Brief Reports

Effect of Simvastatin on Ischemic Signs and Symptoms in the Scandinavian Simvastatin Survival Study (4S)☆

To test the hypothesis that in patients with peripheral arterial disease (PAD) and claudication, treated with maximal tolerated statin therapy, the addition of a monthly subcutaneous injection of evolocumab for 6 months improves treadmill walking performance.

Lipid lowering therapy improves walking parameters in patients with PAD and claudication. Evolocumab decreases cardiac and limb adverse events in patients with PAD; however, the effect of evolocumab on walking performance is not known.

We performed a double-blind, randomized, placebo-controlled study to compare maximal walking time (MWT) and pain free walking time (PFWT) in patients with PAD and claudication treated with monthly subcutaneous injections of evolocumab 420 mg (n = 35) or placebo (n = 35). We also performed measurements of lower limb perfusion, brachial flow mediated dilatation (FMD), carotid intima media thickness (IMT), and serum biomarkers of PAD disease severity.

After six-months of treatment with evolocumab MWT increased by 37.7 % (87.5 ± 24 s) compared to 1.4 % (−21.7 ± 22.9 s) in the placebo group, p = 0.01. PFWT increased by 55.3 % (67.3 ± 21.2 s) in the evolocumab group compared to 20.3 % (8.5 ± 20.3 s) in the placebo group, p = 0.051. There was no difference in lower extremity arterial perfusion measurements. FMD increased by 42.0 ± 73.9 % (1.01 ± 0.7 %) in the evolocumab group and decreased by 16.29 ± 20.06 % (0.99 ± 0.68 %) in the placebo group (p < 0.001). IMT decreased by 7.16 ± 4.6 % (0.06 ± 0.04 mm) in the evolocumab group and increased by 6.68 ± 4.9 % (0.05 ± 0.03 mm) in the placebo group, (p < 0.001).

The addition of evolocumab to maximal tolerated statin therapy improves maximal walking time in patients with PAD and claudication, increases FMD, and decreases IMT.

Peripheral arterial disease (PAD) impairs quality of life by causing lower extremity intermittent claudication, rest pain, or amputation. Evolocumab is a monthly injectable monoclonal antibody medication that reduces cholesterol. In this study, we randomly treated patients with PAD and claudication, and on background statin therapy, with evolocumab or placebo, and found that evolocumab improves walking performance on a treadmill test by increasing maximal walking time. We also found that evolocumab decreases plasma MRP-14 levels, a marker of PAD severity.

The previously published 2017 Taiwan Lipid Guidelines for High Risk Patients becomes the standard guidance of dyslipidemia management for patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan. New clinical trials of lipid lowering therapy were published successively after 2017. The study results changed the treatment concept of ASCVD. Therefore, an update focusing on the lipid treatment strategy for patients with ASCVD becomes necessary. In this focused update of the 2017 guideline, the treatment targets of low-density lipoprotein cholesterol (LDL-C) for patients with ASCVD were modified. The algorithm of LDL-C lowering therapy was revised. The recommendations in this focused update were made mainly based on the scientific evidence from recently published clinical trials and endorsed by the major medical societies in Taiwan.

Peripheral artery disease (PAD) is a morbid and costly disease that can result in loss of limb and life if not managed appropriately with risk factor modification, antithrombotic therapy, and revascularization when necessary. Antithrombotic therapy includes antiplatelet and anticoagulant drugs. Antiplatelet agents used in PAD can include aspirin, reversible and irreversible P2Y12 inhibitors, and PAR-1 antagonists. These drugs are prescribed as both monotherapy or dual-antiplatelet therapy and are critical components of pre- and post-revascularization maintenance. Anticoagulants, such as vitamin K antagonists and heparin products, have long been used in cardiac disease; in patients with PAD, these drugs have been largely supplanted by new direct factor Xa antagonists, which offer superior safety profiles and reduced adverse events after revascularization. Anticoagulants are often used alongside antiplatelet medications after PAD revascularization; however, there is a lack of guideline consensus about therapy selection and large regional disparity in regard to antithrombotic prescribing patterns. In this review, we analyze the existing literature and guidelines regarding the use of antithrombotic therapy in patients with PAD and offer a framework to aid clinicians’ decision making regarding therapy selection and duration based on current existing evidence.

Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and <1.4 mmol/L (<55 mg/dL) in PAD patients. As demonstrated by randomized controlled trials, lowering LDL-C not only reduces cardiovascular events but also major adverse limb events (MALE), including amputations, of the order of 25%. Addition of ezetimibe or a PCSK9 inhibitor further decreases the risk of cardiovascular events, and PCSK9 inhibition has also been associated with reduction in the risk of MALE by up to 40%. Furthermore, statin-based treatment improved walking performance, including maximum walking distance, and pain-free walking distance and duration. This Task Force recommends strategies for managing statin-associated muscle symptoms to ensure that PAD patients benefit from lipid-lowering therapy. Antiplatelet therapy, either daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2 × 2.5 mg) is also indicated to prevent cardiovascular events. Dual antiplatelet therapy (aspirin and rivaroxaban) may be considered following revascularization, taking into account bleeding risk. This Joint Task Force believes that adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality in patients with PAD.

Atherosclerosis is a systemic disease with different faces. Despite identical or similar pathogenetic mechanisms, atherosclerotic lesions and their clinical manifestations vary in different parts of the vascular system. Peripheral arterial disease (PAD) represents one of the most frequent clinical manifestations of atherosclerosis with predominant location in the superficial femoral artery (SFA). Morphological characteristics of atherosclerotic plaques in peripheral arteries differ from lesions in the coronary and carotid arteries. Plaques in SFA have more fibrotic components, less lipids and inflammatory cells, which makes them more stable and less prone to rupture. Factors that determine the different structure of plaques in SFA compared to coronary arteries include hemodynamic forces, vasa vasorum and calcification. Low shear stress in SFA in the adductor canal is one of the factors which determines frequent atherosclerotic lesions in this region. Lower lipid content and fewer inflammatory cells explain higher stability of SFA plaques. The specific structure of SFA plaques may require preventive and therapeutic measures, which to some extent differ from prevention of coronary atherosclerosis and may include inhibition of fibrotic proliferation in SFA plaques and calcification. Revascularization of PAD differs from procedures used in coronary arteries and requires specific technical expertise and devices.