Prognostic Factors Associated with 2-year Mortality in Patients with Intermittent Claudication Treated with Endovascular Therapy for Femoropopliteal Lesions: Results from the Multicenter PROCYON Study

Abstract

Aim: Few studies have evaluated the midterm prognosis of patients with intermittent claudication who underwent endovascular therapy (EVT) for femoropopliteal lesions. Therefore, we aimed to assess 2-year mortality and prognostic factors in these patients.

Methods: We retrospectively analyzed 947 patients who underwent EVT for intermittent claudication between January 2018 and December 2021 at eight Japanese cardiovascular centers. Kaplan–Meier survival analysis was performed for mortality, and prognostic factors were analyzed using the Cox proportional hazards regression model. Patient backgrounds and medications were included in the investigation of prognostic factors.

Results: Notably, 79 deaths occurred during the mean follow-up period of 20.9±6.2 months. The 2-year mortality rate was 9.1%. In multivariate analysis, body mass index (BMI) ＜18.5 kg/m² (p＜0.001), coronary artery disease (CAD) (p＜0.001), dialysis (p＜0.001), and ankle-brachial pressure index (ABI) ＜0.6 (p=0.012) were risk factors. Statins and cilostazol were protective factors (p=0.014 and p=0.036, respectively). When the study population was stratified based on the number of these risk factors, the mortality rate was highest (32.5% at 2 years) in patients with at least three risk factors. However, when stratified according to protective factors, the mortality rate was lowest in patients with two protective factors (2.1% at 2 years).

Conclusions: Dialysis, low BMI, CAD, and low ABI were risk factors for a worse 2-year prognosis in patients with intermittent claudication who underwent EVT for femoropopliteal lesions. Statins and cilostazol may improve the 2-year prognosis of patients with lower extremity artery disease.

Introduction

Femoropopliteal lesions are the most common cause of intermittent claudication in patients with lower extremity artery disease (LEAD)¹⁾. Notably, over 230 million patients worldwide are affected by LEAD, and new interventional treatment devices for femoropopliteal lesions are emerging^2-6). Therefore, the number of patients undergoing endovascular treatment (EVT) for femoropopliteal lesions is likely to increase.

However, the life expectancy of patients with LEAD is relatively poor⁷⁾. LEAD has a poor prognosis in patients with intermittent claudication with and without tissue loss⁸⁾. The Reduction of Atherothrombosis for Continued Health study reported that patients with LEAD have a higher 1-year overall mortality rate, primarily due to cardiovascular death from diseases such as ischemic heart disease and stroke⁹⁾. In addition, according to a report by Takahara et al., patients with LEAD have a significantly higher mortality risk than patients with coronary artery disease (CAD)¹⁰⁾. Therefore, physicians treating patients with LEAD should be aware of the factors associated with prognosis during evaluation, treatment, and follow-up.

Recent studies have been conducted on the life expectancy of an entire patient population with a decreased ankle-brachial (pressure) index (ABI). However, only a few studies have investigated the life expectancies and prognostic factors of patients with LEAD/intermittent claudication after EVT for femoropopliteal lesions.

Aim

This study used a Japanese multicenter database to evaluate midterm mortality in patients who underwent EVT for femoropopliteal lesions for intermittent claudication. Previous reports have indicated that pharmacotherapy improves the prognosis of patients with LEAD¹¹⁾. Therefore, in this study, we aimed to investigate the relationship between various medications and 2-year mortality in the patient study population. We also aimed to examine the prognostic risk factors. Notably, most prognostic studies of patients with LEAD have been conducted in Western countries. Therefore, this study is significant because we explored the prognosis of patients with LEAD in an Asian-Japanese cohort.

Methods

Study Design and Patients

The PRognostic factors associated with 2-year mOrtality in patients with intermittent Claudication treated with endovascular therapY for femOropopliteal lesioNs study is a multicenter retrospective analysis from a database of patients who underwent EVT for femoropopliteal arteries from eight Japanese cardiovascular centers. We enrolled patients who underwent EVT for de novo femoropopliteal lesions between January 2018 and December 2020. From this registry, 1045 patients treated for intermittent claudication were selected. Patients with missing ABI and left ventricular ejection fraction (EF) values were excluded; therefore, 947 patients who underwent EVT for intermittent claudication (Rutherford classification 1–3) were included in the retrospective analysis. Independent investigators collected patient, laboratory, imaging, procedural, and follow-up data were collected from individual hospital databases, and follow-ups after EVT were performed according to individual hospital and physician protocols. Prognostic studies included telephone surveys. The study was conducted according to the Declaration of Helsinki and was approved by the medical ethics committees of the investigators’ eight hospitals. This observational study did not involve any patient intervention; therefore, the need for written informed consent was waived by the ethics committees.

Interventional Procedure

The EVT procedure was performed using a crossover or ipsilateral approach with a 5–7 Fr sheath inserted into the common femoral artery. Immediately before the procedure, 5,000 units of heparin were administered to the patient. Target vessels were accessed using 0.014-, 0.018-, and 0.035-inch guidewires. The final devices and treatment strategies were determined at the discretion of each operator. Furthermore, the need for various oral medications was determined by the respective physician and surgeon.

Outcome Measure

The 2-year mortality rate of enrolled patients was the endpoint of the study. The prognostic factors were also analyzed. Oral medications were included in the analysis to enable an investigation of the protective and risk factors.

Definitions

CAD was defined as previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery. Deaths due to cardiovascular disease included those from myocardial infarction, heart failure, fatal arrhythmia, and sudden death. The left ventricular EF was assessed using echocardiography. Reduced EF was defined as ＜40%. The presence of comorbidities was determined from medical records and oral medications. Chronic kidney disease was defined as an estimated glomerular filtration rate of ＜60 mL/min/1.73 m², and the definition of low ABI was set at ＜0.6 based on the mean value of the study population.

Statistical Analysis

Unless otherwise stated, data are presented as means±standard deviation for continuous variables and as percentages for categorical variables. Kaplan–Meier survival analysis was used to assess mortality. Cox proportional hazards analysis was used for univariate and multivariate analyses of factors associated with 2-year mortality to obtain hazard ratios and 95% confidence intervals. Statistical significance was set at P values ＜0.05.

Results

Baseline Characteristics

Table 1 shows the patient backgrounds/demographics. The mean age of the enrolled population was 73±8.6 years, and 696 (73.5%) patients were male. Regarding comorbidities, 795 (83.9%) patients had hypertension, 594 (62.7%) had dyslipidemia, and 551 (58.2%) had diabetes mellitus. In addition, 251 patients (26.5%) had renal failure on dialysis. Medications included statins (592/947, 62.5%), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor (521/947, 55.0%), beta-blockers (354/947, 37.4%), and sodium-glucose cotransporter 2 inhibitors (54/947, 5.7%). More than 80% of the patients took antiplatelet agents (aspirin and P2Y12 inhibitors). The mean glycated hemoglobin level was 6.4±1.1%, and the mean low-density lipoprotein cholesterol was 93±32 mg/dL. Table 2 shows the patients’ affected limbs, lesions, and procedural characteristics. Overall, 646 (68.2%) patients with intermittent claudication had lesions categorized as Rutherford Classification 3, and 461 (48.7%) lesions were classified as Trans-Atlantic Inter-Society Consensus II C/D. Notably, 329 (34.7%) patients were classified as grade 3/4 in the Peripheral Artery Calcification Scoring System. The procedural success rate was 99.8%, and 199 patients (21.0%) were treated with drug-eluting or drug-coated stents. Drug-coated balloons were used in 574 (60.6%) patients.

Table 1.Baseline patient characteristics

Number of patients	947
Follow-up period, months	20.9±6.2
Male	696 (73.5)
Age, years	73.4±8.6
Body mass index (kg/m2)	22.9±3.5
Smoker	304 (32.1)
Hypertension	795 (83.9)
Dyslipidemia	594 (62.7)
Diabetes mellitus	551 (58.2)
Chronic kidney disease	627 (66.2)
Hemodialysis	251 (26.5)
Coronary artery disease	425 (44.9)
Atrial fibrillation	133 (14.0)
Reduced Ejection fraction ＜40%	62 (6.5)
Statin	592 (62.5)
ACE-I/ARB/ARNI	521 (55.0)
β blocker	354 (37.4)
SGLT-2 inhibitor	54 (5.7)
Aspirin	757 (80.0)
P2Y12 inhibitor	811 (85.6)
Cilostazol	160 (16.9)
Warfarin	53 (5.6)
Direct oral anticoagulant	113 (11.9)
Ankle-brachial pressure index	0.62±0.20
eGFR (mL/min/1.73m2)	45.5±28.9
Missing data of eGFR	1 (0.0)
HbA1c (%)	6.4±1.1
Missing data of HbA1c	21 (2.2)
Total cholesterol (mg/dl)	170±40
Missing data of total cholesterol	19(2.0)
LDL cholesterol (mg/dl)	93±32
Missing data of LDL cholesterol	15 (1.6)
HDL cholesterol (mg/dl)	51±16
Missing data of HDL cholesterol	18 (1.9)
Triglyceride (mg/dl)	150±114
Missing data of HDL cholesterol	12 (1.3)

BMI, body mass index; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; SGLT2: Sodium-glucose co-transporter 2; ABI: Ankle-brachial pressure index; eGFR, estimated glomerular filtration rate; LDL, low- density lipoprotein; HDL, high-density lipoprotein

Values are expressed as means±standard deviations or numbers (percentages).

Table 2.Limb, lesion, and procedural characteristics

Number of patients	947
Rutherford classification
1	44 (4.6)
2	257 (27.2)
3	646 (68.2)
TASC II A/B	486 (51.3)
TASC II C/D	461 (48.7)
Chronic total occlusion	404 (42.7)
Lesion length (mm)	162±102
Proximal reference diameter (mm)	5.8±0.8
Distal reference diameter (mm)	5.5±0.8
PACSS grade
0/1/2	618 (65.3)
3/4	329 (34.7)
Use of DES or DCS	199 (21.0)
Use of BNS	186 (19.6)
Use of covered stent	17 (1.8)
Use of DCB	574 (60.6)
Procedure success	945 (99.8)

TASC II, Trans-Atlantic Inter-Society Consensus II; PACCS, peripheral arterial calcium scoring system; DES, drug-eluting stent; DCS, drug- coated stent; BNS, bare nitinol stent; DCB, drug-coated balloon.

Values are expressed as means±standard deviations or numbers (percentages).

Outcomes

Seventy-nine patients died during a mean observation period of 20.9±6.2 months. The causes of death were cardiovascular disease in 26 patients (32.9%) and infectious disease in 20 patients (25.3%) (Fig.1). Ten patients (12.6%) died of malignant disease, one (1.2%) died of stroke, one (1.2%) died of intestinal ischemia, and one (1.2%) died of renal failure. The 2-year mortality rate in this cohort, evaluated using Kaplan–Meier survival analysis, was 9.1% (Fig.2). Multivariate analysis showed the independent factors associated with 2-year mortality as a low body mass index (BMI) (＜18.5 kg/m²), undergoing dialysis, CAD, low ABI (＜0.6), cilostazol, and statins (Table 3). Low BMI, dialysis, CAD, and low ABI were risk factors for the 2-year mortality, whereas cilostazol and statins were protective factors.

Fig.1.

Causes of death in the study population

Fig.2. Two-year mortality after EVT

Kaplan–Meier survival analysis showed a 2-year mortality rate of 9.1% after EVT.

EVT, endovascular therapy

Table 3.Univariate and multivariate Cox regression analysis for prognostic factors of mortality

	Univariate		Multivariate
	HR [95%CI]	P value	HR [95%CI]	P value
Male	1.07 (0.64, 1.79)	0.80
Age (per 1-year increase)	1.02 (0.99, 1.05)	0.12
BMI ＜18.5 (kg/m2)	3.03 (1.77, 5.19)	＜0.001	2.73 (1.58, 4.71)	＜0.001
Hypertension	1.41 (0.70, 2.82)	0.33
Diabetes mellitus	1.28 (0.81, 2.04)	0.29
Hemodialysis	3.83 (2.45, 5.98)	＜0.001	3.12 (1.96, 4.97)	＜0.001
Coronary artery disease	1.94 (1.23, 3.05)	0.004	1.91 (1.20, 3.04)	0.006
Ejection fraction＜40%	1.83 (1.18, 4.44)	0.014	1.27 (0.64, 2.52)	0.49
Rutherford 3	1.47 (0.88, 2.46)	0.15
ABI ＜0.6	2.06 (1.32, 3.22)	0.001	1.81 (1.16, 2.85)	0.01
Aspirin	1.11 (0.62, 1.98)	0.72
P2Y12-inhibitor	1.4 (0.68, 2.93)	0.36
Cilostazol	0.40 (0.18, 0.93)	0.033	0.41 (0.18, 0.94)	0.036
Statin	0.44 (0.28, 0.69)	＜0.001	0.56 (0.35, 0.89)	0.013
ACE/ARB/ARNI	0.60 (0.41, 1.00)	0.05
β blocker	1.36 (0.87, 2.12)	0.18
SGLT-2 inhibitor	0.64 (0.20, 2.02)	0.44

BMI, body mass index; ABI: Ankle-brachial pressure index; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; SGLT2, sodium glucose cotransporter 2; HR, hazard ratio; CI, confidence interval

Fig.3 shows the 2-year mortality after EVT, stratified based on the number of risk factors, using the Kaplan–Meier survival analysis. The 2-year mortality rates for the groups of patients with 0, 1, 2, and ≥ 3 risk factors were 2.2%, 6.2%, 14.8%, and 32.5%, respectively (p＜0.001). Fig.4 shows the results of evaluating the 2-year mortality rate after EVT, stratified based on protective factors. The 2-year mortality rate was 15.4%, 7.2%, and 2.1% for patients with 0, 1, and 2 protective factors, respectively (p＜0.001). In the group of patients taking statins (n=592), the 2-year mortality rate after EVT tended to be lower in patients taking both cilostazol and statins than in those taking statins alone (7.2% vs 2.1%, p=0.09) (Supplementary Fig.1). However, there was no statistically significant difference in the 2-year mortality rates between the use and non-use of paclitaxel devices in all patient populations (Supplementary Fig.2).

Fig.3. Comparison of 2-year mortality after EVT by number of risk factors

The 2-year mortality rate after EVT was 2.2%, 6.2%, 14.8%, and 32.5% in the patient groups with 0, 1, 2, and ≥3 risk factors, respectively (p＜0.001).

Fig.4. Comparison of 2-year mortality by number of protective factors

The 2-year mortality rate after EVT was 15.4%, 7.2%, and 2.1% in the patient groups with 0, 1, and 2 protective factors, respectively (p＜0.001).

Supplementary Fig.1. Comparison of 2-year mortality after EVT between patients who received statins alone and those who received both cilostazol and statins

The analysis was conducted on 592 patients taking statins. The two-year mortality rate was lower in the group taking cilostazol plus a statin than in the group taking a statin alone.

Supplementary Fig.2. Comparison of 2-year mortality rates after EVT between the paclitaxel and non-paclitaxel device groups

The two groups showed no significant difference in the 2-year mortality rate after EVT.

Discussion

Notably, few studies have been conducted on the midterm prognosis and prognostic factors, including medication, in patients with intermittent claudication who underwent EVT for femoropopliteal lesions. A Kaplan–Meier survival analysis in a study from Sweden revealed a 2-year mortality rate of 7.5% in patients with intermittent claudication undergoing revascularization¹²⁾. The treated lesions in our analysis were limited to the femoropopliteal artery; however, the 2-year mortality rate in our study population was slightly higher than that reported in Sweden. This may be because the percentage of patients with renal failure in the present study was 66%, whereas that in the Swedish report was only 2.5%.

In this study, dialysis, low BMI, CAD, and low ABI were independent risk factors for 2-year mortality. Notably, dialysis and low BMI had a strong influence on patient prognosis. Dialysis is reportedly a risk factor for mortality in patients with all LEADs, including comprehensive advanced chronic limb-threatening ischemia¹³⁾. This is particularly critical in countries such as Japan, where a large percentage of patients are undergoing dialysis¹⁴⁾. In addition, a lower BMI had a significantly greater impact on 2-year mortality than a higher BMI. Previous studies have reported that malnutrition is a poor prognostic factor in patients with LEAD^15-17). The poor prognosis of patients with a low BMI in the present analysis may reflect nutritional status; therefore, BMI measurement may be a useful parameter as a prognostic predictor because it is simple and noninvasive. Thus, improving the nutritional status may also lead to improved prognosis in patients with LEAD. Similar to previous studies^{18, 19)}, comorbid CAD and low ABI were independent poor prognostic factors in the present study population.

Our prognostic analysis included medications, making our study approach novel to other studies. Antiplatelet agents, statins, angiotensin enzyme inhibitors, or angiotensin receptor blockers are recommended as guideline-directed medical therapy (GDMT) for patients with LEAD²⁰⁾. In this study, the drugs considered to affect prognosis, including those constituting the GDMT, were included in the analysis. The results showed that statins and cilostazol were independent protective factors for a 2-year prognosis.

Statins have long been reported to reduce the incidence of cardiovascular events and improve prognosis²¹⁾. They are one of the GDMTs recommended as Class 1 ²²⁾. The statin prescription rate in the current patient cohort was 62.5%, indicating inadequate medical treatment for LEAD in Japan. Our analysis suggests that statins are more effective than other drugs in improving the prognosis of patients with LEAD. These results reaffirm the importance of statins in LEAD treatment.

The administration of cilostazol may have improved the prognosis of the patients in our study. Few studies have reported the effect of cilostazol on the life expectancy of patients with LEAD. In addition to its antiplatelet effects, cilostazol has been reported to induce nitric oxide production, improve endothelial function and lipid profiles, and exert anti-inflammatory and antioxidant effects²³⁾. Therefore, research on atherosclerotic diseases from a vascular biology viewpoint is required. In our study population, the various effects of cilostazol may have positively impacted patient prognosis. Meanwhile, cilostazol may have been selectively administered only to patients without a history of heart failure because of the side effects of tachycardia. Indeed, patients with a left ventricular EF ＜40 tended not to receive cilostazol (3.1% vs. 7.2%, p=0.037). However, further research is warranted on this topic as some studies have shown that the addition of cilostazol to clopidogrel in patients with LEAD reduces ischemic vascular events²⁴⁾.

Study Limitations

This study has some limitations. The analysis was retrospective. Therefore, no information was available on adherence, and various biases could not be completely excluded. In addition, the study was based on a database of patients who underwent EVT for femoropopliteal lesions; therefore, no accurate information was available on the treatment history of other lesions. Furthermore, during this research period, low-dose rivaroxaban was not covered by health insurance in Japan. Therefore, we could not investigate the effects of this drug. Finally, the data lacked information on the dosages of oral medications.

Conclusion

The overall 2-year mortality rate after EVT for intermittent claudication of femoropopliteal lesions in a Japanese cohort was 9.1%. Notably, among the comorbidities and other factors in the study population, dialysis, low BMI, CAD, and low ABI were risk factors for a worse 2-year prognosis. Furthermore, among the drugs that may improve prognosis, statins and cilostazol were independent protective factors for the 2-year prognosis.

Acknowledgements

The authors would like to thank the staff of the catheterization laboratory for their assistance with this study.

Conflicts of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

• 1)  White C: Clinical practice. Intermittent claudication. N Engl J Med, 2007; 356: 1241-1250
• 2)  Criqui MH, Matsushita K, Aboyans V, Hess CN, Hicks CW, Kwan TW, McDermott MM, Misra S, Ujueta F, American Heart Association Council on Epidemiology and Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council: Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: A scientific statement from the American Heart Association. Circulation, 2021; 144: e171-e191
• 3)  Iida O, Fujihara M, Kawasaki D, Mori S, Yokoi H, Miyamoto A, Kichikawa K, Nakamura M, Ohki T, Diaz-Cartelle J, Müller-Hülsbeck S, Gray WA, and Soga Y: 24-month efficacy and safety results from Japanese patients in the IMPERIAL randomized study of the eluvia drug-eluting stent and the zilver PTX drug-coated stent. Cardiovasc Intervent Radiol, 2021; 44: 1367-1374
• 4)  Soga Y, Takahara M, Iida O, Tomoi Y, Kawasaki D, Tanaka A, Yamauchi Y, Tobita K, Kozuki A, Fujihara M, Ando K, and POPCORN Investigators: Vessel patency and associated factors of drug-coated balloon for femoropopliteal lesion. J Am Heart Assoc, 2023; 12: e025677
• 5)  Lammer J, Zeller T, Hausegger KA, Schaefer PJ, Gschwendtner M, Mueller-Huelsbeck S, Rand T, Funovics M, Wolf F, Rastan A, Gschwandtner M, Puchner S, Ristl R, and Schoder M: Heparin-bonded covered stents versus bare-metal stents for complex femoropopliteal artery lesions: the randomized VIASTAR trial (Viabahn endoprosthesis with PROPATEN bioactive surface [VIA] versus bare nitinol stent in the treatment of long lesions in superficial femoral artery occlusive disease). J Am Coll Cardiol, 2013; 62: 1320-1327
• 6)  Scheinert D, Werner M, Scheinert S, Paetzold A, Banning-Eichenseer U, Piorkowski M, Ulrich M, Bausback Y, Bräunlich S, and Schmidt A: Treatment of complex atherosclerotic popliteal artery disease with a new self-expanding interwoven nitinol stent: 12-month results of the Leipzig SUPERA popliteal artery stent registry. JACC Cardiovasc Interv, 2013; 6: 65-71
• 7)  Criqui MH and Aboyans V: Epidemiology of peripheral artery disease. Circ Res, 2015; 116: 1509-1526. Erratum in: Circ Res, 2015; 117: e12
• 8)  Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, and TASC II Working Group: Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg, 2007; 45: S5-S67
• 9)  Steg PG, Bhatt DL, Wilson PWF, D’Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, and REACH Registry Investigators: One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA, 2007; 297: 1197-1206
• 10)  Takahara M, Soga Y, and Iida O: Lower extremity arterial disease vs. coronary artery disease: mortality differences after revascularization. Eur Heart J, 2024; 45: 1634-1643
• 11)  Wong PF, Chong LY, Mikhailidis DP, Robless P, and Stansby G: Antiplatelet agents for intermittent claudication. Cochrane Database Syst Rev, 2011; 11: CD001272
• 12)  Baubeta Fridh E, Andersson M, Thuresson M, Sigvant B, Kragsterman B, Johansson S, Hasvold P, Falkenberg M, and Nordanstig J: Amputation rates, mortality, and pre-operative comorbidities in patients revascularised for intermittent claudication or critical limb ischaemia: A population based study. Eur J Vasc Endovasc Surg, 2017; 54: 480-486
• 13)  Kotov A, Blasche DA, Peters F, Pospiech P, Rother U, Stavroulakis K, Remig J, Schmidt-Lauber C, Zeller T, Görtz H, Teßarek J, and Behrendt CA: The impact of chronic kidney disease on mid-term outcomes after revascularisation of peripheral arterial occlusive disease: results from a prospective cohort study. J Clin Med, 2022; 11: 4750
• 14)  Himmelfarb J, Vanholder R, Mehrotra R, and Tonelli M: The current and future landscape of dialysis. Nat Rev Nephrol, 2020; 16: 573-585
• 15)  Singh S, Bailey KR, Noheria A, and Kullo IJ: Frailty across the spectrum of ankle-brachial index. Angiology, 2012; 63: 229-236
• 16)  McDermott MM, Liu K, Tian L, Guralnik JM, Criqui MH, Liao Y, and Ferrucci L: Calf muscle characteristics, strength measures, and mortality in peripheral arterial disease: a longitudinal study. J Am Coll Cardiol, 2012; 59: 1159-1167
• 17)  Matsuo Y, Kumakura H, Kanai H, Iwasaki T, and Ichikawa S: The geriatric nutritional risk index predicts long-term survival and cardiovascular or limb events in peripheral arterial disease. J Atheroscler Thromb, 2020; 27: 134-143
• 18)  Cho I, Chang HJ, Sung JM, Pencina MJ, Lin FY, Dunning AM, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Callister TQ, Chow BJW, Delago A, Hadamitzky M, Hausleiter J, Maffei E, Cademartiri F, Kaufmann P, Shaw LJ, Raff GL, Chinnaiyan KM, Villines TC, Cheng V, Nasir K, Gomez M, Min JK, and CONFIRM Investigators: Coronary computed tomographic angiography and risk of all-cause mortality and nonfatal myocardial infarction in subjects without chest pain syndrome from the CONFIRM Registry (coronary CT angiography evaluation for clinical outcomes: an international multicenter registry). Circulation, 2012; 126: 304-313
• 19)  Gupta DK, Skali H, Claggett B, Kasabov R, Cheng S, Shah AM, Loehr LR, Heiss G, Nambi V, Aguilar D, Wruck LM, Matsushita K, Folsom AR, Rosamond WD, and Solomon SD: Heart failure risk across the spectrum of ankle-brachial index: the ARIC study (Atherosclerosis Risk In Communities). JACC Heart Fail, 2014; 2: 447-454
• 20)  Smolderen KG, Romain G, Provance JB, Scierka LE, Mao J, Goodney PP, Henke PK, Sedrakyan A, and Mena-Hurtado C: Guideline-directed medical therapy and long-term mortality and amputation outcomes in patients undergoing peripheral vascular interventions. JACC Cardiovasc Interv, 2023; 16: 332-343
• 21)  Sigvant B, Kragsterman B, Falkenberg M, Hasvold P, Johansson S, Thuresson M, and Nordanstig J: Contemporary cardiovascular risk and secondary preventive drug treatment patterns in peripheral artery disease patients undergoing revascularization. J Vasc Surg, 2016; 64: 1009-1017.e3
• 22)  Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RA, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, and Walsh ME: AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation, 2017; 135: e726-e779
• 23)  Sohn M and Lim S: The role of cilostazol, a Phosphodiesterase-3 inhibitor, in the development of atherosclerosis and vascular biology: a review with meta-analysis. Int J Mol Sci, 2024; 25: 2593
• 24)  Kalantzi K, Tentolouris N, Melidonis AJ, Papadaki S, Peroulis M, Amantos KA, Andreopoulos G, Bellos GI, Boutel D, Bristianou M, Chrisis D, Dimitsikoglou NA, Doupis J, Georgopoulou C, Gkintikas SA, Iraklianou S, Kanellas Κ, Kotsa K, Koufakis T, Kouroglou M, Koutsovasilis AG, Lanaras L, Liouri E, Lixouriotis C, Lykoudi A, Mandalaki E, Papageorgiou E, Papanas N, Rigas S, Stamatelatou MI, Triantafyllidis I, Trikkalinou A, Tsouka AN, Zacharopoulou O, Zoupas C, Tsolakis I, and Tselepis AD: Efficacy and safety of adjunctive cilostazol to clopidogrel-treated diabetic patients with symptomatic lower extremity artery disease in the prevention of ischemic vascular events. J Am Heart Assoc, 2021; 10: e018184