Abstract.
Among the 20 recommendations in AT9, the most important include: in patients with asymptomatic peripheral arterial disease, or asymptomatic carotid stenosis, the application of aspirin (75-100 mg/d) (2B) is recommended as primary prevention; in patients with symptomatic peripheral arterial disease (with or without interventional therapy, peripheral artery bridging surgery, or percutaneous transluminal angioplasty), the recommendation is long-term aspirin (75-100 mg/d), or clopidogrel (75 mg/d) for secondary prevention (1A); it is recommended not to combine warfarin and aspirin in patients with symptomatic peripheral arterial disease (1B); for patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, a single antiplatelet therapy is recommended (2C); for patients with severe intermittent claudication , in addition to exercise therapy and smoking cessation, cilostazol (100 mgbid), combined with basic secondary prophylaxis, aspirin (75-100 mg/d), or clopidogrel (75 mg/d) is recommended (2C); for patients with severe limb ischemia in which hemodynamic reconstruction is not possible, or for patients with resting pain, prostaglandin analogs are recommended (2C); for patients with acute thrombosis, or acute arterial embolized limb patients, surgical opening of the embolized vessel is recommended as a preference over arterial thrombolysis (1B).
Background.
The ACCP has upgraded and revised its guidelines based on previous guidelines for antithrombotic prophylaxis and treatment of thromboembolic disease, gathering new evidence-based medical evidence and introducing the ninth edition of the guidelines earlier this year, including various aspects and areas.
In this section, the focus is on antithrombotic therapy for peripheral arterial disease (PAD). patients with PAD often have atherosclerotic lesions in other vascular beds, and their leading cause of death is heart attack or stroke. Therefore, the main goal of antithrombotic therapy in this group of patients is to prevent vascular events and death and, at the same time, to improve claudication distance, quality of life, relief of resting pain, and preservation of the limb.
PAD has different ways of classification, and in this guideline, PAD can be categorized as follows: asymptomatic PAD, where there is no clinical manifestation of limb ischemia, but upper and lower extremity blood pressure ratio (ABI) measurements, or other imaging tests show the presence of lower extremity vascular lesions; and symptomatic PAD, including intermittent claudication and severe lower extremity ischemia. Inadequate blood supply to the limb as a direct result of peripheral arterial disease is manifested by a reduction in limb motility and endurance, that is, a reduction in the ability to walk, in which case we call it intermittent claudication (IC); chronic ischemia that continues to worsen, with insufficient blood supply to maintain a resting state, results in resting pain, ulcers and even gangrene of the limb, in which case it is called critical lower limb ischemia (CLI), a limb survival-threatening Another state that directly threatens limb survival is acute limb ischemia, arterial embolism or acute arterial thrombosis, called acute lower limb ischemia (ALI).
Interpretation of the content
1.Primary prevention for asymptomatic PAD patients
The primary prevention of asymptomatic PAD patients is mainly to prevent the occurrence of cardiovascular and cerebrovascular events and to prolong the life span of patients.The measurement of ABI value, that is, brachial artery pressure/ankle artery pressure, is an important basis for establishing asymptomatic PAD. The literature suggests that an ABI value £0.9, an independent risk factor for cardiovascular and cerebrovascular events, also makes the Flamingham risk score (Framingham
risk score, which assesses the degree of risk of vascular events) overturned. For this group of patients, the guidelines state that 75-100 mg of aspirin should be given daily. For patients with a moderate or higher risk of vascular events, long-term administration is more appropriate.
2. Secondary prevention in patients with symptomatic PAD
As with asymptomatic PAD, the goal of secondary prevention in patients with symptomatic PAD is still to reduce the incidence of vascular events. However, these patients are more severely ill, have a higher chance of vascular events, and prevention is of greater significance. Evidence suggests that a single aspirin is a good prevention of cardiovascular and cerebrovascular events; also, Meta-analysis did not show an advantage of clopidogrel, but it can still be used as a means of prevention, especially in patients at higher risk of gastrointestinal bleeding.
On the question of the need for dual antibiotics, the literature suggests that despite a reduced incidence of nonfatal stroke, the risk of nonfatal extracranial hemorrhage is concurrently increased, and the significance and evidence for dual antibiotics are both insufficient. The guidelines also address the issue of warfarin combined with aspirin for prevention, which in terms of overall regression is associated with a greater risk of bleeding and no increased benefit. Both of these aspects are therefore listed as not recommended in the guideline. That is, in the secondary prevention of symptomatic PAD, the application of dual antibodies, or warfarin combined with aspirin, is not recommended.
3. Antithrombotic therapy for patients with intermittent claudication
IC is a category of symptomatic PAD, and the preferred treatment strategy is still antiplatelet medication for secondary prevention, with corresponding exercise training, and smoking cessation treatment, exercise capacity and endurance will often be improved. And for patients who still cannot improve intermittent claudication distance, evidence suggests that cilostazol 100 mg twice daily significantly improves quality of life as well as maximum claudication distance over placebo; however, for overall mortality, the use of cilostazol does not benefit.
For other clinically applied drugs, such as hexoketococine, heparin, prostaglandins, etc., there is no evidence in the literature to support an improvement in claudication distance in patients with IC. Therefore, in this section, the guidelines recommend the addition of cilostazol for IC receiving secondary prevention if exercise training and smoking cessation do not improve exercise capacity.
4. Antithrombotic therapy for severe lower extremity ischemia
Severe lower extremity ischemia is a serious condition that threatens limb survival, and such a group of patients often requires aggressive revascularization therapy. The pharmacological treatment after revascularization is described accordingly in the following sections. For patients who cannot undergo revascularization, pharmacological treatment, the guidelines state that the application of prostaglandins, which can relieve resting pain and promote ulcer healing; however, the application of such drugs does not reduce amputation rates or mortality. At the same time, this drug is poorly tolerated, and about 75% of patients have side effects, including: headache, nausea, vomiting, diarrhea, flushing, etc. Secondary prophylaxis for these patients is equally essential. This means that prostaglandin treatment is based on aggressive antiplatelet therapy.
5. Interventional treatment of symptomatic PAD
Revascularization therapy is needed for severe lower extremity ischemia, as well as for patients with refractory IC. Percutaneous transluminal angioplasty (with or without stent placement) is one of the popular treatment strategies, and with advances in transluminal intervention techniques, as well as advances in interventional devices, more and more patients are receiving this treatment strategy.
A Cochrane analysis cited in the guideline, which synthesized evidence from clinical trials, showed that: aspirin combined with pansentine treatment after intervention (with or without stent placement) was effective in reducing reocclusion rates compared with placebo; and no positive results were obtained when comparing the differences between antiplatelet agents and anticoagulants. One of the other trials, which included 179 individuals and compared the application of intravenous plain heparin and subcutaneous natriuretic heparin, respectively, for 1 week after the intervention, followed by continuous aspirin treatment, showed a reduction in restenosis and obstruction rates in the natriuretic heparin group (OR, 0.35; 95% CI,0.19-0.65); however, there was no difference in amputation rates (OR, 1.0; 95% CI,0.20- 5.10). Therefore, it remains controversial whether the guidelines suggest that stenting with antiplatelet therapy (aspirin 75-100 mg/d or clopidogrel 75 mg/d) in the first phase after PTA is superior to PTA alone. A recent Meta-analysis that included 10 RCT pilot studies showed that conventional stent implantation in femoral N artery lesions reduced the incidence of restenosis but was not necessary for target revascularization and did not improve overall regression. In fact, however, stenting is very common. There are no relevant experimental RCT studies on antithrombotic therapy after stent implantation and PTA alone. Therefore, experience with antithrombotic therapy after stent implantation is largely derived from studies of cardiac coronary stent implantation, and the evidence is indirectly supportive and the strength is not sufficient in PAD. Moreover, the diameter of the peripheral vasculature is much thicker than the diameter of the coronary arteries. Therefore, the guidelines recommend the administration of antiplatelet alone after stage I stent implantation. In contrast, dual antiplatelet therapy may be an option for patients with a higher risk of limb ischemia and good control of bleeding complications, but it is not listed as a recommended item in the guidelines.
6. Antithrombotic therapy after peripheral arterial bridging
Peripheral arterial bridging is another effective measure for the treatment of symptomatic PAD. A Cochrane analysis (including data from 6 RCTs) showed that aspirin + pansentine, compared with placebo, reduced the incidence of blockage by 22/1000; amputation by 34/1000; may reduce the incidence of non-fatal heart attacks; however, it did not reduce the incidence of non-fatal brain attacks; and increased the incidence of major bleeding by 8/1000. incidence of major bleeding. The effectiveness of aspirin and pentoxifylline was demonstrated.
In other experimental studies involving aspirin +/- pansentin vs. low molecular heparin, heparin, warfarin, indobufen, hexaconitine, prostaglandins, etc. The results showed no superiority over the underlying antiplatelet therapy. the CASPAR trial was about dual anti and single aspirin (clopidogrel + aspirin vs placebo + aspirin) and there was no clear difference in amputation rates, mortality and bleeding risk for patients with sub-knee bridges. Further subgroup analysis, however, showed that for bridging of artificial vascular material, dual antibodies were superior to monotherapy. In contrast, for autologous venous bridging vessels, there was no difference between the two. This is the basis for the recommendation in the guidelines for dual anti-treatment (clopidogrel 75mg/d + aspirin 75-100mg/d) after sub-knee artificial vessel bridging.
7. Antithrombotic therapy for acute arterial ischemia
Acute lower extremity ischemia is the sudden interruption of blood flow to the lower extremity, and the common cause is thrombosis or embolus embolism, in addition to trauma. Eighty percent of these peripheral arterial emboli come from the heart, and emboli may also come from the aorta, peripheral vasculature; or even the venous system (atrial defect, patent ductus arteriosus); thrombosis usually occurs on the basis of atherosclerosis, often with abundant collateral branches, and may pose relatively little threat to the limb. Therefore, once the diagnosis is established, systemic anticoagulation therapy should be initiated. In fact, however, there is no corresponding clinical evidence to support this, let alone a comparison between low molecular heparin and regular heparin. Therefore, although this practice is recommended in the guidelines, the grade is not high (2C).
Rapid revascularization is an important measure to relieve symptoms and preserve the limb, but there are also no relevant clinical studies comparing between open blood and simple anticoagulation, perhaps based on ethical issues. Therefore, like systemic anticoagulation, it is also a grade 2c recommendation, and aggressive open blood flow therapy is recommended.
Although catheter thrombolysis has many potential advantages in acute lower extremity ischemia, Meta-analysis showed that direct catheter thrombolysis had comparable outcomes to surgical opening, however, the risk was higher within 30 days of thrombolysis, including stroke and major bleeding. Also patients are evaluated more often and at higher overall cost. Therefore, in this guideline for acute lower extremity ischemia, surgical opening of the obstructed vessel is recommended as the first choice.
For patients who have opted for catheter thrombolysis, the guideline notes that the previous route of intravenous thrombolysis has been replaced by the current direct catheter thrombolysis. rt-PA has been shown in RCT studies to be more effective than streptokinase for thrombolysis, reducing amputation rates within 30 days and having comparable bleeding complications; however, streptokinase has problems with allergic reactions. In contrast, compared with urokinase, rt-PA was essentially equivalent in terms of amputation rate, limb survival, and bleeding complications. Thus, the guidelines recommend the application of rt-PA or urokinase.
8. Antithrombotic treatment of carotid stenosis
Carotid artery stenosis is a type of peripheral artery disease that can coexist with CAD and PAD. The literature reports a prevalence of about 0.2% in men under 50 years of age and 7.5% in those older than 80 years. Guidelines for the diagnosis and treatment of extracranial vascular lesions are available in the Journal of Stroke. In this section, the main topics covered include antithrombotic therapy for asymptomatic carotid stenosis, antithrombotic therapy for symptomatic carotid stenosis, and antithrombotic treatment strategies after carotid endarterectomy.
For asymptomatic carotid stenosis, as for asymptomatic PAD, primary prophylaxis is administered according to risk factor stratification for good control of vascular events.
For symptomatic carotid stenosis, secondary prophylaxis is recommended, namely long-term antiplatelet therapy with clopidogrel, cerebroconfin (Aggrenox, extended-release dipyridamole 200 mg plus low-dose aspirin 25 mg), or single aspirin, although the first two are more effective than single aspirin.
For post carotid endarterectomy, the principle of treatment is secondary prevention. At present, there is not much evidence to study when antithrombotic therapy should be given and for how long it should be maintained? However, there is a clear advantage of antithrombotic therapy compared to no antiplatelet therapy; also studies have shown that small doses of aspirin are as effective as large doses and have lower bleeding complications.
With guidelines on.
1. For patients with asymptomatic PAD, we recommend aspirin 75-00 mg/d (Grade 2B).
2. For symptomatic PAD, secondary prevention, we recommend aspirin 75-00mg/d or clopidogrel 75mg/d. (both Grade 1A); we do not recommend the combination of aspirin and clopidogrel (Grade 2B); we do not recommend the combination of antiplatelet and warfarin (Grade 1B).
3. for patients with intermittent claudication who have failed to respond to exercise therapy and smoking cessation, we recommend cilostazol combined with basic antithrombotic therapy (aspirin 75-100 mg/d, or clopidogrel 75 mg/d (Grade 2C); we do not recommend the application of hexaconitine, heparin, or prostaglandin drugs (Grade 2C).
4. For patients with symptomatic PAD and severe lower extremity ischemia that cannot be revascularized, we recommend the application of prostaglandin analogs combined with basic antiplatelet therapy (aspirin 75-100 mg/d, or clopidogrel 75 mg/d (Grade 2C).
5. For acute lower extremity ischemia, we recommend immediate systemic heparin anticoagulation (Grade 2C); we recommend flow-opening therapy (surgery or intra-arterial thrombolysis) (Grade2C); we recommend surgery over intra-arterial thrombolysis (Grade1B); and for the choice of intra-arterial thrombolytic agents, we recommend rt-PA, or urokinase ( Grade2C).
6. for patients after PTA, we recommend long-term aspirin 75-100 mg/day or clopidogrel 75 mg/day (Grade1A); for patients with PAD with stenting in stage I, we recommend single antiplatelet therapy (Grade2C).
7. For patients after peripheral vascular bridging, we recommend long-term aspirin 75-100 mg/day or clopidogrel 75 mg/day (Grade 1A); we recommend single antiplatelet therapy rather than antiplatelet combined with warfarin (Grade 1B); for subknee bridging, we recommend dual anti-treatment (aspirin 75-100 mg/d+ clopidogrel 75 mg/d (Grade 2C); for other patients, single antiplatelet therapy is recommended (Grade 2B).
8. for asymptomatic carotid stenosis, aspirin 75-100 mg/d is recommended (Grade 2B)
9. For symptomatic carotid stenosis (including after carotid endarterectomy), long-term antiplatelet therapy with clopidogrel 75mg/d, cerebrospin 25mg/200mg bid, or aspirin 75-100mg/d (Grade1A) is recommended; moreover, clopidogrel and cerebrospin are superior to aspirin (Grade2B).