Effect of alprostadil plus cilostazol on the treatment outcomes and inflammatory factors in patients with lower extremity arteriosclerosis obliterans receiving evidence-based care

Abstract

This study aims to elucidate the effect of alprostadil (ALP) plus cilostazol (CIL) on the treatment outcomes and inflammatory factors in patients with lower extremity arteriosclerosis obliterans (LEASO) receiving evidence-based care. Firstly, 130 patients with LEASO were selected from February 2020 to February 2023 and then randomly divided into two groups with 65 patients each. Excluding the dropouts, 59 patients in the control group (6 cases of dropout) received ALP and 62 patients in the research group (3 cases of dropout) received ALP plus CIL. Both groups were cared for in accordance with the evidence-based care model. Treatment outcomes, arteriosclerosis indexes (blood flow of dorsalis pedis artery [DPA], ankle–brachial index [ABI] and toe–brachial index [TBI]), hemorheological parameters (erythrocyte aggregation index [EAI], erythrocyte deformation index [EDI], high blood viscosity [HBV] and haematocrit [HCT]), inflammatory factors (interleukin [IL]-6, IL-8 and tumour necrosis factor [TNF]-α) and complications (nausea, diarrhoea, headache and transaminase elevation) were compared between the control and research groups. Results show that the overall response rate was markedly higher in the research group (90.32%) than in the control group (74.58%). Additionally, the blood flow of DPA, ABI and TBI in the research group significantly increased after the treatment and were higher than those in the control group. Meanwhile, the EAI, EDI, HBV, HCT, IL-6, IL-8 and TNF-α were significantly lower. The two groups did not differ markedly in the complication rate. The above findings suggest that ALP plus CIL is effective for patients with LEASO receiving evidence-based care. It can significantly improve arteriosclerosis indexes and hemorheological parameters while inhibiting serum inflammatory responses, with some certain safety.

Keywords

Alprostadil cilostazol evidence-based care lower extremity arteriosclerosis obliterans treatment outcomes inflammatory factors

1 Introduction

Lower extremity arteriosclerosis obliterans (LEASO) is a chronic, progressive and disabling peripheral arterial disease [1]. Approximately 70% of arteriosclerosis obliterans cases occurs in the femoral, popliteal and distal arteries, and the remaining 30% occur in the iliac artery. [2]. This disease has a high incidence rate, ranging from 20% in Western countries to 15.91% in China [3, 4]. The aetiology of LEASO is closely related to arterial stenosis and occlusion caused by intimal thickening and atherosclerosis, which can lead to chronic limb ischemia, intermittent claudication, numbness, pain and, in severe cases, gangrene, ulceration and even amputation [5, 6]. Therefore, during disease treatment, nursing intervention is often combined to improve the local blood supply of limbs to avoid associated complications [7, 8]. At present, this disease is mainly treated pharmacologically or surgically, and the main purpose of drug treatment is anticoagulation and anti-platelet aggregation [9]. This study primarily explores LEASO management optimization from the perspective of drug treatment, contributing to the improvement of LEASO patients’ condition and symptoms.

Alprostadil (ALP) can dilate blood vessels and inhibit platelet aggregation, making it suitable for the treatment of arteriosclerosis obliterans, severe bleeding of lower limbs and other diseases, reduction in the degree of lower limb atherosclerosis and alleviation of clinical symptoms such as ulcers and pain [10, 11]. In an animal model experiment, ALP reversed the negative effects of ischemia–reperfusion injury (I/R) on erythrocyte deformability in rats with lower limb I/R, suggesting its potential role in improving hemorheology in patients with ASO [12]. ALP also has an anti-inflammatory action and can curb atherosclerosis by stabilising vascular plaques and inhibiting inflammation in plaques possibly through the suppression of wingless type MMTV integration site family, member 5A/c-Jun N-terminal kinase/nuclear factor-kappa B (NF-κB) axis [13, 14]. Cilostazol (CIL) is a 2-oxoquinolone derivative with antiplatelet, vasodilation and I/R protection properties and can be used to treat intermittent claudication by inhibiting the abnormal increase in phosphodiesterase III and cyclic adenosine monophosphate levels [15]. Brown T et al. [16] reported that CIL significantly increased the total walking distance of patients with arteriosclerosis obliterans.

Only a few related studies were conducted on ALP plus CIL for the treatment of patients with LEASO receiving evidence-based care intervention. Therefore, the present work mainly focuses on this aspect to optimise the management of this disease.

2 Data and methods

2.1 General information

The subjects were 130 patients with LEASO who visited our hospital between February 2020 and February 2023. They were randomly divided into two groups with 65 patients each. Following an evidence-based care model, 59 cases in the control group (6 cases of dropout) were treated with ALP, and 62 cases in the research group (3 cases of dropout) were given ALP + CIL. Ethical approval was obtained from the hospital’s ethics committee. No statistical inter-group difference was found in general data (P > 0.05), which was clinically comparable.

2.2 Eligibility and exclusion criteria

Inclusion criteria: All patients met the diagnostic criteria for LEASO, showed no allergic reactions to the drugs used in this study, did not receive hormone drugs within 3 months before treatment and had intact case data.

Exclusion criteria: Patients with serious diseases of heart, brain, kidney and other vital organs; thromboangiitis obliterans; contraindications to anticoagulant and thrombolytic therapies; mental illness; or cognitive dysfunction were excluded.

Dropout criteria: Patients who changed or added treatment methods midway and those who cannot continue treatment due to various reasons during the trial period were considered as dropouts.

2.3 Treatment methods

The control group was injected with ALP (2 mL) dissolved in 100 mL of 0.9% sodium chloride injection for intravenous infusion once a day. The research group was given CIL tablets with doses of 50 mg/time, twice/day in the 1st week and 100 mg/time, twice/day in the 2nd to 4th week. The treatment lasted for 4 weeks in both groups.

2.4 Detection indicators

Efficacy evaluation criteria: Significant refers to the complete remission of clinical symptoms and a > 90% improvement in various indicators. Effective refers to the improvement of clinical symptoms and various indicators but does not meet the significant response criteria. Ineffectiveness refers to insignificant improvement or worsening of symptoms and indicators. The overall response rate (ORR) of treatment is the sum of significant cases and effective cases as a percentage of the total number of cases.

The ORR of treatment is the sum of marked response cases and response cases as a percentage of the total number of cases.

Atherosclerosis indexes. Blood flow of dorsalis pedis artery (DPA), ankle–brachial index (ABI) and toe–brachial index (TBI) were measured using vascular ultrasound and arteriosclerosis detector.

Hemorheological parameters. An automatic hemorheological analyser was used to measure pre- and post-treatment erythrocyte aggregation index (EAI), erythrocyte deformation index (EDI), high blood viscosity (HBV) and haematocrit (HCT) in the two groups.

Inflammatory factors. From each patient, 5 mL of fasting venous blood was collected to extract serum via centrifugation. The levels of interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α were quantified by ELISA.

Occurrence of complications. The overall complication rate was calculated after recording the cases of side effects such as nausea, diarrhoea, headache and transaminase elevation.

2.5 Statistical analyses

Independent samples t tests and paired t tests were used to identify between- and within-group differences of measurement data (such as age and body mass index [BMI]) expressed by ( $\bar{x}$ ±s). Counting data (including sex, lower extremity lesion site and Fontaine’s classification) for the groups were expressed as n(%) and analysed by χ2 test. SPSS22.0 software was employed for statistical analysis, and significance level was set as P < 0.05.

3 Results

General information of patients with LEASO undergoing evidence-based care intervention.

No statistical difference in general data such as sex, age, BMI, lower extremity lesion site, Fontaine’s classification, smoking history and coronary heart disease was observed between the groups (P > 0.05) (Table 1).

Table 1
General information of patients with LEASO receiving evidence-based care

Factors Control group (n = 59) Research group (n = 62) χ2/t P

Sex (male/female) 35/24 39/23 0.163 0.686

Age (years) 55.66±7.37 54.84±7.96 0.587 0.558

BMI (kg/m2) 22.56±2.74 22.04±2.71 1.049 0.296

Lower limb lesions site (unilateral/bilateral) 39/20 44/18 0.332 0.564

Fontaine’s classification (I/II/III) 15/29/15 12/35/15 0.822 0.663

History of smoking (yes/no) 30/29 33/29 0.069 0.794

Coronary heart disease (with/without) 36/23 37/25 0.023 0.880

Factors	Control group (n = 59)	Research group (n = 62)	χ2/t	P
Sex (male/female)	35/24	39/23	0.163	0.686
Age (years)	55.66±7.37	54.84±7.96	0.587	0.558
BMI (kg/m2)	22.56±2.74	22.04±2.71	1.049	0.296
Lower limb lesions site (unilateral/bilateral)	39/20	44/18	0.332	0.564
Fontaine’s classification (I/II/III)	15/29/15	12/35/15	0.822	0.663
History of smoking (yes/no)	30/29	33/29	0.069	0.794
Coronary heart disease (with/without)	36/23	37/25	0.023	0.880

3.1 Efficacy of treatments for patients with LEASO receiving evidence-based care

The ORRs of the control and research groups were 74.58% and 90.32%, respectively, indicating a markedly higher efficacy in the research group compared with that in the control group (P < 0.05) (Table 2).

Table 2
Efficacy of treatments for patients with LEASO receiving evidence-based care

Factors Control group (n = 59) Research group (n = 62) χ2/t P

Marked response 14 (23.73) 25 (40.32)

Response 30 (50.85) 31 (50.00)

Non-response 15 (25.42) 6 (9.68)

Overall response 44 (74.58) 56 (90.32) 5.226 0.022

Factors	Control group (n = 59)	Research group (n = 62)	χ2/t	P
Marked response	14 (23.73)	25 (40.32)
Response	30 (50.85)	31 (50.00)
Non-response	15 (25.42)	6 (9.68)
Overall response	44 (74.58)	56 (90.32)	5.226	0.022

3.2 Atherosclerosis indexes of patients with LEASO receiving evidence-based care

Arteriosclerosis indexes such as blood flow of DPA, ABI and TBI were evaluated to comparatively analyse the influences of the two medication methods on the development of arteriosclerosis in patients with LEASO receiving evidence-based care intervention. The data showed no inter-group difference prior to the intervention (P > 0.05). After the intervention, the blood flow of DPA, ABI, and TBI in both groups increased significantly (P < 0.05), with more significant elevations in the research group versus the control group (P < 0.05) (Fig. 1).

Fig. 1

Blood flow of dorsalis pedis artery, ABI, and TBI in two groups. A. The blood flow of the dorsalis pedis artery increased markedly in both groups after intervention, with an even higher level in the research group compared with the control group. B. ABI increased markedly in both groups after intervention, with an even higher level in the research group compared with the control group. C. TBI increased markedly in both groups after intervention, with an even higher level in the research group compared with the control group. Note: *P < 0.05, **P < 0.01, compared with before intervention; #P < 0.05, compared with the control group.

3.3 Hemorheological parameters of patients with LEASO receiving evidence-based care intervention

Hemorheological parameters such as EAI, EDI, HBV, and HCT were detected to compare the influence of the two therapies on the hemorheology of patients with LEASO receiving evidence-based care intervention. All the hemorheological parameters were similar between the two groups before intervention (P > 0.05) but reduced after the intervention (P < 0.05). Particularly, the post-interventional levels were lower in the research group compared with those in the control group (P < 0.05) (Fig. 2).

Fig. 2

Hemorheological parameters of tew groups of LEASO patients receiving evidence-based care intervention. A. The erythrocyte aggregation index of both groups decreased obviously after intervention, with an even lower level in the research group compared with the control group. B. The erythrocyte deformation index of both groups reduced markedly after intervention, with an even lower level in the research group compared with the control group. C. The high blood viscosity of both groups dropped significantly after intervention, with a more evident reduction in the research group versus the control group. D. The haematocrit of both groups decreased significantly after intervention, and the reduction was more evident in the research group versus the control group. Notes: *P < 0.05 and **P < 0.01 vs. before intervention; # P < 0.05 vs. control group.

3.4 Inflammatory factors in patients with LEASO receiving evidence-based care intervention

Analysis revealed no significant inter-group difference in inflammatory factors IL-6, IL-8 and TNF-α between the two groups before intervention (P > 0.05). However, their levels reduced significantly after the intervention in both groups (P < 0.05), especially in the research group (P < 0.05) (Fig. 3).

Fig. 3

Inflammatory factors of two groups of LEASO patients receiving evidence-based care intervention. A. IL-6 reduced markedly in both groups after intervention, with an even lower level in the research group compared with the control group. B. IL-8 decreased markedly in both groups after intervention, with an even lower level in the research group compared with the control group. C. TNF-α reduced evidently in both groups after intervention, with an even lower level in the research group compared with the control group. Notes: * P < 0.05 and **P < 0.01 vs. before intervention; # P < 0.05 vs. control group.

3.5 Complications in patients with LEASO receiving evidence-based care intervention

The total complication rates of nausea, diarrhoea, headache and transaminase elevation in the control and research groups were 6.78% and 9.68%, respectively, with no significant inter-group difference (P > 0.05) (Table 3).

Table 3
Complications in patients with LEASO receiving evidence-based care intervention

Factors Control group (n = 59) Research group (n = 62) χ2/t P

Nausea 1 (1.69) 2 (3.23)

Diarrhea 1 (1.69) 2 (3.23)

Headache 1 (1.69) 1 (1.61)

Transaminase elevation 1 (1.69) 1 (1.61)

Total 4 (6.78) 6 (9.68) 0.335 0.563

Factors	Control group (n = 59)	Research group (n = 62)	χ2/t	P
Nausea	1 (1.69)	2 (3.23)
Diarrhea	1 (1.69)	2 (3.23)
Headache	1 (1.69)	1 (1.61)
Transaminase elevation	1 (1.69)	1 (1.61)
Total	4 (6.78)	6 (9.68)	0.335	0.563

4 Discussion

LEASO-related limb ischaemic events are associated with an increased risk of disability and death and have adverse effects on patient outcomes [17]. The pathology of LEASO mainly involves atherosclerosis, hemorheological abnormalities and inflammatory responses [18]. This study analysed the clinical effect of ALP+CIL in LEASO from the aspects of treatment outcomes and safety and the perspectives of arteriosclerosis, hemorheology and serum inflammation.

In this study, the ORR of the research group was 90.32%, which was significantly higher than the 74.58% in the control group. Similar to the research of Hu M et al. [19], this finding suggested that ALP+CIL has a significant advantage in improving the treatment outcomes of patients with LEASO undergoing evidence-based care intervention. Additionally, the post-treatment blood flow of DPA, ABI, and TBI increased greatly in the research group and were higher than those in the control group, suggesting that ALP+CIL can inhibit arteriosclerosis development in patients with LEASO undergoing evidence-based care intervention. This result may be related to the synergistic promotion of vascular smooth muscle dilatation by the two drugs under the combined intervention while improving blood circulation, thereby reducing the resistance of peripheral arteries and preventing the malignant development of arteriosclerosis [20]. The EAI, EDI, HBV and HCT of the research group were reduced statistically after the intervention and were lower than those of the control group, indicating that the combination of ALP and CIL can significantly improve hemorheology in patients with LEASO receiving evidence-based care intervention. CIL significantly improves blood flow during reactive congestion in patients with ASO, suggesting its ability to improve hemorheology in patients with LEASO which is in agreement with our findings [21]. The improvement effect of CIL on hemorheology in patients with LEASO may be attributed to its effective inhibition of platelet aggregation, promotion of vascular smooth muscle cell proliferation, and protection of endothelial cells, leading to significant thrombosis suppression [22]. IL-6, IL-8 and TNF-α are typical inflammatory indicators closely related to the occurrence and progression of peripheral arterial diseases, and their decreased levels are also significantly correlated with the relief of distant lung injury of lower limb I/R [23, 24]. Additionally, IL-6 level reflects tissue destruction during lower limb ischemia and, together with TNF-α, mediates the development of diabetic macroangiopathy and arteriosclerosis obliterans in chronic lower limb ischemia [25, 26]. Herein, the research group showed inhibited IL-6, IL-8 and TNF-α levels that were significantly lower than those of the control group after intervention, suggesting that ALP plus CIL can significantly inhibit serum inflammatory responses in patients with LEASO undergoing evidence-based care intervention. Kawamura T et al. [27] reported the inhibitory effect of ALP against pro-inflammatory factors in patients undergoing cardiopulmonary bypass for cardiac surgery, supporting our findings. Yong J et al. [28] found that CIL effectively reduces serum inflammatory mediators in diabetic patients with thromboangiitis obliterans, corroborating our research results. The anti-inflammatory effect of CIL is related to its interruption of the DNA binding activity of NF-κB from the Toll-like receptor axis [29]. Finally, the research group showed an overall complication rate that was not statistically different from that of the control group (9.68% vs. 6.78%), suggesting that the intervention of ALP+CIL is safe and will not significantly increase the medication side effects.

In summary, ALP plus CIL intervention in patients with LEASO receiving evidence-based care can significantly improve the treatment outcomes, prevent arteriosclerosis progression, improve hemorheology and inhibit serum inflammatory responses without increasing the medication side effects. This treatment has certain clinical promotion value.

Funding

Bozhou Key R&D Program Project (No. bzzc2021021); Anhui Medical University Fund Support Project (No. 2023xkj202).

Conflict of interest

None to report.

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