Introduction
Chronic limb-threatening ischemia (CLTI) represents the end stage of peripheral artery disease (PAD) and is associated with an impaired quality of life due to a high risk of major adverse limb events, including major amputation, adverse cardiovascular events, and mortality. This clinical syndrome is defined by the presence of objectively proven PAD in combination with rest pain, gangrene, or lower limb ulceration greater than 2 weeks duration, and is staged based on wound severity and presence of infection. CLTI often presents in tandem with atherosclerosis in other vascular beds, but can also occasionally manifest as thrombosis isolated to the lower extremities in the absence of significant atherosclerosis, a phenomenon rarely seen in coronary or carotid disease.^1,2 Given the likelihood of systemic atherosclerosis in CLTI patients, optimal medical therapy is focused not only on reducing limb threat but also on improving overall cardiovascular health.¹

Clinical Manifestations
Clinical presentation includes characteristic pain, tissue loss, or both usually at the level of the foot. Pain occurs at rest and is caused by a combination of ischemia, ischemic neuropathy, and tissue loss, if present. Foot wounds in diabetics are frequently painless due to concomitant peripheral neuropathy and can progress from minimal ulceration to extensive gangrene without significant change in symptoms to alert the patient. Loss of distal pulses, dependent rubor, shiny skin, and absence of hair are common on physical exam. Tissue loss (with or without infection) usually starts with the toes though pressure from poorly fitting footwear or minor trauma can present at the foot or even calf level.¹ (Figure 1)

Treatment Strategies
The primary factors that contribute to the risk of limb threat are wound (W), ischemia (I) and foot infection (fI).³ The WIfI classification system should be used in the initial assessment of CLTI patients to determine the severity of ischemia and allow for risk stratification. Such scoring provides estimation of amputation risk and provides an objective method to determine further management regarding benefits of arterial imaging and/or revascularization.⁴ While timely revascularization is a cornerstone of treatment, the optimal revascularization strategy is uncertain and currently under investigation in two large, pragmatic, randomized controlled trials comparing surgical with endovascular revascularization.^5,6 Goals of treating a patient with CLTI are not only to salvage a functional limb but also to improve cardiovascular outcomes through risk factor modification and best medical therapy.⁷

Lifestyle Modifications
A healthier lifestyle should be encouraged and stressed for patients with CLTI. Smoking cessation, adopting a healthy diet, and regular exercise are important for the preservation of both life and limb.⁷ The adverse impacts of tobacco use on cardiovascular health are well established and smokers have a significantly higher rate of PAD progression and major adverse cardiovascular events (MACE).^8,9 Smoking cessation is associated with lower rates of adverse cardiovascular and limb events, bypass graft failure, amputation, and death in PAD patients.^10,11 PAD patients who use any form of tobacco should be advised to quit at every visit and assisted in developing a plan for quitting.^12,13 Numerous trials have demonstrated the benefits of supervised exercise therapy in intermittent claudication.¹⁴ While exercise therapy may be challenging for CLTI patients, it should be considered after successful revascularization.^15,16

Medical Therapy for CLTI
In addition to lifestyle modification, ongoing counseling on preventive foot care should be offered to all patients.^8,17-21 Principles of good wound care should be followed to promote healing and prevent infection.^4,22 Active management of diabetes, treatment of hypertension, use of antiplatelet/antithrombotic and lipid-lowering agents are evidence-based strategies supported by current guidelines to reduce cardiovascular and limb events in patients with symptomatic PAD, including CLTI.^4,23 (Table 1)

Antiplatelets and Antithrombotics
Antiplatelet agents are strongly recommended for all patients with CLTI. While the largest body of evidence supports the use of low-dose aspirin, clopidogrel is approved as an alternative in symptomatic PAD based on a reduction in MACE compared with aspirin in the CAPRIE trial.^4,7,23,24 Recent evidence shows support for the use of low-dose aspirin and rivaroxaban 2.5mg twice daily to reduce major cardiovascular and limb ischemic events in symptomatic PAD, particularly after lower extremity revascularization as seen in the VOYAGER trial.^25,26 VOYAGER randomized 6,564 patients with symptomatic lower extremity PAD undergoing peripheral revascularization to aspirin with rivaroxaban 2.5mg twice daily or aspirin with placebo. The primary efficacy endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction (MI), ischemic stroke, or death from cardiovascular causes while the primary safety endpoint was the Thrombolysis in Myocardial Infarction (TIMI) major bleeding. The incidence of the primary composite endpoint at 3 years was 17.3% in the rivaroxaban group and 19.9% in the placebo group with a hazard ratio of 0.85 (95% CI 0.76-0.96; p=0.0009) and this was largely driven by a reduction in acute limb ischemia. This trial included 1,533 (23%) patients with critical limb ischemia (CLI) at baseline and there was no heterogeneity in the efficacy of rivaroxaban plus aspirin compared with aspirin alone based on the presence of CLI at index revascularization.²⁶

Dual antiplatelet therapy (DAPT) is frequently employed for 1 to 6 months after peripheral revascularization though there is an absence of strong evidence supporting this practice.^27-29 Treatment with DAPT is the standard in coronary artery disease following percutaneous coronary intervention and its use after peripheral revascularization is largely based on coronary literature.^7,30 The CHARISMA trial in patients with stable atherosclerotic vascular disease or multiple atherothrombotic risk factors showed no significant reduction in MACE with clopidogrel plus aspirin (DAPT) compared with aspirin alone.³¹ A post hoc analysis of PAD patients (92% symptomatic PAD) also found no MACE benefit for DAPT.³² PEGASUS-TIMI 54 compared ticagrelor plus aspirin (DAPT) versus aspirin alone for the prevention of MACE in patients with prior MI. Ticagrelor DAPT significantly reduced MACE though increased the risk of major bleeding in the overall trial.³³ In the PAD subgroup, the absolute risk reduction with ticagrelor DAPT for MACE was 4.1% and there was also a significant reduction in major adverse limb events (MALE) with an absolute excess of major bleeding of only 0.12%.³⁴ The THEMIS trial also compared ticagrelor DAPT with aspirin alone for MACE prevention in patients with stable coronary artery disease and type 2 diabetes. While ticagrelor DAPT significantly reduced MACE compared with aspirin alone, there was a significant increase in TIMI major bleeding and intracranial hemorrhage. In the subgroup of patients with PAD, MALE had a significant risk reduction of 55% with ticagrelor DAPT compared with aspirin monotherapy. Despite the large reduction in MALE, the significant increase in major bleeding suggests that ticagrelor DAPT should be used with caution in the PAD population.³⁵ Despite the similarities between percutaneous interventions in coronary and peripheral arteries, PAD patients have diminished responses to DAPT, and this practice is not supported by high quality evidence.³⁶

Lipid-Lowering
Low density lipoprotein (LDL-C) reduction is proven to reduce MACE in patients with atherosclerotic disease.^37,38 The overwhelming majority of CLTI patients qualify for maximally tolerated statin therapy with the goal of LDL-C reduction to <70mg/dL or ≥50% reduction if LDL-C is between 70 and 135mg/dL. If LDL-C levels remain elevated, the addition of non-statin agents should be considered.³⁹ Ezetimibe plus simvastatin significantly reduced adverse cardiovascular outcomes compared with statins alone (HR 0.936, 95% CI 0.89-0.99, p=0.016) in the IMPROVE-IT trial.⁴⁰ A pre-specified subgroup analysis of polyvascular patients, including those with PAD, showed a greater numerical absolute composite endpoint risk reduction with ezetimibe plus simvastatin.⁴¹ The FOURIER trial demonstrated the additional benefits of PCSK9 inhibitors when added to statins by a significant reduction in the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (HR 0.80, 95% CI 0.73-0.88, p<0.001) in patients with atherosclerotic cardiovascular disease (ASCVD) and LDL-C ≥70 mg/dl.⁴² In the subgroup of patients with symptomatic PAD, evolocumab significantly reduced the primary composite endpoint (HR 0.79, 95% CI 0.66-0.94, p=0.0098), MACE (HR 0.73, 95% CI 0.59-0.91, p=0.0040), and MALE (HR 0.58, 95% CI 0.38-0.88, p=0.0093). There was a consistent relationship between lower achieved LDL-C and lower risk of MACE and MALE, and this effect continued to an LDL <10 mg/dL in a nearly linear fashion.^42,43 Despite the greater reduction in cardiovascular risk with PCSK9 inhibitors, ezetimibe is favored as a second agent given the low cost-effectiveness of the former.³⁹

Diabetes Management
Type 2 diabetes mellitus (DM) is present in the majority of CLTI patients and the extent of vascular disease appears related to the duration and severity of hyperglycemia.^44,45 Metformin remains the first line agent for all DM patients with a goal hemoglobin A1c (HbA1c) of <7% for patients with CLTI.^7,46,47 The addition of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) is preferred for patients with ASCVD independent of baseline or target HbA1c. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are reasonable alternatives to GLP-1 RA with beneficial effects on cardiovascular complications, renal disease, and mortality in DM.⁴⁷ Despite the cardiovascular benefits of SGLT-2 inhibitors as a class, the CANVAS Program demonstrated a 2-fold increased risk of lower limb amputations (mainly minor) with the use of canagliflozin though no specific mechanism has been identified.^48,49 While a black box warning was initially issued by the FDA for amputation risk with canagliflozin, recent safety information from real-world studies and a large clinical trial suggests that the risk of amputation is lower than previously described and the black box warning has subsequently been removed.^50-53 If the HbA1c remains above target despite metformin and a GLP-1 RA or SGLT-2 inhibitor, an additional hypoglycemic agent, including a dipeptidyl peptidase 4 (DPP-4) inhibitor, thiazolidinedione, sulfonylurea, or basal insulin can be added with equal effectiveness.^47,54

Antihypertensives
Management of hypertension is well accepted to reduce MACE in patients with PAD with a goal of maintaining systolic blood pressure (SBP) <130mmHg and diastolic blood pressure (DBP) <80mmHg. While certain classes may be preferred according to comorbidities, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium antagonists, beta-blockers, and diuretics are all suitable for antihypertensive treatment in CLTI, as monotherapy or in combinations.^4,55 Additional evidence from two randomized trials favors ACEIs or ARBs as first-line agents in CLTI patients given a reduction in MACE and mortality with no adverse effect on limb outcomes in this subgroup.^4,56

Summary
CLTI confers a high risk for lower extremity amputation, adverse cardiovascular events, and mortality. Lifestyle modification is necessary for all patients and should be addressed at each clinic visit. Timely revascularization is essential and can salvage a threatened limb. Significant progress has been made in the medical management of CLTI patients with numerous evidence-based strategies available that can decrease adverse cardiovascular and limb events and prolong life.

References

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Clinical Topics: Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Novel Agents

Keywords: Aneurysm, Peripheral Arterial Disease, Intermittent Claudication, Tobacco, Antihypertensive Agents, Fibrinolytic Agents, Gangrene, Quality of Life, Risk Factors, Smoking Cessation, Lower Extremity, Goals, Ischemia, Platelet Aggregation Inhibitors, Hemoglobin A, Coronary Artery Disease, Aspirin, Sodium-Glucose Transporter 2, Purinergic P2Y Receptor Antagonists, Antibodies, Monoclonal, Calcium, Cardiovascular Diseases, PCSK9 protein, human

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