Atherosclerosis is the main cause of PAD, and the modifiable risk factors are not different from patients with coronary artery disease. The treatment of LE-PAD aims to reduce CV morbidity and mortality, as well as improve quality of life by decreasing symptoms of claudication, eliminating rest pain and preserving limb viability
[12]. Therapeutic considerations therefore include the aggressive modification of risk factors by modifications in lifestyle and the use of pharmacologic therapy to reduce the risk of adverse CV events such as MI, stroke and death, as well as to decrease limb morbidity.
5.1. Lifestyle Modifications
Lifestyle modifications include healthy diet, weight loss, regular physical exercise and smoking cessation
[27]. Adherence to a healthy diet is associated with a lower incidence of clinical PAD; The Mediterranean diet was associated with a reduced risk of PAD
[37]. Physical activity, especially low- to moderate-intensity aerobic exercise, is associated with a decrease in CV mortality, as well as the risk of developing CV disease
[38]. Moreover, supervised exercise therapy is an effective strategy to reduce claudication symptoms and improve functional outcomes and is recommended for the treatment of symptomatic LE-PAD
[39]. Tobacco exposure, through cigarette smoking, is strongly associated with the development and progression of LE-PAD and its complications
[40]. Smoking cessation is associated with a decreased risk of major adverse cardiac events (MACEs) and major adverse limb events (MALEs)
[41]. Further, patients who stop smoking have improved walking ability and decreased claudication symptoms
[42]. The management of smoking cessation includes behavioral counseling and pharmacological therapy including nicotine replacement therapy, bupropion and varenicline.
5.2. Treatment of Diabetes Mellitus
Diabetes mellitus (DM) is one of the strongest predictors for PAD. Patients with DM have an approximately two-fold increased risk of all-cause mortality than those without diabetes
[43]. Moreover, DM is associated with an increased risk of amputation in LE-PAD patients
[44]. The aggressive treatment of DM decreases the risk of microangiopathic events, but most classes of glucose-lowering drugs have not shown a reduction in macrovascular events. The data to support glycemic control to improve outcomes in patients with PAD and DM are conflicting. The long-term follow-up of the UKPDS (United Kingdom Prospective Diabetes Study) of patients with type 2 DM found that intensive treatment was associated with a 15% reduction in MI, suggesting a positive glycemic legacy in patients with newly diagnosed DM and without prior CV events
[45]. Other studies based on an intensive glucose-lowering strategy demonstrated no benefit for MACE reduction
[46][47]. Newer diabetes therapies have demonstrated large benefits for patients with DM that cannot be explained by glycemic control alone. There is now growing evidence to support the use of sodium–glucose cotransporter inhibitors (SGLT-2is) in patients with PAD and diabetes
[48]. The EMPA-REG OUTCOME trial demonstrated that empaglifozin reduced the risk of CV death, hospitalizations for heart failure and the progression of renal disease with no observed increase in the risk of lower limb amputation in patients with PAD
[49]. A secondary analysis from the DECLARE-TIMI 58 trial demonstrated that dapaglifozin reduced the risk of CV death, hospital admissions for heart failure and the progression of kidney disease with no significant differences in any limb outcome versus the placebo in patients with PAD
[50]. Instead, in the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin was associated with an increased risk of lower limb amputation
[51]. However, this result was not confirmed in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial
[52].
In addition, glucagon-like peptide 1 receptor agonists (GLP-1RAs), due to their pleiotropic effects, are emerging drugs in the treatment of diabetes to reduce the CV risk
[53]. In a post hoc analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the treatment with liraglutide in patients with type 2 diabetes and a high risk of CV events was associated with a significantly lower risk of amputations compared with the placebo
[54]. In a recent observational study, the use of GLP-1RAs was associated with significantly lower risks of MALEs when compared with the use of dipeptidyl peptidase 4 inhibitors (DPP4is). The risk reduction was driven largely by a reduced rate of amputations. Moreover, the treatment with GLP-1RAs was also associated with lower risks of CV death, nonfatal stroke, nonfatal MI and death from any cause
[55]. Two recent meta-analyses demonstrated a lower incidence of lower limb amputations in patients receiving GLP-1RAs in comparison with patients receiving SGLT-2is
[56][57]. In contrast, a meta-analysis comparing the impact of GLP1-RAs and DPP4is versus SGLT-2is showed the incretin-based therapies had a 10% higher risk of lower limb amputation compared to the SGLT-2i group
[58]. Further randomized controlled trials are needed to assess the impact of these antidiabetic drugs on lower-limb-related events.
ESC guidelines recommend SGLT2 inhibitors and GLP-1RAs in patients with type 2 diabetes mellitus and CV disease or a very high/high CV risk to reduce CV events (Class I A). An HbA1c of <7.0% (<53 mmol/mol) is recommended to decrease microvascular complications in individuals with diabetes (Class I A), while the same target should be considered for the prevention of macrovascular complications (Class IIa C)
[59].
5.3. Treatment of Hypertension
Hypertension is a common and important risk factor for PAD. An analysis of 4.2 million relatively healthy adults showed that a 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease
[60].
Diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can be used to treat high blood pressure, as a monotherapy or in different combinations
[61]. The Heart Outcomes Prevention Trial (HOPE) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) have shown that ACEIs and ARBs significantly reduce CV events in patients with PAD
[62][63]. Moreover, ACEIs improved walking ability in patients with intermittent claudication
[64] and are associated with improved amputation-free survival in patients undergoing peripheral vascular intervention for chronic limb-threatening ischemia
[65]. Since beta-blockers have not been shown to worsen the symptoms of claudication
[66], they remain a treatment option in hypertensive patients with LE-PAD. ESC guidelines recommend that ACEIs and ARBs should be considered as the first-line therapy in patients with PAD and hypertension (Class IIa B), with a primary goal of a blood pressure less than 140/90 mmHg (Class I A)
[12] and with specific targets according to the risk factors and associated diseases
[61].
5.4. Lipid-Lowering Treatment
Dyslipidemia is a key pathogenic factor predisposing to atherosclerosis. Patients with PAD, according to the levels of CV risk proposed by guidelines, should be considered to have a very high CV risk, such as patients with previous acute coronary syndrome. Therefore, in the secondary prevention for patients with very high risk, an LDL-C reduction of ≥50% from the baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are recommended
[67]. Different drugs for the treatment of dyslipidemia are available, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab and evolocumab), PCSK9 synthesis inhibitor (inclisiran) and adenosine triphosphate–citrate lyase inhibitor (bempedoic acid)
[68]. Statins represent the first-line treatment and their efficacy in PAD patients, derived from the UK Heart Protection study, was demonstrated in the efficacy of a therapy with 40 mg simvastatin in reducing the incidence of MACEs by 22% compared with the placebo and reducing the risk of the first acute peripheral vascular event (noncoronary revascularization, major amputation, aneurysm repair or death due to PAD) by 16%
[69]. In a recent meta-analysis including 138,060 patients with PAD, the use of statins was associated with a 30% reduction in MALEs and a 35% reduction in amputations. The statin group also had a lower risk of all-cause mortality, CV death, composite CV endpoints and ischemic stroke
[70]. The addition of ezetimibe to statins was associated with an 8% relative risk reduction in CV death, major coronary events and stroke compared to statins alone in patients with acute coronary syndrome
[71], and this benefit was also confirmed in patients with concomitant polyvascular disease
[72]. Confirming the benefit of treatments that reduce plasma LDL levels, the FOURIER trial showed that evolocumab significantly reduced the risk of CV death, MI, stroke and hospitalization for unstable angina or coronary revascularization by 15% and reduced the risk of MALEs by 37%
[73]. Moreover, alirocumab in the ODYSSEY OUTCOMES trial reduced the risk of death related to CAD, nonfatal MI, ischemic stroke or hospitalization for unstable angina by 15% and reduced the risk of PAD events by 31%
[74]. Despite the promising results in patients with high CV risk
[75][76], the effects of inclisiran and bempedoic acid in PAD remain to be explored.
5.5. Antithrombotic Treatment
Antiplatelet therapy remains a key intervention to reduce CV risk in PAD. Antithrombotic treatment is different according to the symptomatic status, history of revascularization and type of revascularization
[12].
In
asymptomatic patients with a low ABI but without clinical limb symptoms or previous vascular intervention, although at an increased risk of MACEs and MALEs, antiplatelet therapy is not recommended
[77][78].
In
symptomatic patients with intermittent claudication and without previous vascular intervention, antiplatelet drugs improve CV prognosis; therefore, ESC guidelines recommend long-term single antiplatelet therapy, preferring clopidogrel to aspirin
[12]. The CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events) demonstrated that patients randomized to 75 mg of clopidogrel daily had a significant reduction in MACEs compared with patients randomized to 325 mg of aspirin
[79]. Single-antiplatelet therapy with ticagrelor and dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel provided no benefit in this group of patients
[80][81]. A consensus document from the ESC working group on aorta and peripheral disease included recommendations about low-dose rivaroxaban, an oral inhibitor of Xa factor, for patients with a low bleeding risk
[82]. The COMPASS trial showed that dual-pathway inhibition (DPI) with low-dose rivaroxaban (2.5 mg twice daily) in addition to 100 mg of aspirin daily reduced the risk of MACEs and MALEs compared with aspirin alone in patients with LE-PAD or significant carotid artery disease, as well as in those with symptomatic LE-PAD. However, the DPI regimen was associated with an increased risk of major bleeding, without increasing the risk for fatal or intracranial bleeding
[83].
In patients undergoing endovascular revascularization, guidelines recommend DAPT with aspirin and clopidogrel for at least one month
[12]; however, the choice, dose and duration of antithrombotic drug therapy in relation to endovascular procedures is unclear. In the MIRROR study (Management of Peripheral Arterial Interventions with Mono- or Dual-Antiplatelet Therapy), patients with LE-PAD after endovascular interventions were randomized to receive either aspirin or aspirin and clopidogrel for 6 months. At 6 months, there was a significant reduction in the need for target lesion revascularization (TLR) in the DAPT group compared to the aspirin monotherapy. All patients discontinued clopidogrel at 6 months and continued aspirin monotherapy per the study protocol. At 12 months, similar TLR rates were observed in patients who had received the DAPT or aspirin monotherapy
[84].
In patients undergoing open revascularization, guidelines recommend single-antiplatelet therapy, but there is no robust evidence for which antithrombotic strategy is most effective to maintain vein graft patency
[12]. Anticoagulation with vitamin K antagonists is recommended in patients who receive infrainguinal bypass using an autologous vein conduit with high-risk features, including poor quality conduit, long conduit, disadvantaged distal runoff or previous failed open revascularization
[85]. The CASPAR trial showed no benefit of DAPT over single-antiplatelet therapy in patients undergoing below-knee bypass grafts, but in a subgroup analysis, DAPT conferred benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk
[86].
The consensus document of the ESC working group on aorta and peripheral disease also included recommendations regarding DPI in patients undergoing revascularization
[82]. The VOYAGER PAD trial randomized patients after endovascular or open revascularization to a combination therapy of rivaroxaban (2.5 mg twice daily) and aspirin or aspirin alone, with the possibility to add clopidogrel up to a maximum of 6 months at the treating physicians’ discretion. Compared with aspirin alone, the combination of rivaroxaban and aspirin reduced the composite endpoint of MACEs and MALEs, largely driven by a significant reduction in acute limb ischemia. Although there was no significant difference in the primary safety outcome of Thrombolysis in Myocardial Infarction (TIMI) major bleeding, the secondary safety outcome of the International Society on Thrombosis and Haemostasis major bleeding was increased, albeit without significant increases in intracranial or fatal bleeding. Approximately one-half of the VOYAGER trial participants were given clopidogrel. The mean duration of clopidogrel use was 30 days, and the use of concomitant clopidogrel after revascularization did not alter the efficacy of DPI compared with aspirin alone in reducing MACEs or MALEs
[87]. However, in those with longer courses of clopidogrel, there was a trend toward increased major bleeding
[88].