Takanobu Toriyama

Long-term outcome of percutaneous transluminal angioplasty in chronic haemodialysis patients with peripheral arterial disease

BACKGROUND Chronic haemodialysis patients are at an increased risk of peripheral artery disease (PAD). Although percutaneous transluminal angioplasty (PTA) has become a widely used therapeutic intervention for PAD, its outcome in haemodialysis patients remains poorly understood. The aim of this study was to clarify the long-term outcome of PTA as a primary treatment for PAD in haemodialysis patients. METHODS Consecutive 118 haemodialysis patients with 205 lesions and 108 non-haemodialysis patients with 143 lesions who underwent successful PTA as a first-choice therapeutic option for PAD were enrolled. Outcome measures included primary patency, limb salvage and survival. RESULTS Incidence of diabetes, history of coronary artery disease and femoropopliteal lesion were significantly more frequent in haemodialysis patients (P = 0.008, 0.005 and 0.0001, respectively), but critical limb ischaemia and TransAtlantic Inter-Society Consensus (TASC) lesion types occurred with comparable frequency in both groups. No patients had in-hospital complications. The 5-year primary patency, limb salvage and survival rates were significantly lower in haemodialysis patients (P = 0.01, 0.029 and 0.0024, respectively). On Cox multivariate analysis, haemodialysis was strongly predictive of amputation and all-cause death, but not of restenosis. In haemodialysis patients, TASC C+D lesion and ulceration/gangrene were independent predictors for restenosis and amputation. CONCLUSIONS The long-term outcome after PTA may be fully acceptable in haemodialysis patients who are at the highest risk of cardiovascular disease. PTA is a useful therapeutic strategy in haemodialysis patients with PAD, but PTA for TASC C+D lesions remains controversial.

Prognostic Value of Reduced Left Ventricular Ejection Fraction at Start of Hemodialysis Therapy on Cardiovascular and All-Cause Mortality in End-Stage Renal Disease Patients

BACKGROUND AND OBJECTIVES Cardiac failure is directly affected by left ventricular (LV) dysfunction, and particularly LV systolic dysfunction is strongly associated with survival in ESRD patients. The aim of this study was to determine the prognostic value of reduced LV ejection fraction (LVEF) measured at the time of initiation of hemodialysis (HD) in incident HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 1254 consecutive ESRD patients who electively started HD therapy were screened by echocardiography within 1 month after its inception. They were divided into five groups according to LVEF levels with a decrease of 0.1 each and were followed up for up to 7 years. Survival was examined with the Kaplan-Meier method and compared using the log-rank test. RESULTS Among the 1254 patients, LVEF levels ≥0.6, 0.5 to 0.6, 0.4 to 0.5, 0.3 to 0.4, and <0.3 were seen in 842 (67.1%), 247 (19.7%), 107 (8.5%), 41 (3.3%), and 17 (1.4%) patients, respectively. On Kaplan-Meier analysis, 7-year event-free rates from cardiovascular death were 84.2, 83.7, 73.6, 59.4, and 30.9% in order of groups with decreasing LVEF of 0.1 each, respectively. Seven-year event-free rates from all-cause death were 69.2, 61.7, 57.1, 45.9, and 23.1% in the respective groups. Even after adjustment for other risk factors, decreasing LVEF was a strong independent predictor for cardiovascular death. CONCLUSIONS Reduced LVEF on starting HD therapy could stratify risk of cardiovascular and all-cause mortality in ESRD patients. Screening by echocardiography at start of HD therapy might be recommended to predict prognosis in patients with ESRD.

Comparison of Atorvastatin 5 and 20 mg/d for Reducing F-18 Fluorodeoxyglucose Uptake in Atherosclerotic Plaques on Positron Emission Tomography/Computed Tomography: A Randomized, Investigator-Blinded, Open-Label, 6-Month Study in Japanese Adults Scheduled for Percutaneous Coronary Intervention

BACKGROUND F-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is a useful tool for the detection of local inflamed atherosclerotic lesions. OBJECTIVE This study used hybrid PET/computed tomography (CT) to examine the effects of 2 doses of atorvastatin on (18)F-FDG uptake in atherosclerotic plaques in Japanese adults with stable angina pectoris who were scheduled to undergo percutaneous coronary intervention (PCI). METHODS This was a prospective, randomized, investigator-blinded, open-label study in patients with dyslipidemia (total cholesterol ≥ 220 mg/dL and/or LDL-C ≥ 140 mg/dL) who were scheduled to undergo PCI for stable angina pectoris and had not received any lipid-lowering drugs within 1 year before enrollment. Patients were randomly allocated to receive atorvastatin 5 or 20 mg/d for 6 months. At baseline (the day after PCI), (18)F-FDG uptake in the ascending aorta and femoral artery was determined using PET/CT imaging, and the mean target-to-background ratio (TBR) was calculated in individual plaques. The same regions were assessed by PET/CT after 6 months of treatment. Changes from baseline to follow-up in the lipid profile, serum malondialdehyde-modified LDL-C (MDA-LDL-C), and serum high-sensitivity C-reactive protein (hs-CRP) were also examined. Drug adherence, adverse events, and changes in medications were monitored at monthly outpatient visits. RESULTS Of 32 patients initially screened, 2 were excluded due to newly diagnosed cancer; thus, 30 patients were randomly assigned to treatment, 15 in each group. Patients were predominantly male (18 [60%]), with a mean (SD) age of 54 (11) years, mean body weight of 65 (12) kg, and mean total cholesterol, HDL-C, and triglyceride concentrations of 240 (29), 48 (14), and 180 (102) mg/dL, respectively. After 6 months, the 20-mg group had significant reductions from baseline in mean (SD) TBR in the ascending aorta (from 1.15 [0.14] to 1.05 [0.12]; percent change, -7.9% [9.4%]; P = 0.007) and the femoral artery (from 1.12 [0.11] to 1.02 [0.11]; percent change, -9.9% [13.8%]; P = 0.012). The corresponding changes from baseline were not statistically significant in the 5-mg group. The differences in percent change in TBR in the 2 locations were not significant between groups. When data from the 2 groups were combined, the overall reduction in TBR from baseline to 6 months was significant in both the ascending aorta (P = 0.003) and the femoral artery (P = 0.021). The decreases in TBR in both arteries were significantly correlated with reductions in LDL-C (ascending aorta: r(2) = 0.230 [P = 0.012]; femoral artery: r(2) = 0.338 [P = 0.003]), MDA-LDL-C (ascending aorta: r(2) = 0.183 [P = 0.028]; femoral artery: r(2) = 0.247 [P = 0.010]), and hs-CRP (ascending aorta: r(2) = 0.132 [P = 0.048]; femoral artery: r(2) = 0.271 [P = 0.007]). One patient in the 5-mg group and 2 patients in the 20-mg group had ∼2-fold increases in serum aminotransferases on a single occasion; however, no specific musculoskeletal or hepatic adverse events were observed, and aminotransferase values decreased to within normal ranges without changes in the atorvastatin dose. CONCLUSION Six months of treatment with atorvastatin 20 mg, but not 5 mg, was associated with a significant reduction in TBR in the ascending aorta and femoral artery in these Japanese adults with dyslipidemia undergoing PCI for stable angina pectoris. University Hospital Medical Information Network Clinical Trials Registry identifier: C000000371.

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

It has been reported that percutaneous coronary intervention (PCI) is beneficial for coronary artery disease (CAD) among the general population. However, its effects in patients who are on hemodialysis (HD) remain unclear. A prospective cohort study was performed to clarify whether PCI has a therapeutic advantage over medical therapy among HD patients with CAD. A follow-up study to 5 yr was conducted among 259 HD patients with ischemic heart disease. Mean follow-up was 39 mo. Patients were divided into three groups: 122 patients without significant stenosis, 88 patients who had significant stenosis and were treated with PCI, and 49 patients who had significant stenosis and were treated with medication only. The primary end point was cardiac death, and the secondary end point was all-cause death. The results showed that the 5-yr cardiac survival rate was 41.6% in the medication group, 77.1% in the PCI group (P = 0.0006), and 84.5% in the nonstenosis group (P < 0.0001). The 5-yr all-cause survival rate was 19.3% in the medication group, 48.4% in the PCI group (P = 0.004), and 64.3% in the nonstenosis group (P < 0.0001). Even after adjustment for other risk factors, effects of PCI on the risk for cardiac and all-cause death remained significant and independent (odds ratio 0.14; 95% confidence interval 0.08 to 0.25, P = 0.0006; and odds ratio 0.37; 95% confidence interval 0.26 to 0.54, P = 0.0062, respectively). Results were consistent when the therapeutic effect of PCI or medication was analyzed using propensity-matched patients. These data suggested that PCI could improve the prognosis of HD patients with CAD. PCI would be recommended for HD patients with CAD.

Effects of Combination Treatment with Losartan and Trandolapril on Office and Ambulatory Blood Pressures in Non-Diabetic Renal Disease: A COOPERATE-ABP Substudy

Background: In the COOPERATE trial, the combination treatment of the angiotensin-II receptor blocker losartan and the angiotensin-converting-enzyme inhibitor trandolapril significantly retarded progression of non-diabetic kidney disease compared with each monotherapy. The benefit could be greatly attributable to the potent reduction of proteinuria, because the three treatment groups showed the same reductions of office blood pressure (OBP). Ambulatory blood pressure (ABP) is reported to be better than OBP in predicting progression of kidney disease. Methods: Ninety-two patients enrolled in the COOPERATE trial underwent 24-hour ABP monitoring at randomization and at month 6, year 1, year 2 and year 3 on randomized treatment. Results: Both OBP and ABP were similarly reduced among the three groups at all measurement points (p = NS) and throughout the whole study period (p = NS). No significant correlation between the change in 24-hour ABP and the change in proteinuria was seen (p = NS). A Cox-multivariable analysis showed that covariates affecting the renal outcomes (a doubling serum-Cr level and/or end-stage renal failure) were the change in proteinuria (hazard ratio 0.49, 95% CI 0.34–0.78, p = 0.01) and treatments (0.58, 0.45–0.99, 0.03), but not 24-hour ABP (0.98, 0.89–2.01, 0.17). Conclusion: The better renoprotective effect of the combination treatment is attributed to BP-independent mechanisms by more complete renin-angiotensin system blockade.

Cilostazol Improves Long-Term Patency after Percutaneous Transluminal Angioplasty in Hemodialysis Patients with Peripheral Artery Disease

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.

Low circulating CD34+ cell count is associated with poor prognosis in chronic hemodialysis patients

Circulating CD34-positive (CD34(+)) cells, a population that includes endothelial progenitor cells, are believed to contribute to vascular homeostasis. Here we determine the prognostic value of CD34(+) cell measurements in 216 chronic hemodialysis patients. A total of 43 cardiovascular events and 13 deaths occurred over an average 23 months follow-up in this cohort. A cutoff number for circulating CD34(+) cells was determined by receiver operating characteristic curve analysis to maximize the power of the CD34(+) cell count in predicting future cardiovascular events. Based on this, 93 patients were categorized as having low and 123 patients as having high numbers of CD34(+) cells, determined by flow cytometry at the time of enrollment. Both cumulative cardiovascular event-free survival and all-cause survival were significantly less in the group of patients with low numbers of CD34(+) cells. By multivariate analyses, a low level of circulating CD34(+) cells was an independent and significant predictor for both cardiovascular events and all-cause mortality. Our study shows that a reduced number of circulating CD34(+) cells is significantly associated with vascular risks and all-cause mortality in patients on chronic hemodialysis. These cells may be a useful biomarker.

Ankle brachial pressure index but not brachial-ankle pulse wave velocity is a strong predictor of systemic atherosclerotic morbidity and mortality in patients on maintenance hemodialysis

BACKGROUND Ankle brachial pressure index (ABPI) and pulse wave velocity (PWV) have been widely recognized as a marker of systemic atherosclerosis. We examined whether ABPI and brachial-ankle PWV (baPWV) predict individual cardiovascular events in patients on maintenance hemodialysis (HD). METHODS We prospectively followed-up 445 HD patients undergoing both ABPI and baPWV measurements for up to 5 years. They were divided into 2 groups [group with ABPI > 0.9 to ≤ 1.3 (n = 328) and group with ABPI ≤ 0.9 or >1.3 (n = 117)] and were also divided into tertiles according to the baPWV level (T1: <1850 cm/s; T2: 1850-2310 cm/s and T3: ≥ 2310 cm/s). RESULTS During the follow-up period (mean 43 ± 17 months), 206 cardiovascular events [cardiac event: 125 (28.1%), cerebrovascular events: 39 (8.8%), and peripheral arterial events: 42 (9.4%)] occurred, and 36 (8.1%) and 42 (9.4%) patients experienced cardiovascular and non-cardiovascular deaths, respectively. Cox multivariable analysis showed that presence of ABPI ≤ 0.9 or >1.3 was a significant predictor of cardiac events [hazard ratio (HR) 1.78, 95% confidential interval (CI) 1.27-2.49, p = 0.0008], cerebrovascular event (HR 1.95, 95%CI 1.13-3.36, p = 0.017), peripheral arterial event (HR 3.64, 95%CI 2.10-6.29, p < 0.0001), composite endpoint of cardiovascular events (HR 2.22, 95%CI 1.64-2.99, p < 0.0001), cardiovascular mortality (HR 2.42, 95%CI 1.44-4.06, p = 0.0008) and all-cause mortality (HR 1.52, 95%CI 1.03-2.25, p = 0.037). However, baPWV did not predict cardiovascular events on multivariate analysis. CONCLUSION ABPI but not baPWV is useful for risk stratification of systemic atherosclerotic morbidity and mortality in HD patients. Furthermore, ABPI could predict not only individual peripheral arterial events but also cardiac and cerebrovascular events.

Prognostic Values of C-Reactive Protein Levels on Clinical Outcome After Implantation of Sirolimus-Eluting Stents in Patients on Hemodialysis

Background—Percutaneous coronary intervention (PCI) using drug-eluting stents significantly reduces the risk of restenosis in the general population. However, in patients on hemodialysis, adverse cardiac events are frequently seen even if treated with drug-eluting stents. Recent studies suggest that C-reactive protein (CRP) reflects vascular wall inflammation and can predict adverse cardiac events. We evaluated possible prognostic values of CRP on outcomes in patients on hemodialysis undergoing PCI with drug-eluting stents. Methods and Results—A total of 167 patients undergoing PCI with sirolimus-eluting stents for stable angina (322 lesions) were enrolled. They were divided into tertiles according to serum CRP levels. We analyzed the incidence of major adverse cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and target lesion revascularization after PCI as well as quantitative coronary angiographic data. The mean follow-up was 31 months (SD, 14). Major adverse cardiac events occurred in 11 patients (19.6%) of the lowest tertile, in 22 patients (39.3%) of the middle tertile, and in 28 patients (50.9%) of the highest tertile during follow-up period (P=0.0009). There was a progressive increase in neointimal growth after sirolimus-eluting stent implantation during follow-up because preprocedural CRP levels were higher, despite similar angiographic data just after PCI. Angiographic restenosis at 6 to 8 months after PCI was seen in 10.6% in the lowest tertile, 17.9% in the middle tertile, and 32.0% in the highest tertile (P=0.0007). Conclusions—Increased preprocedural serum CRP levels would predict higher major adverse cardiac events and restenosis rates after sirolimus-eluting stents implantation in patients on hemodialysis.

Autonomic Dysfunction in Hemodialysis Patients with Persistent Hypotension

To investigate autonomic mechanisms underlying persistent hypotension in long-term hemodialysis patients, high-frequency (HF, > 0.15 Hz) and low-frequency (LF, 0.04-0.15 Hz) components of heart rate variability and plasma noradrenaline were analyzed in 10 persistently hypotensive hemodialysis patients (group H), 11 normotensive patients (group N) and 10 healthy controls (group C). The HF amplitude, an index of cardiac parasympathetic activity, and LF-to-HF ratio, an index of sympathetic predominance, were in the order of groups C > N > H (p < 0.01). While the HF amplitude decreased with standing in all three groups (p < 0.05 for all), the LF-to-HF ratio increased only in groups N and C (p < 0.05 for both) but not in group H. Conversely, plasma noradrenaline level was in the order of groups C < N < H (p < 0.001). Furthermore, while the LF-to-HF ratio correlated positively with the plasma noradrenaline level in group C (r = 0.73, p < 0.01), it correlated negatively in group H (r = 0.69, p < 0.05). These results indicate that an impairment in both parasympathetic and sympathetic functions exists in hemodialysis patients with persistent hypotension, and that the apparent sympathetic dysfunction could result from a reduction in cardiovascular responsiveness to sympathetic stimulation.