Introduction
Patients with severe coronary heart disease (CHD) are commonly treated with percutaneous coronary intervention (PCI).1 However, a loss in vessel lumen area of stented arteries is indicative of in-stent restenosis (ISR), which is a serious complication after PCI.2 Although drug-eluting stents (DES) have dramatically decreased the incidence of ISR, the occurrence of ISR is still approximately 5–10% among CHD patients after PCI.3,4 Therefore, there is a need to explore novel medications that can be administered in the peri-operative period of PCI to decrease the occurrence of restenosis or prevent ISR.
Liposomal prostaglandin E1 (lipo-PGE1) is a kind of nanolipid microsphere (liposome)-based PGE1. Previous studies showed that lipo-PGE1 can decrease coronary restenosis in a canine thrombolysis model5 and reduce the incidence of periprocedural myocardial injury both in patients6 and porcine.7 Lipo-PGE1 was also found to be effective for improving microcirculation.8 The nanoliposome delivery system is also a popular method for targeted drug delivery,9 and reviews have indicated that targeted nanoparticle-mediated delivery of multifunctional drugs could be a promising approach to prevent or treat restenosis.10 Thus, this prospective clinical study was designed to investigate the effects of lipo-PGE1 on coronary stenosis and restenosis after PCI in CHD patients.
Methods
Ethical approval and informed consent
This study was approved by the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (approval registration number BF2020-283). All samples were collected with appropriate participant informed consent in compliance with the Helsinki Declaration.
Patient source
Patients were enrolled into groups according to the diagnostic inclusion and exclusion criteria. Initially, 60 patients diagnosed with CHD scheduled for PCI surgery in Guangdong Hospital of Traditional Chinese Medicine from 2020 to December 2022 were enrolled and divided into two groups: basic medication for prevention and treatment of CHD (Control group, n = 30) and basic medication combined with lipo-PGE1 treatment (PGE group, n = 30).
Group treatments
For the Control group, basic medication normally included drugs for anti-platelet therapy, lipid lowering, controling ventricular rate, and controling hypertension or hyperglycemia. For the PGE group, nanolipid microspheres-based PGE (10 µg) (Penglai Nuokang Pharmaceutical Co., LTD) was added to 0.9% normal saline (NS) (250 ml) for intravenous injection, 20 gtt/min, once a day for 3 days during the peri-operative period of PCI. Basic medications were maintained in the two groups after discharge.
Diagnostic criteria
CHD diagnoses and the criteria for PCI followed the Guidelines for Percutaneous Coronary Intervention (2019) in China.
Inclusion and exclusion criteria
Inclusion criteria were as follows: (1) The diagnosis fulfilled the criteria of CHD. (2) The condition conformed to the criteria for PCI. (3) The patients were able to complete the follow-up interview. (4) The patients voluntarily participated and signed informed consent.
Exclusion criteria included
(1) Patients with abnormal mental consciousness who could not cooperate, or patients with unstable vital signs. (2) Patients with related drug contraindications or allergies. (3) Those who participated in other clinical trials within 1 month. (4) Older than 80 years of age, pregnant or ready to be pregnant, lactating women, or infants.
Abscission criteria
(1) Patients who withdrew from the trial without adverse reactions or poor efficacy. (2) Those who lost connection during follow-up.
Termination criteria
(1) The researchers considered it medically necessary for the patients to terminate the trial. (2) Patients withdrew from the trial autonomously. (3) Those who suffered severe adverse reactions and could not insist on continuous treatments.
Primary and secondary outcomes
The rate of restenosis after PCI was the primary outcome, and the rate of newly increased stenosis was the secondary outcome. The measurement for restenosis and increased stenosis was performed using angiography or coronary computed tomography (CT), with or without transthoracic coronary doppler ultrasound. All outcomes were observed within 1.5 years after PCI.
Safety index monitoring
Adverse reactions were closely monitored when treatments were administered to all patients. All adverse reactions were observed, treated when necessary, and recorded.
Statistical analysis
A dataset was constructed and analyzed using SPSS (v26.0, Inc. USA) and R (v3.6.2, http://www.r-project.org ) software. Continuous data are expressed as mean ± standard deviation, and the Kolmogorov-Smirnov test was used for normally distributed data. If the continuous data fit a normal distribution, comparisons between the two groups were performed using two independent sample Student’s t-tests. Otherwise, the Mann-Whitney U test was used. Categorical variables are expressed in frequency and proportions (%). Chi-square (χ2) tests with or without continuous correction or Fisher’s exact test were used for comparisons between groups. P < 0.05 was considered statistically significant.
Results
Demographic characteristics of patients
In total, 60 patients were enrolled based on the criteria, and 6 patients were lost during follow-up. Finally, 54 patients (Control group, n = 30; PGE group, n = 24) finished the follow-up and were included in the final analysis. There were no significant differences in sex, age, diagnosis subsets, comorbidities, and basic treatments between the Control and PGE groups (Table 1).
Table 1Comparison of baseline characteristics between the control and lipo-PGE1 groups, [n(%)]
| Variables | Control (n = 30) | PGE (n = 24) | P |
|---|
| Sex | | | 0.210 |
| female | 5 (16.7%) | 1 (4.17%) | |
| male | 25 (83.3%) | 23 (95.8%) | |
| Age | 61.2 (11.0) | 61.2 (9.21) | 0.986 |
| Diagnosis | | | 0.063 |
| ACS | 7 (23.3%) | 1 (4.17%) | |
| CCS | 23 (76.7%) | 23 (95.8%) | |
| Comorbidity | | | |
| hypertension | 18 (60.0%) | 14 (58.3%) | 1.000 |
| hyperlipidemia | 9 (30.0%) | 6 (25.0%) | 0.919 |
| DM | 10 (33.3%) | 10 (41.7%) | 0.729 |
| Other | 0 (0.00%) | 2 (0.08%) | 0.193 |
| Basic treatments | | | |
| anti-platelet | 23 (76.7%) | 23 (95.8%) | 0.113 |
| lipid-lowering | 9 (30.0%) | 6 (25.0%) | 0.919 |
| Number of comorbidities | | | 0.261 |
| 0 | 2 (6.67%) | 5 (20.8%) | |
| 1 | 15 (50.0%) | 8 (33.3%) | |
| 2 | 8 (26.7%) | 6 (25.0%) | |
| 3 | 5 (16.7%) | 3 (12.5%) | |
| 4 | 0 (0.00%) | 2 (8.33%) | |
Baseline of vessel features in stenosis before PCI
We first compared the baseline of vessel features in stenosis before PCI between the Control and PGE groups. Stenosis location was defined as proximal, middle, and distant. We observed no significant difference in stenosis vessel features between the two groups (P > 0.05). The stenosis degree was also calculated by the percentage of area occluded and distinguished by either total occlusion or partial occlusion. The results showed no obvious differences between the two groups (P > 0.05) (Table 2). Comparisons of the number of vessels in stenosis before PCI were not statistically different (χ2 = 5.982, P = 0.050) (Table 3).
Table 2Characteristics of vessels in stenosis and stents between the control and lipo-PGE1 groups, [n(%)] or [M(IQR)]
| Variables | Control (n = 30) | PGE (n = 24) | P |
|---|
| Location of stenosis |
| LAD | | | 1.000 |
| proximal | 17 (56.7%) | 15 (62.5%) | |
| middle | 8 (26.7%) | 6 (25.0%) | |
| distant | 1 (3.33%) | 0 (0.00%) | |
| none | 4 (13.3%) | 3 (12.5%) | |
| LCX | | | 0.184 |
| proximal | 3 (10.0%) | 5 (20.8%) | |
| middle | 11 (36.7%) | 11 (45.8%) | |
| distant | 3 (10.0%) | 4 (16.7%) | |
| none | 13 (43.3%) | 4 (16.7%) | |
| RCA | | | 0.225 |
| proximal | 10 (33.3%) | 7 (29.2%) | |
| middle | 3 (10.0%) | 7 (29.2%) | |
| distant | 5 (16.7%) | 5 (20.8%) | |
| none | 12 (40.0%) | 5 (20.8%) | |
| Stenosis in vessels (%) |
| LAD | 80.0 [50.0;90.0] | 75.0 [57.5;86.2] | 0.512 |
| LCX | 32.5 [0.00;72.5] | 80.0 [37.5;90.0] | 0.050 |
| RCA | 43.5 [0.00;90.0] | 85.0 [36.2;90.0] | 0.275 |
| Total occlusion | 12 (40.0%) | 8 (33.3%) | 0.825 |
| Stent diameter (mm) |
| LAD | 2.75 [0.00;3.00] | 2.00 [0.00;2.78] | 0.130 |
| LCX | 0.00 [0.00;0.00] | 0.00 [0.00;2.12] | 0.572 |
| RCA | 0.00 [0.00;1.88] | 0.00 [0.00;2.75] | 0.921 |
| Stent length (mm) |
| LAD | 16.5 [0.00;29.0] | 22.5 [0.00;29.0] | 0.843 |
| LCX | 0.00 [0.00;0.00] | 0.00 [0.00;4.75] | 0.747 |
| RCA | 0.00 [0.00;18.0] | 0.00 [0.00;29.2] | 0.499 |
Table 3Comparisons of the number of vessels in stenosis before PCI between the control and lipo-PGE1 groups, [n(expected)]
| Group | Number of vessels in stenosis
| Total | χ2 | P |
|---|
| 1 | 2 | 3 |
|---|
| Control | 9 (7.2) | 11 (8.3) | 10 (14.4) | 30 (30.0) | 5.982 | 0.050 |
| PGE | 4 (5.8) | 4 (6.7) | 16 (11.6) | 24 (24.0) | 5.982 | 0.050 |
| Total | 13 (13.0) | 15 (15.0) | 26 (26.0) | 54 (54.0) | | |
Characteristics of implanted stent features during PCI
As the characteristics of implanted stent features during PCI may affect the prognosis of restenosis,11 we collected and compared the stent features. There were no statistical differences in the stent diameter and stent length between the two groups (P > 0.05) (Table 2). Comparisons of the number of stents implanted during PCI also demonstrated no significant differences between the two groups (χ2 = 1.520, P = 0.615) (Table 4). These results showed that vessel features in stenosis before PCI and implanted stent features during PCI were similar between the Control and PGE groups. This, combined with the demographic characteristics of the patients, indicates that the two groups were comparable at baseline.
Table 4Comparisons of the number of stents in PCI between the control and lipo-PGE1 groups, [n(expected)]
| Group | Number of stents
| Total | χ2 | P |
|---|
| 1 | 2 | 3 |
|---|
| Control | 24 (22.8) | 6 (6.7) | 0 (0.6) | 30 (30.0) | 1.520 | 0.615 |
| PGE | 17 (18.2) | 6 (5.3) | 1 (0.4) | 24 (24.0) | 1.520 | 0.615 |
| Total | 41 (41.0) | 12 (12.0) | 1 (1.0) | 54 (54.0) | | |
Effects of PGE on restenosis in culprit vessels after PCI
The percentage of restenosis was generally divided into less or more than 50% of the artery lumen area, and the number of restenosis in each vessel was calculated.12,13 We found that restenosis in the LCX was the least severe, and the percentage of restenosis in the LCX was less than 50%. Statistical analysis showed no obvious difference in restenosis percentage of each of these three arteries between the Control and PGE groups (χ2 = 1.520, P = 0.615) (Table 5). Analysis of the restenosis type14 of each vessel showed similar results, with no significant difference in each artery between the two groups (P > 0.05) (Table 6). Comparisons of the number of vessels in restenosis showed no statistical differences (χ2 = 0.070, P = 0.791) (Table 7). These data suggest that lipo-PGE1 has no significant effects on ameliorating restenosis after PCI.
Table 5Characteristics of vessels in restenosis after PCI between the control and lipo-PGE1 groups, [n(%)]
| Variables | Control (n = 30) | PGE (n = 24) | P |
|---|
| LAD | | | 0.684 |
| 0 | 27 (90.0%) | 21 (87.5%) | |
| −50 | 1 (3.33%) | 2 (8.33%) | |
| 50− | 2 (6.67%) | 1 (4.17%) | |
| LCX | | | 1.000 |
| 0 | 29 (96.7%) | 24 (100%) | |
| −50 | 1 (3.33%) | 0 (0.00%) | |
| RCA | | | 1.000 |
| 0 | 27 (90.0%) | 23 (95.8%) | |
| -50 | 2 (6.67%) | 0 (0.00%) | |
| 50− | 1 (3.33%) | 1 (4.17%) | |
Table 6Characteristics of restenosis types after PCI between the control and lipo-PGE1 groups, [n(%)]
| Variables | Control (n = 30) | PGE (n = 24) | P |
|---|
| LAD | | | 0.805 |
| none | 27 (90.0%) | 21 (87.5%) | |
| type1 | 2 (6.67%) | 3 (12.5%) | |
| type2 | 1 (3.33%) | 0 (0.00%) | |
| LCX | | | 1.000 |
| none | 29 (96.7%) | 23 (95.8%) | |
| type1 | 1 (3.33%) | 1 (4.17%) | |
| RCA | | | 0.747 |
| none | 27 (90.0%) | 23 (95.8%) | |
| type1 | 2 (6.67%) | 0 (0.00%) | |
| type3 | 1 (3.33%) | 1 (4.17%) | |
Table 7Comparisons of the number of vessels in restenosis after PCI between the control and lipo-PGE1 groups, [n(expected)]
| Group | Number of vessels in restenosis
| Total | χ2 | P |
|---|
| 0 | 1 |
|---|
| Control | 23 (23.9) | 7 (6.1) | 30 (30.0) | 0.070 | 0.791 |
| PGE | 20 (19.1) | 4 (4.9) | 24 (24.0) | 0.070 | 0.791 |
| Total | 43 (43.0) | 11 (11.0) | 54 (54.0) | | |
Effects of PGE on newly increased stenosis in non-culprit vessels after PCI
As there was no obvious effect of lipo-PGE1 on restenosis, we further investigated the effect of PGE on newly increased stenosis after PCI, which was calculated by comparing the baseline of vessel stenosis and the stenosis in non-culprit vessels after PCI. The Kolmogorov-Smirnov test indicated abnormal distribution and the Mann-Whitney U test was used for comparison. Results showed that the percentage of increased stenosis of the RCA in non-culprit vessels was much lower after PCI in the PGE group compared to the Control group (U = 263.0, P = 0.048), while no significant differences were observed in the LAD and LCX arteries (Table 8). The number of non-culprit vessels in increased stenosis after PCI was also calculated; we found no significant differences between the Control and PGE groups (χ2 = 3.902, P = 0.272) (Table 9). These data suggest that lipo-PGE1 treatment may be effective in decreasing newly increased stenosis in non-culprit vessels after PCI.
Table 8Characteristics of the percentage of increased stenosis after PCI between the control and lipo-PGE1 groups, [M(IQR)]
| Variables | Control (n = 30) | PGE (n = 24) | Mann-Whitney U | P |
|---|
| LAD | 0.00 [0.00;17.5] | 0.00 [0.00;0.00] | 313.0 | 0.288 |
| LCX | 0.00 [0.00;0.00] | 0.00 [0.00;10.5] | 340.5 | 0.659 |
| RCA | 0.00 [0.00;28.8] | 0.00 [0.00;0.00] | 263.0 | 0.048* |
Table 9Comparisons of the number of vessels in increased stenosis after PCI between the control and lipo-PGE1 groups, [n(expected)]
| Group | Number of vessels in increased stenosis
| Total | χ2 | P |
|---|
| 0 | 1 | 2 | 3 |
|---|
| Control | 10 (12.8) | 10 (9.4) | 8 (5.6) | 2 (2.2) | 30 (30.0) | 3.902 | 0.272 |
| PGE | 13 (10.2) | 7 (7.6) | 2 (4.4) | 2 (1.8) | 24 (24.0) | 3.902 | 0.272 |
| Total | 23 (23.0) | 17 (17.0) | 10 (10.0) | 4 (4.0) | 54 (54.0) | | |
Adverse reactions
The most frequently observed adverse reactions of lipo-PGE1 were phlebitis and anaphylaxis, and most of these adverse reactions disappeared after discontinuation of medication (Table 10). No severe adverse reactions were found with lipo-PGE1 treatment.
Table 10Comparisons of the number of adverse reactions between the control and lipo-PGE1 groups, [n(expected)]
| Group | Number of adverse reaction
| Total | χ2 | P |
|---|
| No | Yes |
|---|
| Control | 30 (28.3) | 0 (1.7) | 30 (30.0) | 1.946 | 0.163 |
| PGE | 21 (22.7) | 3 (1.3) | 24 (24.0) | 1.946 | 0.163 |
| Total | 51 (51.0) | 3 (3.0) | 54 (54.0) | | |
Discussion
This study examined the effects of nanolipid microspheres (liposome)-based PGE1 on coronary stenosis and restenosis after PCI using a prospective clinical trial design. We found that lipo-PGE1 treatment may be effective in decreasing newly increased stenosis in non-culprit vessels after PCI.
Nanolipid microspheres (e.g. liposome) are a novel drug delivery system. It was reported that drug-loaded liposomes applied on a multilayer-coated balloon catheter improved the limitations of drug-eluting balloons (DEB) for the treatment of coronary artery disease.15 A double-blind, randomized clinical trial (BLAST study) used liposomal Alendronate as a single intravenous bolus and showed that treatment with liposomal Alendronate could significantly decrease in-stent late loss in patients with baseline monocyte counts higher than the median value.16 These data suggested that nanolipid microspheres could be a potential method for improving restenosis treatment.
Restenosis in coronary arteries after PCI has several underlying pathogenic causes, such as activation of the clotting system by injured endothelial cells and healing facilitated by vascular smooth muscle cell migration, proliferation, and synthetic activities.4,14 The average time from restenosis occurrence after PCI has been reported to be within 12 months with drug-eluting stents (DES), and typically presents as recurrent angina.17 Evaluation of staged, target lesions, and other unplanned revascularization procedures during the first year after PCI showed that target lesion revascularization (TLR) occurred with higher hazard rates between 2 to 9 months after PCI.18 The commonly used technologies for restenosis treatment include bare metal stents, DES, conventional and cutting balloon angioplasty, drug-coated balloons (DCB), and atherectomy devices.14,19 However, there is still a population of patients who suffer restenosis more than once even with suitable treatments. Thus, adjuvant medication becomes more important in the peri-operative period of PCI.
PGE1 (also named Alprostadil) has been used to treat chronic arterial obliterans (thromboangiitis obliterans, obliterans arteriosclerosis, etc.) and improve cardiovascular and cerebrovascular microcirculation disorders. A prospective, single-blind, randomized trial of 30 patients administered intravenous PGE-1 by hemodynamically based titration at a mean dosage of 10–20 ng/kg/min at 2 hours before angiography. The 6-month follow-up showed that restenosis occurrence was 17% in the PGE-1 treated group, compared with 33–50% in the control group which only received basic medication (P < 0.05). These data indicated that PGE-1 was effective in decreasing coronary restenosis at 6 months after percutaneous transluminal coronary angioplasty.20 Since restenosis usually occurs during the first year after PCI,17 we examined the effect of PGE-1 at 1.5 years after PCI initially to obtain a more comprehensive understanding of the role of PGE-1 in preventing restenosis occurrence. However, we did not find positive results. The reason may lie in the time point for outcome observation and relatively small sample size.
Although our data did not show significant effects of lipo-PGE1 treatment for restenosis after PCI, we did observe a decrease in restenosis percentages in each of the three arteries examined. Furthermore, the newly increased stenosis in vessels was affected by lipo-PGE1 treatment, and a significant difference was observed in the RCA artery. A previous randomized controlled trial indicated that intracoronary administration of Nicorandil and PGE1 was more effective in improving myocardial perfusion than Nitroglycerin.21 Another randomized-controlled study administered lipo-PGE1 at 20 µg/day diluted in 10 ml of NS through an intravenous injection over 5 min, starting at 3 days before PCI and continuing for 4 days after PCI. The results suggested that the cardioprotective effects of lipo-PGE1 were associated with its anti-inflammatory properties and its ability to improve microvascular perfusion.6 Another clinical study suggested a relationship between the microcirculation and restenosis, evidenced by the finding that lower coronary blood flow responded to an endothelium-dependent vasodilator stimulus and was associated with long-term recurrence of restenosis.22 Thus, the anti-inflammatory and microvascular improvement effects of lipo-PGE1 may underlie the reduction of newly increased stenosis in arteries.
Future directions
The main limitation of this study was the relatively small sample size. Further studies with more subjects are needed to validate our conclusions. New studies can be designed to evaluate the treatment effect of lipo-PGE1 on restenosis, which can be assessed by quantifying the degree of restenosis before and after lipo-PGE1 treatment. Moreover, the underlying mechanisms of lipo-PGE1’s cardioprotective effects should be done by examining endogenous plasma PGE1 levels from CHD patients before and after PCI.
Conclusions
The current study was designed to evaluate the protective effects of lipo-PGE1 on coronary stenosis and restenosis after PCI. Our study showed the lipo-PGE1 did not affect restenosis after PCI, but it may be effective in ameliorating newly increased stenosis in arteries.
Abbreviations
- ACS:
acute coronary syndrome
- CCS:
chronic coronary syndrome
- CHD:
coronary heart disease
- DCB:
drug-coated balloon
- DES:
drug-eluting stents
- DM:
diabetes mellitus
- ISR:
in-stent restenosis
- lipo-PGE1:
liposomal Prostaglandin E1
- PCI:
percutaneous coronary intervention
- TLR:
target lesion revascularization
Declarations
Ethical statement
This study was approved by the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (approval registration number BF2020-283). All samples were collected with appropriate participant informed consent in compliance with the Helsinki Declaration.
Data sharing statement
The authors confirm that the data supporting the findings of this study are available within the article, and these data are also available from the corresponding author upon reasonable request.
Funding
This study was supported by Guangdong Medical Science and Technology Research Fund Project (No. B2020155, to QL), Municipal School (College) Joint Funding Project of Guangzhou Science and Technology Bureau (No. SL2023A03J00081, to QL), National Natural Science Foundation of China (No. 82274279, to QL), Guangdong Provincial Bureau of Chinese medicine Fund Project (No. 20221360, to QL), Municipal School (College) Joint Funding Project of Guangzhou Science and Technology Bureau (No. 202201020382, to RY), Zhuhai Medical Science and Technology Research Fund Project (No. ZH24013310210002PWC, to QL) and Special Funding for Chinese medicine Science and Technology Research of Guangdong Provincial Hospital of Chinese Medicine (No. YN2020QN10, to QL).
Conflict of interest
The authors declare that there is no conflict of interest in the authorship and publication of this contribution.
Authors’ contributions
QL designed the study and finalized the manuscript. AZ, JQ, CW, PL, and CL collected patient information and constructed the dataset. RY and QL completed the first version of manuscript. QL finished manuscript corrections. QL, CW, and GL contributed to manuscript revision. All authors read, revised, and approved the final manuscript.