Commonly used antithrombotic drugs in vascular surgery Peripheral arteriosclerotic occlusive disease (PAOD) refers to a group of diseases in which the lumen of peripheral arteries is progressively narrowed or occluded due to atherosclerotic lesions, resulting in acute or chronic ischemia in the blood supplying organs or tissues of the arteries. Peripheral arteries generally refer to the branches of the aorta except coronary arteries, pulmonary arteries and cerebral arteries, including all arteries of the neck, upper limbs, thoracic cavity, abdominal cavity and lower limbs. The disease does not include functional (vascular reactive) disease of the arteries or aneurysmal disease. Because PAOD involves peripheral arteries throughout the body, and clinical symptoms and pathophysiology vary depending on the artery involved, the most common clinical condition is arteriosclerosis obliterans (ASO) of the lower extremities. Therefore, the most attention of PAOD pharmacotherapy is focused on lower extremity ASO, and the focus of this article is to introduce the progress of pharmacotherapy of lower extremity ASO. The basic principles of lower extremity ASO treatment are: 1) prevention and control of disease progression; 2) promotion of collateral circulation to improve blood supply to the lower extremity; 3) protection of the lower extremity and foot from external injury; 4) reduction of ischemic pain in the extremity; and 5) management of ischemic ulcers in the extremity. The basic methods of treatment for ASO of the lower extremity are: 1) basic treatment; 2) pharmacological treatment; 3) interventional treatment; and 4) surgical treatment. According to the survey, only 2% to 3% of patients with lower extremity atherosclerosis over 5O years old have lower extremity ischemic symptoms; and among patients with ischemic symptoms such as intermittent claudication, only 1O% to 15% of the patients’ condition will deteriorate rapidly. Therefore, the majority of patients with lower extremity atherosclerosis should be treated with medication regardless of whether they have clinical symptoms. Drug therapy includes: 1. Risk factor control drugs: control of blood pressure, blood lipids, blood sugar, hyperhomocysteinemia, etc. 2, antiplatelet drugs: aspirin, clopidogrel, ticlopidine,. 3, both anti-platelet effect and vasodilator drugs: cilostazol, beraprost, butalbital, nafurolamine oxalate, hexoketone cocaine, etc. 4, vasodilator drugs: prostaglandin E1 (prostaglandin), iloprost. 5.Anticoagulant drugs: Agatroban, heparin and low molecular heparin, etc. 6. Thrombolytic drugs: urokinase, streptokinase, alteplase, ralteplase, tenecteplase, etc. can be used in acute limb ischemia. 7. Traditional Chinese medicine: According to the diagnosis and treatment of Chinese medicine, different decoctions or fixed prescriptions of traditional Chinese medicine can be effective in improving symptoms and slowing down the progress of the disease. The following is a list of risk factor control drugs: control of blood pressure, blood lipids, blood sugar, hyperhomocysteinemia, etc. Since peripheral atherosclerosis is a local manifestation of systemic atherosclerosis, all anti-atherosclerotic measures including drug therapy and non-drug therapy are the most basic treatment. This paper does not go into details. 2.Anti-platelet drugs: In addition to controlling the presence of high-risk factors, the early use of anti-platelet drugs is of considerable importance to patients with PAD, including those with intermittent claudication and severe limb ischemia. 1) Aspirin: It can inhibit the production of thromboxane TXA2, which promotes platelet aggregation, by inhibiting platelet cyclooxygenase 1 (COX-1), and thus is antithrombotic. A meta-analysis of 174 randomized trials conducted by the Antiplatelet Trials Collaborative Group found that 75-325 mg of aspirin daily in patients with PAD prevented vasculopathy at other sites: -Reduced death from complications of myocardial infarction, stroke, or arterial embolism by 32% -Reduced death from non-fatal complications of myocardial infarction, stroke, or arterial embolism by 32% -Reduce non-fatal myocardial infarction by 32% and non-fatal stroke by 46% -Reduce total vascular mortality by 20% Unless contraindicated, low-dose aspirin, 75-325 mg, 1 dose should be used with or without symptoms. 2) Clopidogrel (Bolivar): Clopidogrel 75 mg once/d inhibits fibrinogen binding to platelet adenosine diphosphate (ADP), thereby inhibiting platelet adhesion and aggregation.The CAPRIE study compared the efficacy of the ADP antagonist clopidogrel (Bolivar) or acetylsalicylates in 19,185 patients with cardiovascular disease over an observation period of 1-3 years, of whom 6. 452 had peripheral arterial disease, 452 patients had peripheral arterial disease. Overall, the annual incidence of ischemic stroke, myocardial infarction, or vascular death was lower in the clopidogrel group (5.32%) than in the aspirin group (5.83%). For the 6,452 patients in the PAD subgroup, the corresponding incidence was 3.71% in the clopidogrel group and 4.86% in the aspirin group. Side effects were very rare in both groups. According to these data guidelines or recommendations from various countries (USA, Germany, China, etc.) suggest that every patient with symptomatic PAD should be treated with antiplatelet drugs if there are no contraindications. Antiplatelet agents not only reduce the risk of atheroembolism and maintain patency of arteries and bypass arteries after endarterectomy, but more importantly, they reduce morbidity and mortality in patients with underlying atherosclerotic disease. However, based on current data, it is not clear how antiplatelet agents should be used in patients with PAD in the asymptomatic phase. (3) Ticlopidine: It can bind to the platelet surface adenylate cyclase-coupled ADP receptor and mainly inhibit ADP-induced platelet aggregation, and is only used for those who cannot apply both aspirin and clopidogrel due to serious adverse effects (such as platelet and neutropenia, liver function impairment, etc.), 250 mg 2 times/d. 3. Drugs with both anti-platelet and vasoactive effects (to improve symptoms of intermittent claudication) (1) Cilostazol: Inhibits platelet and vascular smooth muscle phosphodiesterase activity, increases cyclic adenosine monophosphate (cAMP) concentration, and has both anti-platelet aggregation and vasodilator effects, improving blood flow in the lower extremities through a variety of mechanisms: (1) antiplatelet and vasodilator effects by increasing intracellular cAMP levels; (2) mildly increases (3) Cilostazol can also increase HDL-C and lower triglyceride levels; (4) In vitro experiments have shown that cilostazol can inhibit the proliferation of vascular smooth muscle cells. The efficacy of cilostazol in improving the symptoms of intermittent claudication and improving the quality of life of patients with PAD has been confirmed by a large number of phase III clinical studies. Six randomized clinical studies in the United States were conducted to evaluate the effect of cilostazol in improving walking distance and quality of life in patients with intermittent claudication. 1751 patients were enrolled, including 741 in the placebo group, 281 in the cilostazol 50 mg bid group, and 730 in the cilostazol 100 mg bid group. The results showed that compared with placebo, patients taking cilostazol showed significant improvement in somatic pain, somatic function, somatic role and other quality of life indicators (P<0.0001); walking ability was significantly improved and maximum walking distance was significantly prolonged, and the improvement in walking distance was quantitatively related to the dose of cilostazol. A randomized study comparing cilostazol with hexaconitine showed a significant improvement in maximum walking distance in patients taking cilostazol, while the change in maximum walking distance in the hexaconitine group was similar to that in the placebo group. The cilostazol group showed an advantage as early as 4 weeks of dosing. It should be noted that the cilostazol group showed a significant decrease in treatment benefit and a significant reduction in maximum walking distance after discontinuation of the drug, while the hexaconitine group showed no such change, further confirming the role of cilostazol in improving walking ability in patients with PAD. Moreover, cilostazol was well tolerated by the patients, and the complication rate and mortality rate in the cilostazol group were not significantly different from those in the hexaconitine and placebo groups. Whether the combination of cilostazol with other antiplatelet agents increases the risk of bleeding is of concern to clinicians. The Wilhite et al. trial compared the effects of several antiplatelet therapy drugs on bleeding time in patients with PAD. Preliminary results showed that cilostazol had the least effect on bleeding time compared with aspirin or clopidogrel when the drugs were applied alone; when combined, cilostazol did not increase the effect of aspirin or clopidogrel on bleeding time. Therefore, cilostazol is a drug that has a relatively small effect on bleeding time and does not increase the risk of bleeding. Intermittent claudication is the most common symptom of PAD. A large number of clinical studies have shown that cilostazol is an effective drug for the treatment of intermittent claudication in PAD, and has been listed as a highly recommended drug for the treatment of PAD by ACC/AHA guidelines, and is also the drug of choice for the treatment of intermittent claudication. In addition, the guidelines for the diagnosis and treatment of peripheral arterial disease jointly developed by 14 societies in Europe and the United States in the fields of vascular surgery, vascular medicine, circulatory system, interventional radiology and diabetologists and cardiologists (TASC) also recommend cilostazol as the first-line drug for the treatment of intermittent claudication. In 2006, the Chinese Physicians Association conducted an evidence-based study on the treatment of peripheral arterial disease with cilostazol (PEDA) 100mg/bid, involving 93 hospitals in 16 provinces and cities, and collected 4276 questionnaires, of which 3215 were valid. 100mg.bid was used for particularly severe symptoms, and the observation period was 8 weeks. The patients were followed up three times (0, 4, and 8 weeks) to observe the improvement of their conscious symptoms such as pain, numbness, coldness, and maximum walking distance (MWD). The results of the study showed that the treatment of clinical PAD was commonly applied to PED® and a higher dose (100 mg/bid) was preferred for patients with obvious self-conscious symptoms for rapid relief. For patients with high risk factors such as hyperlipidemia and hyperglycemia, a smaller dose (50mg/bid) is preferred for prophylaxis to improve the atherosclerotic process. In the PEDA® 2006 evidence-based medical study, headache (tolerated) occurred in 461 patients, with an incidence of 14.3%, due to the effect of PEDA® dilation of carotid and vertebral arteries, which was transient and resolved upon discontinuation. Other possible adverse effects were palpitations (92 patients, 2.9%), swelling (11 patients, 0.3%), and rash (5 patients, 0.2%). If patients start with small doses and gradually increase the dose, no adverse reactions usually occur. It should be noted that cilostazol and its various metabolites are phosphodiesterase III inhibitors, and various drugs with this pharmacological effect may increase the risk of death in patients with chronic heart failure of class III-IV compared with placebo; therefore, cilostazol is contraindicated in any patient with chronic heart failure. The ACC/AHA guidelines for the treatment of peripheral vascular disease recommend that cilostazol 100 mg bid is effective in improving symptoms of intermittent claudication and increasing walking distance in patients with PAD, but is contraindicated in patients with heart failure (Class IA evidence). Therefore, although cilostazol is identified by national guidelines as a first-line treatment for intermittent claudication in patients with PAD, its use should be noted for its side effects: possible palpitations, fever, decreased blood pressure, headache, dizziness, vertigo, insomnia, tingling, sleepiness, and abnormal digestive function. Contraindicated in patients with bleeding disorders due to the risk of bleeding. Use with caution in patients with severe liver and kidney impairment, taking anticoagulant and antiplatelet drugs. Cilostazol should be discontinued for 4-5 d before surgery. Clinical trials on cilostazol are emerging. 2008 Stone WM et al. reported that in 1435 patients with intermittent claudication in peripheral arterial obstructive disease, application of cilostazol not only resulted in improvement of claudication symptoms but also reduced cerebral ischemic events (stroke, TIA, carotid revascularization). Led by Prof. Huang Yining of Peking University and over 3 years in a dozen hospitals in China, cilostazol was similar in stroke prevention compared to aspirin (12/360 vs. 20/360), but significantly less hemorrhagic stroke (1/12 vs. 7/20). Since lower extremity atherosclerosis is only a local manifestation of systemic atherosclerosis, patients with lower extremity atherosclerosis are often combined with atherosclerosis of other arteries, including cardiovascular disease, and special attention must be paid to cardiovascular and cerebrovascular disease and complications while treating lower extremity arterial lesions. Although this trial was not conducted in patients with peripheral arterial occlusive disease, its results may give us some hints that if a patient with peripheral arterial occlusive disease also has stroke, cilostazol may be more appropriate than aspirin in the selection of antiplatelet agents. In 2008, Hiatt WR et al. reported a randomized, placebo-controlled clinical trial on the safety of long-term cilostazol use in 717 patients using 1046 person-years (718 in the placebo group/1090 person-years), with no significant increase in all-cause mortality, cardiovascular death, or serious bleeding events in the cilostazol group compared with placebo, and concluded that cilostazol was safe for long-term use . (2) Beraprost: A prostacyclin (PGI2) biologic agent that has anti-platelet and vasodilatory effects by activating adenylate cyclase, increasing intracellular cAMP concentration, inhibiting Ca2+ influx and thromboxane A2 production through PGI2 receptors in platelets and vascular smooth muscle. Studies have shown a small improvement in walking distance in patients with intermittent claudication. 40 ug 3 times/d. Headache, facial flushing, gastrointestinal reactions, elevated TG, and elevated liver enzymes may occur. Contraindicated in patients with active bleeding, hemophilia. Use with caution in patients with bleeding risk, such as those taking anticoagulant and antiplatelet drugs. Discontinue for 4~5 d before surgery. 3) Buflomedil: It has adrenergic a1 and a2 receptor antagonism, inhibits vasoconstriction and platelet aggregation, improves erythrocyte deformability, and has mild calcium antagonism. 450~600 mg /d in 2~3 doses. Gastrointestinal discomfort, headache, dizziness, drowsiness, insomnia, burning sensation in the extremities, skin flushing or itching may occur. Contraindicated in patients with acute myocardial infarction, angina pectoris, hyperthyroidism, paroxysmal tachycardia, cerebral hemorrhage, other bleeding tendencies, or recent massive blood loss. Use with caution in patients with hepatic or renal insufficiency and in patients taking antihypertensive drugs. This drug affects the ability to drive vehicles and operate machinery. (4) Naftidrouryloxalate: 5-HT antagonist, improves anaerobic metabolism in hypoxic tissues, may also reduce platelet and red blood cell aggregation. 100-200 mg, 3 times/d, with meals. Gastrointestinal reactions, elevated liver enzymes, and esophagitis may occur. Oxalate may cause kidney stones and should be taken with 200-300 mL of water. Patients with high oxaluria and a history of calcium-containing kidney stones are prohibited. (5) Pentoxifylline: Improves red blood cell deformability, reduces fibrinogen levels, and inhibits platelet aggregation. 400 mg, 3 times/d, with meals. The 2007 ACCP/AHA guidelines for the treatment of lower extremity arterial disease evaluate this drug as an alternative to cilostazol for prolonging pain-free walking distance (Level A evidence), while suggesting that further validation is needed (Level C evidence). The drug may present with facial congestion, arrhythmias, hypotension, gastrointestinal reactions, skin redness, purpura, dizziness, headache, and irritability. Elevated liver enzymes, bleeding, and thrombocytopenia may occur in a small number of patients. Contraindicated in severe bleeding, extensive retinal hemorrhage. Use with caution in patients with severe cardiac arrhythmias, acute myocardial infarction, hypotension, renal impairment, severe hepatic impairment, presence of bleeding risk (e.g., on anticoagulants, clotting disorders). Nafuramine, hexoketococine, and butorphanolide have not been approved for the treatment of Fontaine III and IV in Germany, and there is a lack of evidence for their efficacy. 4. Vasoactive drugs (drugs for limb ischemia): Prostaglandins: In Germany, the indications for prostaglandins include patients who are unable to perform revascularization, or who are unable to provide satisfactory perfusion after revascularization, and who are not ready for amputation but have to undergo amputation. Prostaglandin E1 is approved for the treatment of stage III and IV PAD, but the prostacyclin analogue iloprost is approved only for the treatment of thromboembolic vasculitis. According to recent findings, a rigorous treatment regimen significantly resulted in ulcer healing, reduced resting pain, and lower amputation rates. Initially, prostaglandin E1 was administered arterially, but now it is usually administered intravenously in high doses. Iloprost can only be administered intravenously. In 14 controlled studies of prostaglandin E1, iloprost, and placebo, most results showed that prostaglandin E1 and iloprost significantly reduced resting pain and reduced ulcer size with statistically significant differences. Prostaglandin E1 (Prostil, Alproadil), which may be considered for use in the critical phase for 7-28 d, reduces pain caused by local ischemia and promotes ulcer healing. 40-60 ug, 1-2 times/day diluted intravenously. Headache, gastrointestinal reactions, flushing, abnormal sensation may occur. Rarely, decreased blood pressure, tachycardia, angina pectoris, elevated hepatic transaminases, abnormal white blood cells, joint symptoms, cerebral spasms, increased body temperature, sweating, chills. Contraindicated in patients with uncontrolled heart failure, arrhythmias, coronary artery disease, previous myocardial infarction within the past 6 months, suspected pulmonary edema or pulmonary infiltrative lesions, severe chronic obstructive pulmonary disease, liver disease that may cause bleeding disorders. Iloprost: 0.5 to 2.0 ng?kg-1?min-1 intravenously over 6 h for 1 to 4 weeks. Flushing, hypotension, fainting, palpitations, headache, insomnia, gastrointestinal discomfort, dental closure, back pain, muscle cramps, jaw pain, cough, flu-like symptoms, elevated liver enzymes, and local skin reactions at the injection site may occur. Contraindicated in patients with peptic ulcer, trauma, intracranial hemorrhage, coronary artery disease, heart failure, cardiac arrhythmia, pulmonary congestion, hypotension (systolic blood pressure <80 mm Hg). Use with caution in patients with hepatic impairment. The 2007 ACCP/AHA guidelines for the treatment of lower extremity arterial disease do not consider oral prostaglandins, including iloprost, to prolong pain-free walking distances. The 2007 ACCP/AHA guidelines for the treatment of lower extremity arterial disease suggest that Ginkgo biloba preparations may prolong pain-free walking distances, but confirmatory evidence is needed (Level of Evidence B). Anticoagulants may also be used when the thrombotic component is large; to prevent vascular embolism after bypass surgery, both antiplatelet agents and anticoagulants may be used; however, there is no data to show which one is more effective. Heparin is mainly used in emergency situations, short-term use and in patients who cannot take oral anticoagulants. (1) Argatroban: It is a highly active and selective thrombin inhibitor, directly inactivating the activity of thrombin (factor IIa); it has no direct effect on the production of thrombin, and its effect does not depend on the antithrombin in the body; it not only inactivates thrombin in the free state of the blood, but also inactivates thrombin bound to the fibrin thrombus; it blocks the coagulation waterfall Positive feedback; inhibits platelet coagulation induced by thrombin at very low concentration; indirectly inhibits the production of thrombin. It can increase the oxygen partial pressure, skin temperature and deep temperature of the affected limb. It is indicated for the improvement of ulcers, resting pain and cold symptoms in the extremities. 10 mg, 2 times/d. Dilute and administer intravenously for 2 to 3 h. The course of treatment is within 4 weeks. Precautions: Bleeding tendency, blood abnormalities, hypersensitivity, vasodynia, vasculitis, hepatic and renal dysfunction and gastrointestinal reactions and headache may occur. Rarely, pain or numbness in extremities, vertigo, arrhythmia, heat sensation, flushing, chills, fever, sweating, chest pain, hyperventilation syndrome, dyspnea, abnormal blood pressure, edema, fatigue, and decreased total serum protein. Contraindicated in patients with hemorrhage and cerebral embolism. Use with caution in patients with severe hypertension, diabetes mellitus, hepatic dysfunction, patients who are using anticoagulants, platelet aggregation inhibiting drugs, thrombolytic drugs or enzymes that have the effect of lowering blood fibrinogen. Strict coagulation examination should be performed when using. (2) Heparin and low molecular heparin: Low molecular heparin (LMWH) is a degradation product of heparin, and its antithrombotic effect is better than that of common heparin (SH), while its anticoagulant effect is lower than that of SH, and it has the characteristics of high bioavailability, long half-life in vivo, and low bleeding tendency, especially the risk of bleeding is greatly reduced and intensive monitoring is not required after the drug is administered, which facilitates long-term use. Low-molecular heparin will gradually replace common heparin. Low-molecular heparin sodium has been approved for this disease. 6, fibrinogen reduction therapy Two large placebo-controlled studies found that the use of snake venom preparations to reduce fibrinogen did not have any effect. Intermittent, low-dose administration of thrombolytic agents (e.g., urokinase) may also reduce fibrinogen, but has not been evaluated in controlled trials. 7. Thrombolytic drugs: urokinase, streptokinase, alteplase, ralteplase, tenecteplase, etc. can be used in acute limb ischemia. 8. Chinese medicine: according to the diagnosis and treatment of Chinese medicine, taking different decoctions or fixed prescriptions of Chinese medicine for different stages of the disease is effective in improving the symptoms and delaying the progress of the disease. In addition, the 2007 ACCP/AHA guidelines for the treatment of arterial disease of the lower extremities concluded that vitamin E is not effective for intermittent claudication (Level of Evidence C); griddle combination (e.g., tetrabromovinic acid) cannot be used to treat claudication and may be harmful (Level of Evidence A). Because atherosclerosis is a polygenic, multifactorial disease that defines the comprehensive nature of treatment for peripheral arterial occlusive disease, there is no single treatment that can replace all treatments, nor is there a single drug that can replace other drugs. The 8 major classes (actually 12 classes) of dozens of drugs listed in this article reflect such a situation. Although the 2006 US ACC/AHA guidelines, the 2007 treatment recommendations in China, and the 2007 German guidelines have all analyzed and identified various clinical trials in recent years, and put forward some principles and more specific guidance, it is still a problem that clinicians must solve on their own, specifically for each patient, when and under what circumstances, and how to choose drugs and select treatments.