I. Pharmacological treatment
Drug therapy refers to the systemic application of drugs. Nowadays, the recognized effective methods to control RS after stenting are aggressive anticoagulation, antiplatelet therapy and control against risk factors.
1.Anti-platelet drugs
Several trials have demonstrated the role of aspirin after revascularization, i.e., to improve the long-term patency of the reconstructed vessel and to reduce the chance of secondary surgery for the reconstructed vessel. A meta-analysis of 11 randomized controlled trials found that long-term aspirin use significantly reduced the rate of reconstructed vessel reocclusion in patients after peripheral arterial revascularization (16% vs. 25%, p < 0.01); the proportion of beneficiaries was 90/1000 over a period of 19 months. Clopidogrel (75 mg/day) compared with aspirin (325 mg/day) in the CAPRIE study was found to be more effective in reducing the risk of heart attack, stroke, and cardiovascular death. Smout et al. randomized patients after subinguinal vascular bypass surgery to two groups, aspirin + clopidogrel and aspirin + placebo, and followed them for 3 months to determine their degree of platelet aggregation and found that the former was more effective in inhibiting platelet aggregation than the latter. Clopidogrel may be considered instead of aspirin if the patient has a clear history of intolerance to aspirin or a history of recent coronary stenting within 6 months.
2.Anticoagulant drugs
Heparin and low molecular heparin are rarely used as long-term anticoagulation therapy due to the limitation of dosage form, but mostly as a transition of perioperative anticoagulation therapy. Generally, intraoperative application of heparin is added intravenously before blocking the vessel at a dose of 100-150 U/Kg, followed by an additional 50 U/Kg every 45-50 minutes until the blocking clamp is opened and circulation is re-established. In contrast, the initial dose in China is mostly 50-100 U/Kg.
In the prospective randomized multicenter BOA trial, 2690 patients after lower extremity revascularization were randomized into two groups, one with anticoagulation therapy (target international normalized ratio [INR] 3.0-4.5) and the other with oral antiplatelet therapy (aspirin 80 mg/day). There was no significant difference in the rate of revascularization patency between the two groups, but subgroup analysis suggested that anticoagulation therapy improved the patency of the venous bridge, whereas aspirin improved the patency of the artificial graft.
The WAVE trial, which investigated the addition of anticoagulation to antiplatelet therapy, randomly assigned patients to the antiplatelet agent combined with oral anticoagulant therapy group (target INR values of 2.0-3.0) versus the antiplatelet therapy alone group. The mean follow-up period was 35 months. There were no significant differences between the two groups for myocardial infarction, stroke, or severe peripheral arterial ischemia requiring emergency intervention. However, 4.0% of patients in the combined treatment group and 1.2% in the antiplatelet therapy alone group developed life-threatening bleeding, with a significant difference between the two groups. Thus indicating that the combined application of oral anticoagulation and antiplatelet therapy is not more effective than treatment with antiplatelet agents alone in preventing major cardiovascular complications and increases the risk of life-threatening bleeding, and therefore the combined administration of warfarin is not routinely recommended.
3. Drugs to control risk factors For patients after revascularization below the level of the groin, the application of statins to lower lipids has unexpected effects. abbruzzese et al. retrospectively studied 172 patients who underwent revascularization below the level of the groin and divided them into two groups, one taking statins after surgery and one control, and matched their age, surgical indications, atherosclerosis risk factors were well matched. The results found that patients taking statins within 2 years had higher rates of both phase I and phase II patency than the control group (94% vs. 83% vs. 97% vs. 87%, P < 0.02). Currently, studies have confirmed that cilostazol inhibits smooth muscle cell proliferation and platelet aggregation, and that concomitant administration with aspirin significantly reduces the incidence of RS. Probucol (probucol1) is an effective antioxidant and lipid-lowering agent that slows down the formation of atheromatous plaques and is now found in clinical trials to inhibit intimal and vascular smooth muscle cell proliferation, thereby preventing the occurrence of RS. Other treatments include antihypertensive, hypoglycemic, homocysteine lowering, and therapeutic agents for immune disorders.
II. Re-application of local vascular endoluminal techniques
The local management of RS after peripheral arterial intervention is mainly derived from the treatment of RS in the coronary stent, which mainly includes balloon dilation, re-stenting, endoluminal radiotherapy, and endoluminal plaque spinotomy.
1.Balloon dilation
Balloon dilation is the most commonly used method to treat in-stent RS, with a high success rate, simple operation and very economical. Initially, several small studies reported that the clinical recurrence rate of RS treated with PTCA ranged from 11% to 35%, but not all RS lesions can be treated with balloon dilation with good results, and the recurrence rate of RS was significantly higher in some studies. The cut balloons reduce RS by reducing the elastic retraction of the vessel wall and vascular injury through mechanical and biological effects, reducing the local inflammatory response, endothelial injury, cellular proliferation response and maximizing the lumen compared to normal balloons. on improving femoral N artery in-stent RS over plain balloon angioplasty (CBA) was prospectively studied. Patients were followed up clinically at 1, 3, and 6 months postoperatively and examined for the occurrence of ≥50% RS using duplex ultrasound. statistical analysis was performed using the exact probability method and nonparametric u test. The mean lesion length was (80±68)mm. The incidence of RS at 6 months postoperatively was 65% in the PCBA group (11/17 patients, 95% confidence interval 42%-88%) and 73% in the CBA group (16/22 patients, 95% confidence interval 54%-92%) (p=0.73). There was no significant difference in ankle-brachial index (0.83 and 0.75, respectively, p = 0.26) and maximal exercise capacity of the exercise plate (117 m and 103 m, respectively, p = 0.97) between the 2 groups after 6 months. Preliminary studies have shown that PCBA did not show superiority over CBA in the treatment of in-stent RS in the femoral N artery. for RS lesions with a mean length close to 8 cm the patency rate at 6 months after surgery was suboptimal for both approaches.
2. Re-stenting
The latter has been widely used in the coronary arteries and has played a better role in reducing RS. In peripheral arteries, it is currently in clinical trials, and its short-term effect has been initially confirmed, but the long-term effect must be further observed. the SIROCCO trial conducted a prospective randomized double-blind controlled study on patients with lower limb ischemia in the femoral N artery, and the early results found that the degree of RS at six months was 22.6% for drug-coated stents and 30.9% for plain stents (p = 0.294), and the long-term results Local reprocessing rates were found to be 22% and 13% for plain and coated stents, respectively. In addition, trials on drug-coated stents for the lower extremities are being conducted by STRIDES and other studies in the United States, 100 patients have been recruited, and the stents are currently safe to apply, no serious side effects have been found, and the results of the studies will be published.
3.Intracavitary radiation therapy
This method has been widely used in the clinic, and some clinical trials have confirmed that it can reduce the incidence of RS, but there are also certain complications, such as easy formation of local thrombosis. Catheter-borne radiation source afterloading treatment system connects the radiation source to the catheter and delivers it to the lesion site for irradiation through the afterloading treatment machine. It is characterized by precise positioning and artificial control of the irradiation dose. The radiation sources that have been used in clinical experiments are γ-ray sources and β-ray source radiation. Among them, the preventive effect of β-ray source on RS after irradiation is higher than that of γ-ray source, and with the advantage of easy protection, it is more suitable for wide clinical application.
4. Other methods
Other treatment methods include catheter thrombolysis, intraluminal plaque spinning, laser angioplasty, cryoballoon, drug-coated balloon, PTFE-coated stent, application of biodegradable stent, etc. If there is ischemia due to thrombosis after stenting, direct thrombolysis can be used. the Schwierz T study concluded that thrombus less than 3 days old should be treated with thrombolysis. rutherford RB considered catheter thrombolysis as one of the important methods to treat acute lower extremity ischemia, on which open surgical treatment can be performed.
Intraluminal plaque resection is performed by puncturing a catheter with a rotary cutting blade into the lumen of the artery at the site of the lesion. The rotary cutting blade is activated by a power source and the catheter is pushed through the lesion several times to remove the plaque from the vessel wall and store it at the head end of the catheter, and the catheter is removed along with the plaque after the cutting is completed. The excimer laser is an ultraviolet laser emitted in a pulsed fashion that vaporizes tissue through a photochemical effect rather than a photothermal mechanism. The emitted UV light is absorbed by the diseased tissue and can directly cleave molecular bonds to pin down or remove the diseased tissue. However, the long-term efficacy of the laser is not very promising, with a six-month RS rate of 65% in one study. Many other treatments, such as cryoballoon, drug-coated balloon, PTFE-coated stent, and biodegradable stent, are being or have been tried in the treatment of RS after lower limb stenting, and hopefully good clinical trials will emerge.
III. Surgical treatment
If the patient’s in-stent RS fails through interventional treatment or if the success rate of re-luminal treatment is judged to be low according to the preoperative examination results, surgical treatment should be adopted.
1.The way of re-operation after stenting
For cases with extensive bilateral iliac artery stenosis or completely occlusive stent lesions with poor inflow tracts and existing outflow tracts, anatomical extra-pubic femoral artery bypass is feasible; for cases with extensive unilateral iliac artery stenosis or occlusive stent lesions with good contralateral limb arteries, anatomical extra-pubic femoral artery bypass is feasible In cases of diffuse lower extremity arterial disease, arterial bypass to the dorsalis pedis or posterior tibial artery is an option. Materials for arterial bypass include autologous materials such as saphenous vein, cephalic arm vein, radial artery, and artificial materials such as polyester and polytetrafluoroethylene (ePTFE). For patients lacking autologous vascular materials, ePTFE materials and anastomotic sites have been improved in recent years to maintain or increase the patency rate of the graft after small-diameter arterial bypass diversion, and a composite vascular graft composed of ePTFE and autologous vessels has also been used for surgical treatment.
2. Several issues need to be noted for reoperation after stenting
If the patient is combined with atrial fibrillation or hypercoagulable state and other diseases, and the onset time is short and the stent has been implanted for a long time, it can be tried to remove the embolus by incision and exploration, but the operation should be gentle and the location of the stent should be clear through imaging; the stent endothelial hyperplasia should be abandoned and the artificial vessel or autologous vessel graft should be performed separately; if the caliber of the recipient vessel is too thin and the outflow tract condition is poor and other factors, the autologous vessel should In the application of autologous vessels, inversion or in situ grafting should be chosen according to the caliber of the vessels at both ends of the anastomosis.
3. About the selection of grafts
For the revascularization of femoral, N and the following arteries, autologous saphenous vein is a more ideal graft material, and its 5-year patency rate is reported in the literature as 50%-70%; using PTFE as graft material, its postoperative patency rate decreases, and the patency rates at 1 and 3 years are 70% and 57%, and the limb salvage rates at 1 and 3 years are 97% and 70%, respectively. In order to improve the patency rate of re-repair, the use of autologous veins should be sought. However, many patients have no saphenous vein available, and the use of upper limb veins can be considered at this time.
IV. Gene and stem cell therapy
In recent years, gene and stem cell therapy for RS after endovascular treatment has become a new field of interest, and the main methods are as follows.
1.Inhibition of smooth muscle (SMC) proliferation and migration
Smooth muscle cells are the main component of proliferating endothelium. In the early stage of endothelial formation, platelet-derived growth factors stimulate smooth muscle cells in the middle layer of the vessel wall to migrate to the endothelium, proliferate and secrete extracellular matrix, which leads to the formation of new endothelium and thus causes RS in the stent. RS in the stent.
2.Promote endothelial repair
Endothelial cells are important components of the vascular wall and are important for maintaining the normal physiological function of blood vessels. The endothelial function of diseased vessels is already impaired, and stent implantation aggravates endothelial cell dysfunction. Local transfer of vascular endothelial growth factor and nitric oxide synthase accelerates endothelial repair at the injury site to maintain the integrity of the vascular endothelium; Nishio et al. illustrated through clinical studies that improving endothelial cell function contributes to the reduction of in-stent RS. All of these studies suggest that endothelial cell function affects the occurrence of in-stent RS. Plasmid-mediated local introduction of VEGF gene into the vasculature by coated balloons has achieved some efficacy in clinical trials.
3.Inhibition of inflammatory factor production
Inflammatory response is an important factor affecting in-stent RS. Stent as a foreign body into the body, will inevitably cause rejection, causing acute and chronic inflammatory reactions in the vessel wall. Transferring important antisense genes of inflammatory process such as MCP-1 and interleukins into smooth muscle cells to inhibit the production of inflammatory factors is a good therapeutic idea.
4.Stem cell therapy
Endothelial stem cell transplantation or mobilization can promote the re-coverage and functional recovery of endothelial cells after vascular injury, inhibit the inflammatory response of the vessel wall, inhibit the proliferation of new endothelium, and reduce the narrowing of the lumen. coverage was 86.4%;, significantly higher than that of the control group 71.3%; and the endothelial/mesothelial area ratio, which reflects the degree of neoplastic endothelial proliferation, was reduced by 108%;. Human telomerase reverse transcriptase active subunit (hTERT) was transfected into human endothelial stem cells in vitro, and the proliferation, migration, and survival abilities of stem cells modified with this gene were found to be stronger than those of unmodified EPCs.
Although the mechanisms and influencing factors of RS have not been thoroughly studied, several clinical trials have been conducted for RS after stenting for lower extremity atherosclerosis occlusive disease, and there are various management options. Risk factors can be effectively prevented and controlled through pharmacological treatment and lifestyle changes. With the development of interventional devices and techniques, improvement of traditional surgery, and continuous genetic research, the management of post-stent RS will continue to increase, the incidence will gradually decrease, and the treatment effect will further improve.