Peripheral arterial disease (PAD) is broadly defined as arteries other than the heart and brain vessels, which comprise the largest single “organ system” in the body. The prevalence of PAD is increasing as our population ages, and is estimated to be four times higher than that of coronary artery disease, and patients with PAD have a significantly increased risk of amputation and cardiovascular events, making it one of the most important causes of death and disability in the elderly.
In fact, both are affected by the same atherosclerotic disease process and commonly coexist. It should be recognized that cardiovascular health is no longer limited to the coronary arteries (coronary arteries), and that the treatment of PAD is equally important.Treatment measures for PAD include lifestyle/risk factor interventions, pharmacotherapy, and surgical treatment. Pharmacotherapy plays an important role in the management of PAD.
I. Treatment goals of PAD
The prevalence of cardiovascular disease and mortality in patients with PAD is much higher than that in the general population. Since PAD is a common manifestation of systemic atherosclerosis, the treatment goals are not only to maintain the function of the affected limb, reduce or eliminate symptoms, and prevent disease progression, but also to reduce the risk of cardiovascular and cerebrovascular events. Treatment measures include conservative treatment, percutaneous intervention and surgical procedures.
In terms of conservative treatment, all patients with PAD need to make every effort to correct risk factors that may lead to vascular obstruction in order to slow the progression of the disease. A combination of therapeutic modalities is required, including changes in lifestyle habits, dietary and exercise interventions. The necessary medications should be administered. For patients with worsening intermittent claudication or severe limb ischemia, hemodynamic reconstruction should be considered.
Lifestyle/risk factor interventions
Smoking cessation: Smoking is the most important risk factor in the development of atherosclerotic PAD, which not only increases the risk of developing PAD, but also reduces the success rate of surgical treatment and increases the risk of amputation. Therefore, many guidelines recommend that patients with PAD quit smoking.
2, control hyperglycemia: Although studies conducted in diabetic patients have not confirmed that aggressive glycemic control can reduce the risk of PAD, given the important role of hyperglycemia in atherosclerotic scar, patients with PAD should control blood glucose in the normal range as much as possible. Currently, guidelines use glycosylated hemoglobin (HbAlc) <7% as the glycemic control goal. PAD patients with combined diabetic neuropathy need to pay special attention to maintain hhale in the normal range.
3, lipid regulation: dyslipidemia is an important risk factor for the development of PAD. Statins can regulate blood lipids and anti-atherosclerosis, and long-term adherence to statins can benefit PAD patients. Cardioprotection studies have shown that daily simvastatin 40mg in PAD patients can reduce cardiovascular mortality by 17% and non-coronary revascularization requirements by 16%. Guidelines recommend that patients with PAD with LDL-C ≤ 2.6 mmol/L ( 100mg/dl) receive statin therapy if dietary exercise interventions do not bring lipids to standard.
4. Anti-hypertension: Hypertension is an important risk factor for PAD. Strict blood pressure control can reduce the risk of PAD by 50%; however, it is not clear whether antihypertensive treatment can slow down the progression of PAD. It is generally believed that patients with PAD combined with hypertension should receive antihypertensive therapy to reduce the risk of cardiovascular and cerebrovascular events. Blood flow to the affected limb may decrease during the process of blood pressure lowering, which is tolerated by most patients, but a few patients with severe ischemia may experience a further decrease in blood flow, leading to worsening of symptoms, so patients with severe disease need to consider this possibility when lowering blood pressure and avoid excessive lowering of blood pressure.
5. Aerobic walking: The efficacy of appropriate walking exercise in patients with PAD has been widely recognized, not only for increasing pain-free walking distance, but also for reducing cardiovascular and cerebrovascular disease-related deaths. a Cochrane analysis showed that walking exercise two or more times per week improved walking distance in patients with intermittent claudication. Considering the benefits of walking exercise, patients with intermittent claudication should engage in planned walking exercise. If exercise can be sustained while controlling cardiovascular risk factors, the risk of cardiovascular events can be further reduced and the prognosis improved.
Third, drug treatment
1.Anti-platelet therapy: Anti-platelet therapy can reduce the risk of death from cardiovascular and cerebrovascular diseases in patients with PAD. The principle is to inhibit the excessive activation of platelets during atherosclerosis, thus preventing thrombus formation at plaque sites. A meta-analysis showed that the use of aspirin reduced cardiovascular events by 23% in patients with PAD. An ischemic events study comparing the efficacy of aspirin and clopidogrel and analyzing the PAD subgroup found that clopidogrel resulted in a 24% relative reduction in cardiovascular events. Dual antiplatelet therapy is not recommended for long-term use in patients with PAD because it may increase the risk of bleeding.
2. Anticoagulation therapy: For patients with PAD who have a history of cardiac thrombosis leading to peripheral arterial embolism or a history of peripheral arterial thrombotic disease, anticoagulation therapy may be administered to prevent recurrence of cardiac or peripheral arterial thrombosis. However, some studies have shown that in the PAD population, warfarin anticoagulation does not reduce the risk of ischemic cardiovascular and cerebrovascular events in patients with PAD when compared with oral aspirin.
3, pharmacological treatment of claudication: There are several drugs used for the treatment of claudication, such as cilostazol, prostaglandins, and hexoketococine. Cilostazol inhibits phosphodiesterase activity in platelets and vascular smooth muscle, thus increasing the concentration of cAMP in platelets and smooth muscle and exerting an anti-platelet and vasodilatory effect. It is used in patients with intermittent claudication to improve symptoms and increase walking distance.
The most common side effects of oral cilostazol are headache, diarrhea, abnormal stools, palpitations and dizziness. Prostaglandin E1 (PGE1) acts on vascular smooth muscle cells and dilates blood vessels. In addition, PGE1 inhibits platelet aggregation by stabilizing the platelet cell membrane, preventing the release of lysosomal enzymes, and affecting the platelet surface charge. Beraprost, a prostacyclin analogue, also has vasodilating and antiplatelet effects and improves symptoms such as ulceration, intermittent claudication, pain and coldness caused by PAD.
The side effects of PGE1-like agents include occasional allergy, headache, and gastrointestinal reactions. Hexaconitine reduces blood viscosity and fibrinogen levels and has an antiplatelet effect, but the clinical effect of treating claudication is not clear. Side effects include sore throat, indigestion, nausea and diarrhea. Sagrelide is a specific antagonist of 5-hydroxytryptamine 2 (5-HT2) receptor, which inhibits platelet aggregation, vasoconstriction and vascular smooth muscle proliferation by inhibiting 5-HT2 receptors. Some studies have demonstrated that sargrete can improve the symptoms of the affected limb in patients. Some studies have also used the thrombin inhibitors argatroban and oxalate nafuro in the treatment of PAD, but the effect is not yet certain.
Reconstruction of blood flow
Hemodynamic reconstruction is suitable for patients with severe intermittent claudication affecting quality of life, ineffective drug therapy, associated with resting pain, skin ulcers and gangrene.
There are two methods of revascularization: endovascular intervention and surgical treatment, each with its own advantages and disadvantages, which can be reasonably selected according to the Trans-Atlantic Peripheral Artery Consensus (TASC II) staging. Since TASC II staging has an impact on the long-term patency rate of pure percutaneous transluminal angioplasty (PTA)/stenting, the long-term patency rate of type A/B is better than that of type C/D. Therefore, surgical treatment should still be considered for some complex lesions of type C/D. Recently, it has been recommended to relax the indications, and most lesions of type C/D can be considered for percutaneous intervention first.
The TASC II staging criteria are for clinicians’ reference only, and patient-specific conditions and operator experience should be fully considered when selecting treatment modalities. Perioperative medication is essential, and all patients with PAD undergoing revascularization should receive anticoagulation and/or antiplatelet therapy, with careful monitoring of bleeding risk.
V. Other treatment methods
In recent years, new treatments such as stem cell therapy and gene therapy have been introduced, but their efficacy is still controversial and large randomized controlled studies are needed to confirm their efficacy.
VI. Outlook
Clinicians are now beginning to focus on the increasing incidence of arterial disease outside of the coronary arteries and its disabling effects, as well as on PAD and its associated management measures. Available treatment options are also expanding. A number of novel agents currently under development may be effective in the treatment of intermittent claudication. Percutaneous interventional approaches will become more effective and safe in the future and will play an important role in the treatment of PAD. The possibility of introducing vascular regeneration factors to induce vascular regeneration in patients whose limbs have previously had to be amputated because of the failure to survive using traditional revascularization methods offers new hope for saving the affected limb.