In alignment with current guidelines, ^, threshold decision-making should incorporate a structured assessment of patients’ motivation and readiness for lifestyle change before considering invasive therapy. This includes a stepwise care pathway in which supervised exercise therapy is the first-line intervention for intermittent claudication, reserving revascularization for individuals who have persistent functional limitation despite adequate exercise therapy, symptom modifying agents (eg, cilostazol), medical optimization. In patients with CLTI, revascularization to prevent progression of tissue loss and amputation should be leveraged as an opportunity to engage patients in escalation of medical therapy and modification of risk factors. Guidelines further recommend ensuring that optimal secondary prevention (including antithrombotic therapy, lipid lowering, blood pressure control, glycemic management, smoking cessation, and vaccination). ^, While all secondary prevention decisions should be evaluated and discussed, individual patients often have a clear opportunity for intensification in 1 to 2 risk areas that can be optimized before or alongside any invasive treatment. These elements reinforce the need to view LER as part of a comprehensive longitudinal management strategy rather than a standalone intervention. The decision to perform intervention on patients with LE PAD should prompt all clinicians to lower the threshold for routine medical decision-making due to the enhanced risk profile, and it is a clear opportunity to escalate the intensity of secondary prevention strategies.

Numerous lipid measures have been associated with the development and progression of LE PAD, including elevated triglycerides, lower high-density lipoprotein cholesterol and higher low-density lipoprotein (LDL) cholesterol. ^,, Among patients with LE PAD, current guidelines recommend a ≥ 50% reduction in LDL cholesterol with a target of <70 mg/dL. Current guidelines do not suggest different targets or treatment algorithms for individuals with LE PAD who have undergone peripheral revascularization. ^, When parallels are drawn from the setting of coronary atherosclerosis, there is a linear reduction in adverse cardiovascular events with LDL cholesterol. This has led the European Society of Cardiology to provide a Class I recommendation for an LDL cholesterol treatment goal of <55 mg/dL for very high-risk patients. This population includes those that have documented atherosclerotic cardiovascular disease, which includes either clinical or imaging evidence of PAD. In the PAD population, this is supported by evidence of a consistent relationship between lower LDL cholesterol and lower risk of limb events that extends down to <10 mg/dL. Based on this evidence, it may be reasonable to attempt to achieve lower LDL cholesterol targets in patients with PAD, especially those who have undergone peripheral revascularization who represent a higher-risk population.

As there have not been dedicated lipid lowering trials in an isolated PAD population, the majority of these recommendations are extrapolated from broader atherosclerotic populations. This may contribute to the observation that lipid lowering therapies are underutilized in PAD, with the use of any lipid lowering agent ranging from 34% to 72%. ^,,,, Among those prescribed a statin, nonadherence has also been identified as a barrier with a cumulative incidence of nonadherence of 28%. As a consequence, LDL cholesterol targets are infrequently (27%-50%) reached among individuals with LE PAD undergoing revascularization. ^, This is despite strong evidence that statin therapy and adherence to statin therapy is associated with significantly reduced risk of cardiovascular morbidity ^,, and a reduction in limb events has also been observed in observational studies. ^, While the rates of statin prescription in the United States among those undergoing revascularization procedures has improved over the past decade (87% in 2019), only 33% of those not on baseline statin are prescribed one at the time of discharge. The de novo use of statin therapy among individuals with established LE PAD who have undergone peripheral revascularization is safe and associated with similar benefits to other PAD populations.

Using subgroups of large clinical trials, several other oral lipid lowering therapies have been examined in the LE PAD population. However, no studies have examined the utility of these agents in the post LER period ( Table ). In a posthoc analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), participants who had experienced a recent acute coronary syndrome (<10 days) and had a baseline history of LE PAD (n = 1,005) demonstrated a reduction in the composite of worsening symptoms and critical limb ischemia when randomized to treatment with simvastatin + ezetimibe compared to simvastatin alone (RR 0.77; 95% CI 0.62-0.96). In the Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial (REDUCE-IT) trial, participants with known cardiovascular disease or had diabetes with additional risk factors were randomized to either icosapent ethyl or placebo. In a subset of 688 participants had a history of LE PAD, icosapent ethyl was associated with an absolute risk reduction of 6.6% for the composite outcome of time to cardiovascular death, myocardial infarction, stroke, coronary revascularization or unstable angina, which was similar to participants without LE PAD. Of note, the comparator arm of the REDUCE-IT trial used a placebo mineral oil. The placebo mineral oil arm of the trial was subsequently found to elevated inflammatory biomarkers, which has raised concerns as to whether the observed benefits of the trial was due to the benefits of icosapent ethyl or the harms of the mineral oil placebo.

In the cholesterol lowering via bempedoic acid, an ACL-inhibiting regimen (CLEAR) Outcomes trial, bempedoic acid was evaluated against placebo in statin intolerance participants who had a history of, or were high risk of, cardiovascular disease. Among the 1,624 participants with a history of baseline LE PAD, bempedoic acid was associated with an absolute risk reduction of major limb events of 2.5%.

Both monoclonal antibodies to proprotein convertase subtilisin-kexin type 9 (PCSK9) and inclisiran, a small interfering RNA to the precursor to PCSK9, represent promising therapeutic avenues for this population. In the further cardiovascular outcomes research with PCSK9 inhibition in subjections with elevated risk (FOURIER) trial, 13% (n = 3,642) had a history of LE PAD (claudication with ABI < 0.85 or prior revascularization). When compared to placebo, evolocumab significantly reduced the composite risk of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization with an absolute risk reduction of 3.5%, which was more than double the benefit observed in the absence of LE PAD (absolute risk reduction 1.6%). In addition, evolocumab reduced the risk of major limb events by 42%. The Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome (ODYSSEY OUTCOMES) trial provides further data highlighting that after an acute coronary syndrome, treatment with alirocumab was associated with a reduction in limb events (Hazard Ratio 0.69; 95% CI 0.54-0.89). In both the ODYSSEY OUTCOMES and further cardiovascular outcomes research with PCSK9 inhibition in subjections with elevated risk trial, individuals with an elevated Lp(a) and LE PAD derived the greatest benefit from PCSK9 inhibition. ^,

Inclisiran inhibits hepatic production by binding to the mRNA precursor of PCSK9 and has demonstrated similar lipid lowering and cardiovascular benefits in both patients with established atherosclerotic cardiovascular disease or equivalent. Ongoing clinical trials are studying the use of inclisiran in patients with atherosclerotic cardiovascular disease, including LE PAD. This includes the upcoming VictORION—INTERVENTION trial, a planned randomized controlled trial that will aim to provide definitive evidence regarding the utility of inclisiran at reducing cardiovascular events in the LE-PAD population. The trial aims to randomize 6,000 participants undergoing either coronary or peripheral revascularization to inclisiran therapy or placebo and will assess the treatment effect on both major adverse cardiovascular and limb events. There is a specific need to evaluate the use of these therapies in the postintervention period, where there is a paucity of data to guide treatment decision making.

Studies in the diabetic population have raised the possibility that triglyceride lowering medications, such as fibrates, may be associated with a reduction in a lower risk of amputations. ^, However, there is no robust evidence to support the use of fibrates among patients with LE PAD and are not recommended in current guidelines. ^,

Despite the strong rationale for intensive lipid lowering in PAD, therapeutic inertia and nonadherence reflect barriers that extend beyond the absence of PAD-specific trial evidence. A growing body of work highlights patient-level beliefs and perceptions as major determinants of treatment uptake. Previous work has highlighted that elegantly in the SAMSON trial, where participants crossed over between no treatment, placebo and statin therapy. They demonstrated that the vast majority of “statin-associated” symptoms were similar in both the statin and placebo exposure periods, underscoring the influence of the nocebo effect on perceived intolerance and subsequent discontinuation. Similarly, prior work has illustrated that many patients rely on information from social networks or online sources, possess limited awareness of PAD as a high-risk condition, and often receive insufficient explanation about their prescribed medications, all of which contribute to early cessation or reluctance to initiate statin therapy. Additionally, nearly one-third of patients with PAD are unaware of the indication for their cardiovascular medications, emphasizing persistent communication gaps in routine care. Collectively, these findings suggest that improving lipid-lowering therapy use in PAD will require strategies that address not only evidence dissemination, but also patient education, expectation setting, and shared decision-making to mitigate misconceptions and enhance long-term adherence.

While the use of aspirin or other antiplatelet therapies have clear demonstrable benefits among individuals with coronary artery disease, the evidence supporting its use among those with LE PAD is less robust. In a meta-analysis of 18 randomized controlled trials that included 5,269 participants, aspirin was associated with a nonsignificant reduction in the risk of cardiovascular events (relative risk 0.88; 95% confidence interval 0.76-1.04). This early meta-analysis highlighted the need for dedicated clinical trials on the use of aspirin in the LE PAD population. The subsequent Aspirin for Asymptomatic Atherosclerosis trial included individuals between the ages of 50 and 80 with known cardiovascular disease who were found to have a reduced ankle branchial index (≤0.95) were randomized to placebo or 100 mg of aspirin. Among 3,350 randomized participants followed for a mean of 8.2 years, aspirin therapy did not reduce the composite risk of nonfatal coronary events, stroke or revascularization compared to placebo (10.8% vs 10.5%). Despite this finding, aspirin use is associated with graft patency among individuals undergoing revascularization and reduces cardiovascular risk among individuals with concomitant coronary artery disease, and remains with a Class 1 Recommendation in current guidelines.

However, aspirin monotherapy may not be sufficient to reduce residual cardiovascular risk. In the clopidogrel vs aspirin in patients at risk of ischemic events (CAPRIE) trial, 19,185 participants with known atherosclerotic cardiovascular disease were randomized to either aspirin 325 mg or clopidogrel 75 mg daily. Among the prespecified subgroup of 6,452 individuals with LE PAD (ABI ≤ 0.85 and claudication or treated PAD) clopidogrel was associated with a 23.8% (95 % CI 8.9%-36.2%) relative risk reduction in the composite of stroke, myocardial infarction or vascular death. This was a significantly greater risk reduction than what was observed among other subgroups of atherosclerotic cardiovascular disease (stroke- 7.3% and myocardial infarction +3.7%). Similarly, in a subgroup analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance (CHARISMA) trial, participants with symptomatic or asymptomatic LE PAD (n = 3,096) demonstrated that dual antiplatelet therapy with aspirin and clopidogrel was associated with a 1.3% absolute risk reduction of the composite endpoint of cardiovascular death, myocardial infarction and stroke when compared to aspirin alone. The subsequent examining use of ticagrelor in peripheral artery disease (EUCLID) explored the benefits of ticagrelor vs clopidogrel among participants with symptomatic LE PAD (ABI ≤ 0.8) which demonstrated no significant difference in the composite endpoint of cardiovascular death, myocardial infarction or ischemic stroke between agents (10.8% vs 10.6%). This was an important and striking finding given the more potent antiplatelet activity of ticagrelor compared to clopidogrel, where it is still recommended (Class I indication) for patients undergoing PCI. In the PAD subgroup of the ticagrelor with aspirin or alone in high-risk patients after coronary intervention (TWILIGHT) trial, ticagrelor monotherapy was associated with similar rates of major adverse cardiovascular events but lower bleeding risk, providing an additional strategy in this population. In the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events—Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50 Trial), patients with PAD randomized to vorapaxar (protease-activated receptor 1 antagonist) demonstrated a 15% reduction in major adverse cardiovascular events and a 30% reduction in major limb events, but the benefits appear to be dependent on the presence of either concomitant coronary disease or a history of prior revascularization. Based on the above, single antiplatelet therapy (either aspirin or clopidogrel) is recommended among individuals with symptomatic (Class I recommendation) or asymptomatic (ABI ≤ 0.9) (Class IIa recommendation) LE PAD, with the utility of dual antiplatelet therapy being uncertain and generally reserved for those with prior coronary or peripheral revascularization.

A greater understanding of the role a prothrombotic state on the development of atherosclerosis and PAD has spurred investigations of the use of anticoagulant therapies in the LE PAD population. Early trials of exploring the role of warfarin demonstrated no therapeutic benefit with the addition of warfarin to aspirin therapy but was associated with a significantly increased risk of major bleeding. ^, In the chronic LE PAD setting, the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial was designed to evaluate the efficacy and safety of vascular dose rivaroxaban (2.5 mg BID) with or without concomitant aspirin therapy among patients with established atherosclerotic cardiovascular disease. Regardless of the presence of symptoms of LE PAD, vascular dose rivaroxaban with aspirin (dual pathway inhibition—DPI) was associated with a significant reduction in major adverse limb events (Number needed to treat [NNT]—96) and major cardiovascular events (NNT—52) in patients with stable, chronic PAD. However, this was coupled with an increase in major bleeding events (Number needed to harm [NNH]—85). In the recent revascularization setting, the vascular outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for lower extremity PAD (VOYAGER PAD) study demonstrated that among individuals with LE PAD undergoing either endovascular or surgical revascularization compared to aspirin alone, the combination of aspirin and vascular dose rivaroxaban was associated with a 2.6% absolute risk reduction (NNT 39) in acute limb ischemia, major amputations, myocardial infarction, ischemic stroke or cardiovascular death. This was associated with a higher risk of major bleeding (2.65% vs 1.87% NNH 128.2). Among the highest risk LE PAD population (prior revascularization or ambulation, Fontaine III or IV symptoms, concomitant kidney dysfunction, heart failure, diabetes or polyvascular disease), the greatest benefit was observed with the addition of vascular dose rivaroxaban to aspirin with a 4.2% absolute risk reduction for major vascular events.

Current guidelines no longer recommend that individuals with asymptomatic chronic LE PAD should be treated with single antiplatelet therapy. ^, However, patients with polyvascular disease (CAD + PAD) represent a unique population with a higher risk of both cardiovascular and limb events and have a higher net clinical benefit with dual pathway inhibition (rivaroxaban 2.5 mg twice daily + aspirin 81 mg daily). Based on this, dual pathway inhibition should be considered in patients with polyvascular disease, regardless of the presence of LE PAD symptoms.

Among patients with symptomatic PAD in the absence of recent revascularization, antiplatelet therapy (aspirin 81 mg daily or clopidogrel 75 mg daily) or dual pathway inhibition are recommended, the choice being driven by individual bleeding risk. In the post myocardial infarction population, clopidogrel monotherapy was associated with similar ischemic events to aspirin monotherapy, with a more desirable bleeding profile. While there are concerns with the use of clopidogrel monotherapy driven predominantly by its substantial interindividual variability in effects, based on available evidence, we would recommend the use of clopidogrel monotherapy as our single antiplatelet regimen of choice ( Figure 2 ).

Antiplatelet and anticoagulation strategies following percutaneous peripheral revascularization. ACS, acute coronary syndrome; CAPRIE, clopidogrel vs aspirin in patients at risk of ischemic events; CLTI, chronic limb threatening ischemia; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition (aspirin 81 to 100 mg daily + 2.5 mg rivaroxaban twice daily); PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; VOYAGER PAD, Vascular outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for lower extremity PAD.

In the recent revascularization (either endovascular or surgical) population, dual pathway inhibition (Class I recommendation) is recommended. However, short duration use of dual antiplatelet therapy can be considered after endovascular revascularization (Class 2a recommendation) or surgical revascularization (Class 2b recommendation).

Observational data suggests that DPI reduces limb events when compared to DAPT with no difference in bleeding events following peripheral revascularization. However, DAPT remains the most common antiplatelet/anticoagulation strategy following peripheral revascularization, highlighting the need for robust evidence to guide this decision.

We would highlight that among patients with high bleeding risk following revascularization, shorter duration DAPT or DPI may be considered before transitioning to single antiplatelet therapy (preference to clopidogrel monotherapy). Similarly, in those at high ischemic risk (such as recurrent events), prolonged DPI should be considered regardless of bleeding risk after a value-based discussion with the patient.

Patients with peripheral artery disease frequently present with multiple cardiometabolic and end-organ comorbidities that both accelerate disease progression and complicate secondary prevention strategies. These conditions not only increase cardiovascular and limb risk, but also influence medication tolerability, therapeutic prioritization, and the feasibility of guideline-directed care. A structured consideration of these comorbidities is therefore essential when translating trial-based recommendations into routine practice. Several of the most prevalent comorbidities in PAD cluster within a shared cardiometabolic risk profile, with overlapping mechanisms and therapeutic implications.

Hypertension is one of the most prevalent concomitant comorbidities and affects more than half of all individuals with LE PAD. While the optimal systolic blood pressure target remains uncertain, concern exists that very low systolic blood pressures (<120 mmHg) may be associated with increased limb events by exacerbating impaired peripheral oxygen delivery. Nonetheless, the best available evidence supports a systolic blood pressure target between 120 and 129 mmHg ^, consistent with guideline recommendation of a target of <130 mmHg.

Beyond traditional vascular risk factors, individuals with obesity are also 1.5 times more likely to develop incident LE PAD. While glucagon-like peptide 1 (GLP1) agonists are efficacious for weight loss regardless of LE PAD status. However, whether behavioural or pharmacological management of obesity meaningfully alters the natural history of LE PAD remains uncertain. Further data on the utility of GLP-1′s in this population is derived from the Semaglutide and Walking Capacity in People with Symptomatic Peripheral Artery Disease and Type 2 Diabetes (STRIDE) trial (n = 1,363; 24% with prior peripheral revascularization). When compared to placebo, semaglutide was associated with a 13% increase in walking distance at 52 weeks. Of note, the effects of semaglutide appear to be independent of weight loss, with only a modest −4.1 kg observed weight loss.

Type 2 diabetes mellitus represents one of the most prominent risk factors for LE PAD, especially in the setting of long-standing diabetes or severely uncontrolled diabetes. Additionally, the presence of diabetes modulates the risk of life threatening events and mortality among patients with LE PAD. It is worth highlighting that the use of canagliflozin (a sodium glucose cotransporter 2 [SGLT2]) inhibitor was associated with an increased risk of lower extremity amputation among patients with diabetes. However, this association has largely been refuted in subsequent clinical trials and real-world datasets. Glycemic control remains an important modulator of risk, with PAD subgroup analyses demonstrating cardiovascular benefits with the use of semaglutide, liraglutide, canagliflozin, dapagliflozin, and empagliflozin. ^,,, These therapies may reduce the risk of diabetic-related foot ulcers among patients with diabetes and improve functional capacity among patients with symptomatic LE PAD. ^, Of note, the cardiovascular benefits do not appear to extend to all GLP1 agonists and SGLT2 inhibitors; as such, the use of specific agents with demonstrated cardiovascular benefits should be preferred among patients with PAD and concomitant diabetes.

Beyond cardiometabolic risk factors, chronic kidney disease represents a particularly high-risk comorbidity in PAD, amplifying both ischemic and bleeding risk while narrowing therapeutic margins. Patients with chronic kidney disease have a higher risk of incident LE PAD due to the presence of shared risk factors but also unique pathophysiological mechanism which may include endothelial dysfunction and albumin mediated calcification. Individuals with either chronic kidney disease or diabetes and LE PAD demonstrate a higher severity of LE PAD, have worse outcomes and are less likely to undergo revascularization procedures. ^,, While no unique PAD-specific interventions are currently available for these populations, these observations highlight important gaps in evidence and support further evaluation of LE PAD surveillance strategies and multidisciplinary care models to enable earlier diagnosis and intervention.

Taken together, the high burden of multimorbidity in PAD underscores the need for individualized prevention strategies that account for competing risks, polypharmacy, and treatment interactions. Many patients require prioritization across multiple conditions rather than condition-specific optimization, particularly in the postrevascularization period when cardiovascular, limb, and bleeding risks converge. Recognizing these complexities is critical for implementing secondary prevention strategies that are both evidence-based and feasible in real-world practice.

Cilostazol is currently the only recommended pharmacotherapy for symptom control for individuals with LE PAD. A meta-analysis of randomized controlled trials, demonstrated that cilostazol therapy increased maximal walking distance by 30% with a safe side effect profile. After peripheral revascularization procedures, cilostazol therapy is associated with improved patency of grafts and reduced rates of restenosis. ^,

As LE PAD is predominantly a progressive condition, there is a need for stronger emphasis on modifiable lifestyle risk factors to slow the development of atherosclerosis. Supervised exercise therapy as part of cardiac rehabilitation, is associated with significant improvements in outcomes following an acute coronary syndrome. In the LE PAD population, similar benefits are also derived, despite a lack of utilization. Supervised exercise therapy among individuals with LE PAD is associated with improvements in cardio-respiratory fitness and pain free walking. In fact, supervised exercise therapy and revascularization procedures independently improve functional capacity, ^, highlighting the need for an integrated approach among individuals undergoing revascularization procedures. A healthy diet with adequate nutrition carries many cardiovascular benefits, which may extend to individuals with LE PAD. While robust data demonstrating clear benefits for patients with established LE PAD with any specific diet is not available, the Mediterranean diet has been shown to be associated with a reduction in incident PAD. One of the largest risk factors for development and progression of LE PAD, as well as failure of lower extremity revascularization procedures, is smoking, ^, yet despite this effective smoking cessation interventions in this population are lacking and available therapies/resources are underused. ^, This represents an easily accessible intervention considering overall cost-effectiveness of risk reduction and warrants the utilization of resources for intensive smoking cessation programs in this high risk population.

As highlighted above, individuals with LE PAD undergoing a peripheral endovascular intervention represent a particularly high-risk population, with substantially elevated rates of subsequent cardiovascular and limb events compared with those with chronic or asymptomatic PAD. ^, This raises the question of whether secondary prevention strategies should be intensified in proportion to this heightened risk. Revascularization also represents a discrete and actionable touchpoint within the healthcare system that may facilitate the initiation or escalation of evidence-based risk-reduction therapies.

Several interventions have demonstrated benefit in patients following lower extremity revascularization, including optimization of antithrombotic therapy, intensive lipid lowering, and structured exercise-based rehabilitation. Contemporary guidelines consistently emphasize the importance of supervised exercise therapy, aggressive lipid lowering, smoking cessation, blood pressure control, and optimization of diabetes management in patients with symptomatic PAD, including those undergoing revascularization. ^, However as highlighted above, real-world adherence to these recommendations remains suboptimal, and the peri‑procedural period is likely underutilized as an opportunity to implement or intensify guideline-directed medical therapy.

From an implementation perspective, postintervention care pathways may provide a practical framework for systematic risk reassessment and therapy escalation. This may include referral or rereferral to supervised exercise rehabilitation, reassessment of glycemic control and antidiabetic therapy, ambulatory blood pressure monitoring, referral to obesity management programs and evaluation of lipid parameters with subsequent intensification of lipid-lowering therapy when indicated. A structured, checklist-based approach delivered by a multidisciplinary team may help ensure that this high-risk population receives comprehensive secondary prevention aligned with guideline recommendations, while also acknowledging the logistical and clinical complexities inherent to routine practice.

Importantly, evidence directly evaluating structured postrevascularization prevention strategies remains limited and optimal models for implementation have not been well defined. This highlights a critical evidence gap and underscores the need for pragmatic studies focused on care delivery strategies that can translate guideline recommendations into sustained improvements in outcomes for patients undergoing peripheral endovascular intervention.

In addition to limitations in trial-based evidence, it is important to recognize that many patients with PAD seen in clinical practice differ substantially from those enrolled in randomized studies. Real-world PAD populations tend to be older, frailer and have a higher burden of comorbidities, frequently leading to trial ineligibility. This is exemplified in real world cohorts where only 23% to 30% of PAD patients would have been eligible for low-dose rivaroxaban trials. ^,, These findings highlight the need to interpret trial evidence within the context of a more complex, heterogeneous patient population and they reinforce the importance of developing pragmatic, inclusive approaches to secondary prevention and revascularization decision-making.

Although this highlights the value of pragmatic research, it also reveals a broader imperative to deploy complementary strategies that can more effectively improve care and outcomes. This process begins by understanding current challenges with implementation of guidelines directed therapies in this population, which will require multisite, real-world registries to assess the current state of secondary prevention therapy use, a contextual understanding of barriers to appropriate care and a collaborative approach to creating scalable solutions. Implementation strategies to improve care in this population are emphasized in recent guidelines, ^, with studies highlighting several potential strategies and models to improve the diagnosis and use of appropriate therapies and interventions. These strategies include improving access to supervised exercise therapy, ^, adoption of system-wide changes such as interdisciplinary limb salvage teams, use of electronic health records to identify patients with PAD and implement clinical decision support tools ^, and education initiatives for both patients and providers. ^, Effective implementation strategies to address adherence to guideline-recommended therapies are lacking and remain a high-priority in this population. A recent scoping review identified 12 multicomponent interventions in PAD, of which 7 reported medication adherence outcomes. None of the interventions improved adherence across all targeted behaviours, and most trials were underpowered or showed only modest, nonsignificant changes. Effective implementation strategies will need to move beyond solely providing education and incorporate elements such as promotion of self-management, goal setting and problem solving using robust behaviour change theoretical frameworks. System based strategies in improve adherence may include development of dedicated risk reduction clinics that adopt systematic assessments that may be technology-enabled and virtual to improve functionality and accessibility. ^,, The timing of endovascular intervention may represent an opportunity to capture these individuals to understand and modulate their residual risk.

The role of inflammation in the pathogenesis of atherosclerosis is attributable to many inflammatory pathways. ^, LE PAD is especially susceptible to the effects of systemic inflammation, compared to other forms of atherosclerosis. ^,, This is further supported by the emerging data demonstrating the prognostic role of high-sensitivity c-reactive protein among patients with PAD. Despite this, there is a paucity of clinical trial data exploring the role of anti-inflammatory therapies in this population. Among individual with chronic coronary disease and recent acute coronary syndromes, colchicine therapy has demonstrated the ability to reduce cardiovascular events. Whether these benefits extend to individuals with LE PAD will be explored in the low-dose colchicine in patients with peripheral artery disease to address residual vascular risk (LEADER-LE PAD; NCT04774159). Other inflammatory modulating therapies such as ziltivekimab (interleukin 6 inhibitor) is being investigated in the research study to look at how ziltivekimab works compared to placebo in people with cardiovascular disease, chronic kidney disease and inflammation (ZEUS; NCT 05021835). Additionally, the presence of PAD is an enrichment criterion in the research study to look at how ziltivekimab works compared to placebo in people with a heart attack (ARTEMIS; NCT 06118281) trial exploring the effects of ziltivekimab in patients with a type 1 myocardial infarction, which will provide further insight into the use of anti-inflammatory therapies in the PAD population. Based on the relative effects of systemic inflammation on LE PAD compared to other forms of atherosclerosis, this population may derive a greater benefit of anti-inflammatory therapies and is a research priority in this field. Lipoprotein a (Lp(a)) levels are known to be associated with increased risk of PAD and adverse limb events among the general population, however the utility of agents specifically targeting Lp(a) in the PAD population remain to be seen. ^,

It is important to recognize that most of the clinical trial evidence on the effectiveness of secondary prevention therapies in LE PAD originate from subgroup analysis of clinical trials, highlighting the need for dedicated PAD trials. Additionally, it is important to recognize that individuals with asymptomatic LE PAD, chronic PAD and recent PAD revascularization carry unique cardiovascular and limb risk profiles and therapies, which may lead to nonuniform effectiveness of secondary prevention therapies. This has direct implications when assessing the clinical risks, benefits and cost-effectiveness of these therapies. The results of subsequent trials should highlight any observed differences in these populations, that can aid in addressing evidence gaps in risk reduction across the spectrum of LE PAD ( Figure 3 ).

Unanswered questions in risk reduction therapy in individuals with peripheral artery disease undergoing peripheral revascularization. CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition (aspirin 81 to 100 mg daily and rivaroxaban 2.5 mg twice daily); GLP-1, glucagon like peptide 1; LDL, low-density lipoprotein; LE, lower extremity; PAD, peripheral artery disease; PSCK9i, proprotein convertase subtilisin-kexin type 9 inhibitor; SAPT, single antiplatelet therapy.

Once an individual has established LE PAD, they are at high risk of developing both adverse cardiovascular and limb events. To mitigate this risk, aggressive secondary prevention approaches are required that harness behaviour interventions and lifestyle modifications, management of concomitant comorbidities, risk factor modification, and adjunctive pharmacological therapies. As individuals with LE PAD, especially those with polyvascular disease, demonstrate the highest risk profiles for cardiovascular events, it raises the question whether advanced secondary prevention therapies should be used as first line therapies in this high-risk population. Ongoing clinical trials will inform the clinical benefit and cost-effectiveness of such an approach.

Pishoy Gouda: Writing– review & editing, Writing– original draft, Conceptualization. Eric A. Secemsky: Writing– review & editing, Writing– original draft, Conceptualization. Connie N. Hess: Writing– review & editing, Writing– original draft, Conceptualization. Shipra Arya: Writing– review & editing, Writing– original draft, Conceptualization. Foluso Fokorede: Writing– review & editing, Writing– original draft, Conceptualization. Roxana Mehran: Writing– review & editing, Writing– original draft, Conceptualization. Marc P. Bonaca: Writing– review & editing, Writing– original draft, Conceptualization. Manesh R. Patel: Writing– review & editing, Writing– original draft, Conceptualization. William Schuyler Jones: Writing– review & editing, Writing– original draft, Supervision, Conceptualization.