P = 0.0005].
Table 2.
Predictive risk for restenosis after PTA by Cox multivariate analysis
| Variable | Univariate
|
Multivariate
|
||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Men | 1.34 (0.98 to 1.84) | 0.065 | ||
| Age | 1.02 (1.01 to 1.05) | 0.0020 | 1.03 (1.01 to 1.05) | 0.0060 |
| Duration of HD | 1.01 (0.95 to 1.03) | 0.51 | ||
| Diabetes | 1.23 (0.87 to 1.73) | 0.23 | ||
| Hypertension | 1.48 (0.98 to 2.21) | 0.056 | ||
| Hyperlipidemia | 1.16 (0.84 to 1.60) | 0.36 | ||
| Smoking | 1.19 (0.86 to 1.65) | 0.28 | ||
| TASC C + D versus A + B | 2.09 (1.54 to 2.85) | 0.0024 | 1.43 (0.93 to 2.21) | 0.10 |
| Femoropopliteal versus iliac | 2.44 (1.60 to 3.72) | <0.0001 | 3.20 (1.67 to 5.13) | 0.0004 |
| Critical limb ischemia | 1.89 (1.25 to 2.86) | <0.0001 | 2.41 (1.53 to 3.82) | 0.0001 |
| Stenting | 0.92 (0.68 to 1.26) | 0.63 | ||
| Cilostazol | 0.55 (0.39 to 0.77) | 0.0005 | 0.56 (0.36 to 0.87) | 0.010 |
| ACE inhibitors | 0.67 (0.46 to 0.99) | 0.046 | 0.62 (0.36 to 1.07) | 0.085 |
| A-II receptor blockers | 0.60 (0.41 to 0.88) | 0.0089 | 0.98 (0.57 to 1.67) | 0.94 |
| β -blockers | 0.77 (0.52 to 1.14) | 0.19 | ||
| Calcium antagonists | 0.71 (0.52 to 0.98) | 0.039 | 0.98 (0.60 to 1.60) | 0.94 |
| Statins | 0.73 (0.51 to 1.05) | 0.090 | ||
| Warfarin | 0.53 (0.19 to 1.43) | 0.21 | ||
| Ticlopidine | 0.66 (0.48 to 0.91) | 0.010 | 0.81 (0.54 to 1.21) | 0.30 |
| Sarpogrelate | 0.70 (0.42 to 1.15) | 0.16 | ||
CI, confidence interval.
The secondary endpoints significantly differed between the two groups. The limb salvage rate for the 5-yr period with Kaplan-Meier analysis was 95.4% in the cilostazol group and 79.9% in the control group (HR 0.20, 95% CI 0.04 to 0.87, P = 0.032). The survival from all-cause mortality was significantly higher in the cilostazol group (79.0 versus 50.9%, HR 0.35, 95% CI 0.19 to 0.64, P = 0.0007). Particularly, cardiovascular deaths including congestive heart failure and myocardial infarction were prevented in the cilostazol group (93.0 versus 65.1%, HR 0.19, 95% CI 0.063 to 0.54, P = 0.0021). Freedom from TLR was significantly higher in the cilostazol group than in the control group (66.9 versus 50.1%, HR 0.51, 95% CI 0.30 to 0.87, P = 0.014). Death due to stroke occurred in two patients in each group.
Propensity-Matched Patients Analysis
One-hundred two lesions from each group were matched according to the estimated propensity scores. The baseline clinical and angiographic characteristics are listed in Table 3.
Table 3.
Characteristics of patients and lesions after propensity score matching
| Variable | Cilostazol (n = 102) | Control (n = 102) | P value |
|---|---|---|---|
| Number of patients | 54 | 52 | |
| Men (%) | 66.7 | 71.2 | 0.61 |
| Age (years) | 66 ± 10 | 65 ± 8 | 0.56 |
| Duration of HD (years) | 5.6 ± 6.8 | 4.9 ± 5.1 | 0.48 |
| Diabetes (%) | 59.3 | 55.8 | 0.71 |
| Hypertension (%) | 62.9 | 63.5 | 0.89 |
| Hyperlipidemia (%) | 22.2 | 26.9 | 0.61 |
| Smoking (%) | 22.2 | 25.0 | 0.65 |
| Coronary artery disease (%) | 50.0 | 36.5 | 0.14 |
| Past history of stroke (%) | 5.6 | 13.5 | 0.16 |
| Indication for PTA (%) | 0.67 | ||
| Intermittent claudication | 51.8 | 46.2 | |
| Rest pain | 27.8 | 26.9 | |
| Ulcer/gangrene | 20.4 | 26.9 | |
| Preoperative ABPI | 0.67 ± 0.26 | 0.62 ± 0.35 | 0.31 |
| Lesion location (%) | |||
| Iliac | 32.4 | 26.5 | 0.36 |
| Femoropopliteal | 67.6 | 73.5 | |
| TASC classification (%) | 0.92 | ||
| Type A + B | 64.4 | 63.7 | |
| Type C + D | 35.6 | 36.3 | |
| Stent use (%) | 55.9 | 52.9 | 0.67 |
| Medication (%) | |||
| ACE inhibitors | 18.5 | 26.9 | 0.30 |
| A-II receptor blockers | 25.9 | 32.7 | 0.44 |
| β-blockers | 20.4 | 15.4 | 0.50 |
| Calcium antagonists | 68.5 | 63.5 | 0.58 |
| Statins | 16.7 | 9.6 | 0.28 |
| Warfarin | 7.4 | 11.5 | 0.46 |
| Ticlopidine | 38.9 | 44.2 | 0.57 |
| Sarpogrelate | 5.6 | 36.5 | <0.0001 |
PTA, percutaneous transluminal angioplasty.
Figure 2 shows Kaplan-Meier curves for the primary endpoint in propensity-matched patients. The 5-yr event-free rate from the primary endpoint by Kaplan-Meier analysis was 58.4% in the cilostazol group and 34.7% in the control group (HR 0.47, 95% CI 0.30 to 0.75, P = 0.0017). By Cox multivariable analysis, cilostazol treatment (HR 0.50, 95% CI 0.26 to 0.87, P = 0.014), age (HR 1.03, 95% CI 1.01 to 1.07, P = 0.041), TASC type C or D (HR 2.85, 95% CI 1.56 to 5.20, P = 0.0006), femoropopliteal lesion (HR 2.62, 95% CI 1.22 to 5.62, P < 0.0001), and incidence of critical limb ischemia before PTA (HR 4.09, 95% CI 2.10 to 7.94, P < 0.0001) were independent predictors for the primary endpoint (Table 4). Ticlopidine treatment was of borderline significance (HR 0.54, 95% CI 0.30 to 1.01, P = 0.051).
Figure 2.
Kaplan-Meier curves for the primary endpoint in propensity-matched patient: The event-free rate from the primary endpoint for 5 yr was 58.4% in the cilostazol group and 34.7% in the control group (HR 0.47, 95% CI 0.30 to 0.75, P = 0.0017).
Table 4.
Predictive risk for restenosis after PTA by Cox multivariate analysis after propensity score matching
| Variable | Univariate
|
Multivariate
|
||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Male | 0.52 (0.33 to 0.82) | 0.0048 | 0.55 (0.30 to 1.02) | 0.058 |
| Age | 1.02 (1.01 to 1.05) | 0.036 | 1.03 (1.01 to 1.07) | 0.041 |
| Duration of HD | 1.03 (0.95 to 1.12) | 0.42 | ||
| Diabetes | 1.42 (0.89 to 2.26) | 0.14 | ||
| Hypertension | 1.57 (0.84 to 2.91) | 0.15 | ||
| Hyperlipidemia | 1.27 (0.82 to 1.99) | 0.28 | ||
| Smoking | 1.12 (0.69 to 1.82) | 0.61 | ||
| TASC C + D versus A + B | 1.89 (1.21 to 2.94) | 0.0051 | 2.85 (1.56 to 5.20) | 0.0006 |
| Femoropopliteal versus iliac | 3.57 (1.88 to 6.77) | <0.0001 | 2.62 (1.22 to 5.62) | 0.013 |
| Critical limb ischemia | 3.10 (1.72 to 5.63) | 0.0002 | 4.09 (2.10 to 7.94) | <0.0001 |
| Stenting | 0.98 (0.63 to 1.53) | 0.95 | ||
| Cilostazol | 0.47 (0.30 to 0.75) | 0.0017 | 0.50 (0.26 to 0.87) | 0.014 |
| ACE inhibitors | 0.60 (0.34 to 1.08) | 0.086 | ||
| A-II receptor blockers | 0.52 (0.31 to 0.89) | 0.015 | 0.88 (0.43 to 1.79) | 0.73 |
| β-blockers | 0.59 (0.37 to 0.96) | 0.033 | 0.78 (0.44 to 1.38) | 0.40 |
| Calcium antagonists | 0.57 (0.30 to 1.07) | 0.081 | ||
| Statins | 0.73 (0.43 to 1.22) | 0.23 | ||
| Warfarin | 0.37 (0.19 to 1.51) | 0.16 | ||
| Ticlopidine | 0.59 (0.37 to 0.92) | 0.021 | 0.54 (0.30 to 1.01) | 0.051 |
| Sarpogrelate | 0.78 (0.40 to 1.51) | 0.45 | ||
Limb amputation was needed in 3.7% of the cilostazol group and 20.7% in the control group. Cilostazol treatment significantly avoided limb amputation (HR 0.10, 95% CI 0.01 to 0.91, P = 0.014). The rates for survival from all-cause death for the 5-yr period with Kaplan-Meier analysis were 76.3% in the cilostazol group and 62.5% in the control group (HR 0.39, 95% CI 0.17 to 0.85, P = 0.014). The survival rates from cardiovascular death were significantly higher in the cilostazol group (91.7 versus 63.1%, HR 0.26, 95% CI 0.072 to 0.94, P = 0.039). Also the rate of freedom from TLR was significantly higher in the cilostazol group (65.7 versus 44.7%, HR 0.45, 95% CI 0.23 to 0.87, P = 0.013).
Discussion
We performed this study to evaluate the efficacy of cilostazol in patients on HD after successful PTA. Although interventional strategies have been tried to overcome atherosclerosis in patients on HD, beneficial effects are limited. For example, patients with end-stage renal failure on hemodialysis and treated with drug-eluting stents for coronary artery disease are at high risk of restenosis after PCI (18,19), although drug-eluting stents significantly reduce the risk of restenosis after PCI in many patients (20–24). Under such conditions, significant improvement in long-term clinical outcome was observed with cilostazol in the study presented here. The addition of cilostazol to standard therapy may be a useful strategy for patients with renal failure receiving HD, i.e., with a high risk of accelerated atherosclerosis. Some possible mechanisms to explain these results were considered, although this study was not designed to elucidate the precise mechanisms.
Cilostazol, a phosphodiesterase 3 inhibitor has antiplatelet action and vasodilatory effects and inhibits smooth muscle cell proliferation (11,25 to 27). It has been reported that HD patients have abnormalities in platelet function (28). Furthermore, HD itself may activate plasma coagulation factors (29). These phenomena may lead to mural thrombus formation and may induce restenosis after PTA. It has been reported that cilostazol increases the cyclic AMP level in vascular smooth muscle cells, resulting in upregulating antioncogenes p53 and p21 and hepatocyte growth factor (30). Because the increase in P53 protein blocks cell cycle progression and induces apoptosis in vascular smooth muscle cells, these mechanisms have an antiproliferative effect (31). Furthermore, hepatocyte growth factor stimulates the re-endothelization after vascular injury, inhibits abnormal vascular smooth muscle cell growth, and improves endothelial function (32). Because the major cause of recurrent stenosis after PTA is neointimal hyperplasia (33), these actions may possibly explain the beneficial effect of cilostazol on reducing TLR rate. Cilostazol also inhibits P-selectin-mediated leukocyte activation, platelet-leukocyte interaction, and subsequent Mac-I-mediated leukocyte activation (34). Because inhibition of these actions is thought to reduce neointimal thickening after balloon injury, this mechanism may be also be important to the reduction of restenosis after PTA.
In the study presented here, lower extremity amputation was significantly prevented in the cilostazol group. Because amputation remains a threat and worsens patients' quality of life, this point is very important. Furthermore, the rate of all-cause mortality, particularly cardiovascular mortality, was also lower in the cilostazol group. Although incidence of stroke was similar between the two groups, thrombogenic events such as myocardial infarction might be prevented. On the other hand, cilostazol did not affect major bleeding complication such as intracranial hemorrhage, in concurrence with the previous studies (14,35).
Potential Limitations
The first limitation of this study is that it was retrospective. There was much chance for bias in many of the data assignments, although we also used propensity-matched scores. Second, this was a single-center study. Third, although Doppler ultrasound scanning and clinical observations were obtained from all patients, we did not perform follow-up angiography in all patients. It is possible that patients might have no ischemic symptoms because of adequate collateral flow even if angiographical restenosis existed. A large, prospective, randomized multicenter study is needed.
Conclusions and Clinical Implications
Results obtained in this study indicate that cilostazol treatment not only prevented restenosis but also improved clinical prognosis after PTA in HD patients with PAD. PAD itself has greatly affected clinical prognosis (36). Furthermore, patients on HD with PAD have much higher risk for their prognosis. Therefore, the results of our study are clinically of great importance, making a valuable contribution to this field.
Disclosures
None.
Acknowledgments
This study was presented at the American Heart Association Scientific Sessions, Orlando, Florida, November 7, 2007.
Published online ahead of print. Publication date available at www.cjasn.org.
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