Medical Management of Peripheral Artery Disease

INTRODUCTION

Lower extremity peripheral artery disease (PAD) is a malignant form of atherosclerosis associated with a heightened risk of cardiovascular morbidity and mortality.¹ Many patients with PAD have additional comorbidities, such as diabetes mellitus or atherosclerosis in additional vascular beds, further amplifying this risk.² Much of the medical management of PAD overlaps with secondary prevention of coronary artery disease (CAD) and cerebrovascular disease. In the last 2 decades, greater attention to PAD has led to the development of novel therapies that decrease adverse cardiovascular and limb events in this patient population. This review focuses on the components of optimal medical management of patients with PAD.

SMOKING CESSATION

Tobacco use is strongly associated with cardiovascular disease and remains an important risk factor for the development and progression of PAD.³ Ongoing smoking is associated with an increased risk of chronic limb-threatening ischemia (CLTI), need for revascularization and amputation, and major adverse cardiovascular events (MACE).^4,5 Observational data from patients with PAD who successfully stop smoking demonstrate improved outcomes,⁶ making smoking cessation a primary target for clinicians.

Current smoking cessation strategies consist of both counseling and pharmacologic intervention with nicotine replacement therapy (NRT), bupropion, or varenicline. A previous study randomizing patients with PAD to either intensive counseling intervention or minimal intervention showed that patients in the intensive intervention group were more likely to achieve smoking abstinence at 6 months compared with the minimal intervention group (21.3% vs 6.8%, P = .023).⁷ However, long-term abstinence often requires medical therapy (Table 1).

Table 1.

Pharmacologic treatment options for smoking cessation

Pharmaceutical	Dosing Strengths	Dosing	OTC	Evidence	Precautions	Side Effects	Dose Adjustments
Short-acting agents
Nicotine gum	2 mga 4 mgb	1 pc, ql-2 h × 6 wk 1 pc, q2–4 h × 3 wk 1 pc, q4–8 h × 3 wk Max: 24 pc/d	Yes	RCT53	None	Jaw pain, sleep disturbance, vivid dreams, oral irritation	Nonec
Nicotine lozenge	2 mga 4 mgb	1 pc, ql-2 h × 6 wk 1 pc, q2–4 h × 3 wk 1 pc, q4–8 h × 3 wk Max: 20 pc/d	Yes	RCT53	None	Jaw pain, sleep disturbance, vivid dreams, oral irritation	Nonec
Nicotine inhaler	10 mg/cartridge	6–16 cartridges/d × 3–6 wk Reduce dose × 6–12 wk Max: 16 cartridges/d	No	RCT54,55	None	Headache, oral irritation, nasal discomfort, dyspepsia	Nonec
Nicotine intranasal spray	10 mg/mL (1 spray = 0.5 mg) (2 spray = 1 dose) (1 spray/nostril)	1–2 dose/h (1 spray/ nostril) No more than 5 doses (10 sprays) per hour Max: 40 mg/d (80 spray) or 3 mo treatment	No	ND	None	Headache, oral irritation, nasal discomfort, dyspepsia	Nonec
Long-acting agents
Nicotine patch	14 mg (< 10 cig/d) 21 mg (>10 cig/d)	14 mg/d × 6 wk 7 mg/d × 2 wk 21 mg/d × 6 wk 14 mg/d × 2 wk 7 mg/d × 2 wk	No	RCT56	None	Local skin irritation, headaches, insomnia	Nonec
Bupropion	150 mg	150 mg/d × 3d followed by 150 mg bid × 712 wk Max: 300 mg/d	No	RCT8	Seizure disorder, SI, use of MAOIs, simultaneous cessation of EToH or Benzos	Insomnia, agitation, constipation	Nonec
Varenicline	0.5 mg	0.5 mg/d × 3d 0.5 mg bid × 4–7 d 1.0 mg bid × 11 wk Max: 2.0 mg/d	No	RCT9	*Black box warning for neuropsychiatric events removed in 201657	Nausea, vivid dreams	CrCl <30 mL/min Initial: 0.5 mg/d Max: 0.5 mg bid

Abbreviations: benzos, benzodiazepines; bid, twice daily; cig, cigarettes; CrCl, creatinine clearance; EtOH, alcohol; MAOi, monoamine oxidase inhibitors; ND, no data; OTC, over-the- counter; pc, piece; RCT, randomized controlled trial; SI, suicidal ideation.

Consider adjustments in moderate to severe renal/hepatic impairment.

^aSmoke first cigarette after 30 minutes of waking.

^bSmoke first cigarette within 30 minutes of waking.

^cNone provided on manufacturer labeling.

Bupropion is a norepinephrine and dopamine reuptake inhibitor. When used alone or in addition to nicotine replacement, bupropion leads to higher rates of smoking cessation at 12 months compared with placebo or NRT alone.⁸ Varenicline is a partial agonist of α-4 and β-2 nicotinic acetylcholine receptors and remains the most effective smoking cessation aid. Randomized controlled trial data demonstrate that varenicline is more effective than placebo (odds ratio [OR], 3.61; 95% confidence interval [CI], 3.07–4.24), bupropion (OR, 1.68; 95% CI, 1.46–1.93) and nicotine patch (OR, 1.75; 95% CI, 1.52–2.01) at improving 12-week smoking abstinence rates.⁹ Importantly, varenicline does not lead to an increase risk of neuropsychiatric side effects.⁹

Recommendations

Current professional guidelines recommend that all patients using tobacco should be advised to quit.¹⁰ For patients that are willing to quit, shared decision-making can be used to determine the best pharmacologic treatment option with either NRT, bupropion, or varenicline.¹¹ Varenicline, either alone or in combination with NRT, is recommended as the first-line treatment in patients with cardiovascular disease. Based on availability of tobacco cessation programs and patient preference, counseling or group therapy may also be used.¹¹

LIPID-LOWERING THERAPY

Dyslipidemia is an important modifiable risk factor in the development of cardiovascular disease and atherosclerosis. Atherogenic dyslipidemia, which is characterized by elevated concentrations of total cholesterol and low levels of high-density lipoprotein cholesterol, is a strong risk factor for PAD development.¹² In contrast with CAD, data demonstrating a link between low-density lipoprotein cholesterol (LDL-C) and incident PAD are sparse. Nonetheless, recent studies have shown a consistent benefit in lipid reduction to decrease MACE, as well as limb outcomes in patients with PAD.

Statin Therapy

Although many patients with PAD participated in the landmark statin trials, PAD-specific outcome data are limited. In the Heart Protection Study, 20,536 high-risk patients with stable vascular disease, of whom 6748 had PAD, were randomized to either simvastatin or placebo. Simvastatin not only decreased the risk of all-cause mortality, but also led to a 16% relative decrease in the rate of first peripheral vascular event, irrespective of baseline LDL-C levels.¹³ There was no decrease in amputations with simvastatin compared with placebo.

Observational studies have helped solidify the role of statins in improving PAD outcomes. The international Reduction of Atherothrombosis for Continued Health Registry, which included 5861 patients with symptomatic PAD, demonstrated that statin use was associated with a reduction in adverse limb events compared with those not taking statins (hazard ratio [HR] 0.82; 95% CI, 0.72–0.92, P = .01).¹⁴ Among 155,647 patients with newly diagnosed PAD in the Veterans Affairs health system, statins, particularly high-intensity statin therapy, significantly decreased the rates of lower extremity amputation compared with antiplatelet therapy alone (HR, 0.67; 95% CI, 0.61–0.74).¹⁵

Ezetimibe

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (n = 18,144) examined the addition of ezetimibe, which inhibits absorption of cholesterol from the intestine, to simvastatin in patients with recent acute coronary syndrome. Within the trial, 1005 participants had a prior history of PAD. The addition of ezetimibe further decreased LDL-C by approximately 24% along with a reduction in MACE (HR, 0.94; 95% CI, 0.89–0.99; P = .016).¹⁶ Limb events were not reported in this study.

PCSK9 inhibition

More recently, inhibitors of protein convertase subtilisin kexin type 9 (PCSK9) have been shown to not only decrease LDL-C concentrations in patients on statin therapy, but also to decrease the risk cardiovascular and limb events. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk trial randomized 27,564 patients with known atherosclerotic disease already on a statin to either evolocumab, a PCSK9 inhibitor, or placebo. In a subgroup analysis of 3642 patients with PAD, evolocumab led to a greater decrease in MACE (HR, 0.73; 95% CI, 0.59–0.91; P = .0040).¹⁷ Although evolocumab led to a decrease in major adverse limb events in the overall study population, this decrease did not reach statistical significance in the PAD subgroup. In the ODYSSEY Outcomes trial, treatment with the PCSK9 inhibitor alirocumab did demonstrate a statistically significant reduction in a composite of CLTI, lower extremity amputation, or revascularization (HR, 0.69; 95% CI, 0.54–0.89; P = .004).¹⁸

Recommendations

The US guidelines recommend that all patients with PAD be treated with high-intensity statin therapy for a goal LDL-C decrease of 50% or greater,¹⁹ whereas the European guidelines recommend a target LDL-C of less than 70 mg/dL.²⁰ High-intensity statin options include atorvastatin 40 to 80 mg/d or rosuvastatin 20 to 40 mg/d. In patients with PAD who do not achieve their target LDL-C on statin therapy alone, additional lipid-lowering therapy with ezetimibe or a PCSK9 inhibitor should be used.¹⁹

HYPERTENSION

Hypertension is associated with a doubling in the risk of death from stroke, heart disease, or other vascular disease.²¹ Current professional guidelines recommend a target blood pressure less than 130/80 mm Hg in patients with cardiovascular disease, including PAD.²² There remain few studies guiding target blood pressure or specific hypertensive therapeutic choices in patients with PAD. The subgroup analysis of the Appropriate Blood Pressure Control in Diabetes study examined patients with diabetes and PAD (ankle-brachial index [ABI] of <0.90) who were randomized to moderate blood pressure control (placebo, no intended change in diastolic blood pressure) or intensive blood pressure control (enalapril or nisoldipine, target decrease in diastolic blood pressure of 10 mm Hg). The intensive treatment group had a larger reduction in cardiovascular events compared with moderate treatment.²³ The Heart Outcomes Prevention Evaluation trial (n = 4051) randomized patients with vascular disease or diabetes, of whom 44% had PAD, to ramipril 10 mg/d or placebo. Overall, ramipril significantly decreased the risk of MACE in the PAD subgroup.²⁴ Other clinical trials have found similar reductions in MACE for patients with PAD treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.^25,26

There has long been concern that intensive blood pressure control may contribute to adverse limb outcomes in patients with PAD owing to worsened limb perfusion. Among 2699 participants with PAD in the INternational VErapamil-SR/Trandolapril Study, there was a J-shaped relationship between systolic blood pressure and a composite of all-cause death, myocardial infarction, or stroke.²⁷ Excess risk occurred with a systolic blood pressure of less than 135 mm Hg, suggesting that these patients might require different blood pressure targets. Similarly, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (n = 33,357) found that patients with a systolic blood pressure of less than 120 mm Hg or greater than 160 mm Hg were at greater risk of PAD-related outcomes.²⁸ In contrast, recent data from the Examining the Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial showed that every 10 mm Hg decrease in systolic blood pressure of 125 mm Hg or less was associated with an increased risk of MACE (HR, 1.19; 95% CI, 1.09–1.31; P<.001) but no increased risk of adverse limb events (HR, 1.02%; 95%, 0.84–1.23; P = .824).²⁹ Additional work is needed to better understand the link between PAD and hypertension.

Recommendations

In patients with PAD, the American College of Cardiology/American Heart Association PAD guidelines recommend targeting a blood pressure of less than 130/80 mm Hg.¹⁰ Angiotensin-converting enzyme inhibitors of angiotensin receptor blockers are the only antihypertensive medications with a mortality benefit in the PAD population and should remain the first-line therapies in this population. Current data suggest that intensive blood pressure control in patients with PAD, particularly those with more advanced PAD, may worsen limb symptoms, thus necessitating a more liberal target in select groups. PAD-specific blood pressure targets have yet to be defined.

ANTIPLATELET AND ANTITHROMBOTIC THERAPY

Antiplatelet Therapy

Antiplatelet and antithrombotic therapy remain key components of primary and secondary prevention of cardiovascular disease. Although antiplatelet therapy has historically been used to treat a wide range of atherosclerotic diseases, data supporting the use of these drugs in PAD, particularly in terms of decreasing adverse limb outcomes, are inconsistent. More recently, a combination of antiplatelet and antithrombotic therapy has shown significant benefits among patients with PAD, and these drug regimens represent a paradigm shift in PAD management (Table 2).

Table 2.

Antiplatelet and antithrombotic trials in patients with PAD

Antiplatelet therapy
Trial	POPADAD 31	Aspirin for Asymptomatic Atherosclerosis Trialists32	CAPRIE33	CHARISMA36	EUCLID34	TRA 2°P-TIMI 5035
Intervention	Aspirin 100 mg/d vs placebo	Aspirin 100 mg/d vs placebo	Aspirin 325 mg/d vs clopidogrel 75 mg/d	Clopidogrel 75 mg/d plus either aspirin 75–162 mg/d or placebo	Ticagrelor 90 mg twice daily vs clopidogrel 75 mg/d	Vorapaxar 2.5 mg/d vs placebo
Study population	1276 patients with diabetes and an ABI of ≤ 0.99	3350 patients with an ABI of ≤0.95	19,185 total 6452 patients with intermittent claudication and either an ABI of ≤0.85 or prior revascularization/ amputation	15,603 total 3096 patients with intermittent claudication and either an ABI of ≤0.85 or prior revascularization/ amputation	13,885 patients with and ABI of ≤0.85 or prior revascularization	26,449 total 3787 patients with an ABI of ≤0.85 or prior revascularization
MACE outcomes	Vascular death, MI, stroke: HR, 0.98; 95% CI, 0.76–1.26	Fatal or nonfatal MI, stroke, or revascularization: HR, 1.03; 95% CI, 0.84–1.27	Vascular death, MI, or ischemic stroke in PAD subgroup: HR, 0.76; 95% CI, 0.64–0.91	CV death, MI, or stroke: HR, 0.85; 95% CI, 0.66–1.08	CV death, MI, or stroke: HR, 1.02; 95% CI, 0.92–1.13	CV death, MI, stroke: HR, 0.94; 95% CI, 0.78–1.14
MALE outcomes	Major amputation: 2% vs 2%	None reported	None reported	None reported	Hospitalization for ALI: HR, 1.03; 95% CI, 0.79–1.33 Lower limb revascularization: HR, 0.95; 95% CI, 0.90–1.05	Hospitalization for ALI: HR, 0.58; 95% CI, 0.39–0.86 Lower limb revascularization: HR, 0.84; 95% CI, 0.73–0.97
Antithrombotic therapy
Trial	WAVE38	COMPASS40	VOYAGER PAD42
Intervention	Warfarin with an INR goal of 2.0–3.0 plus antiplatelet monotherapy vs antiplatelet monotherapy alone	Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/d, rivaroxaban 5 mg twice daily plus placebo, or aspirin 100 mg/d plus placebo	Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/d vs aspirin plus placebo
Study population	2161 patients with symptomatic PAD or carotid/ subclavian stenosis	27,395 7470 patients with symptomatic PAD or carotid stenosis	6564 patients with PAD and recent lower extremity revascularization
MACE outcomes	CV death, MI, stroke: RR, 0.92; 95% CI, 0.73–1.16	CV death, MI or stroke: ASA + rivaroxaban vs ASA + placebo: HR, 0.72; 95% CI, 0.57–0.90; P = .0047	Primary outcome MACE + MALE: HR, 0.85; 95% CI, 0.760.96
MALE outcomes	Revascularization: 3.3% vs 3.7%; P = .64 Amputation: 0.7% vs 1.1%; P = .37	MALE: HR, 0.54; 95% CI, 0.35–0.82; P = .0037	ALI: HR, 0.67; 95% CI, 0.55–0.82

Abbreviations: ABI, ankle-brachial index; ALI, acute limb ischemia; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; CHARISMA, Clopidogrel for High Athe- rothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; CV, cardiovascular; INR, international normalized ratio; MALE, major adverse limb event; MI, myocardial infarction; POPADAD, Progression of Arterial Disease and Diabetes; RR, relative risk; VOYAGER PAD, Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; WAVE, Warfarin Antiplatelet Vascular Evaluation.

Aspirin

Aspirin is a cyclooxygenase-1 inhibitor that inhibits the effect of thromboxane A2, thus inhibiting platelet aggregation. The ATT Collaboration meta-analysis showed that patients with symptomatic PAD on antiplatelet therapy had a 22% reduction in MACE. Although this analysis used various aspirin doses and other antithrombotic therapies, this marks the earliest clinical evidence supporting antiplatelet therapy in PAD.³⁰

More recent studies have shown a less consistent benefit of aspirin therapy. The Prevention of Progression of Arterial Disease and Diabetes trial (n = 1276) assessed the efficacy of aspirin 100 mg versus placebo in patients with diabetes and PAD. The study found no difference between groups in cardiovascular end points (18.2% vs 18.3%), nor was there a difference in lower extremity amputation.³¹ The Aspirin for Asymptomatic Atherosclerosis Trial (n = 3350) examined aspirin 100 mg versus placebo in patients with PAD (ABI of ≤0.95), and once again found no difference in cardiovascular end points or improvement in intermittent claudication.³²

Clopidogrel

Clopidogrel is a prodrug, metabolized by the liver, that irreversibly binds and inactivates the platelet receptor, P2Y₁₂. The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (n = 19,185) randomized patients with symptomatic atherosclerotic disease to clopidogrel 75 mg/d versus aspirin 325 mg/d. In the PAD subgroup (n = 6452), clopidogrel decreased MACE (relative risk reduction 23.8%; 95% CI, 8.9–36.2; P = .0028) compared with aspirin with similar bleeding rates.³³

Ticagrelor

The EUCLID trial sought to build on the results of CAPRIE. Ticagrelor is also an inhibitor of the P2Y₁₂ platelet receptor but, unlike clopidogrel, is not a prodrug and does not require activation by the body. In this study, 13,885 patients with symptomatic PAD (ABI of <0.80 or prior revascularization) were randomized to either ticagrelor 90 mg or clopidogrel 75 mg/d. The primary end point of MACE was similar between groups (HR, 1.02; 95% CI, 0.92–1.13; P = .65) with no differences observed in the rates of acute limb ischemia (ALI) or lower limb revascularization.³⁴

Vorapaxar

Vorapaxar is a novel antiplatelet drug that inhibits platelet aggregation by the irreversible inhibition of protease-activated receptor-1. In TRA 2° P-TIMI 50, 20,170 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or symptomatic PAD) were randomized to vorapaxar 2.5 mg/d or placebo. Among the subgroup with PAD (n = 3787), there was no significant reduction in MACE with vorapaxar therapy (HR, 0.94; 95% CI, 0.78–1.14; P = .53), although there was a decrease in hospitalization for ALI (HR, 0.58; 95% CI, 0.39–0.86; P = .006) and peripheral artery revascularization (HR, 0.84; 95% CI, 0.73–0.97; P = .017). This came at the cost of increased bleeding with vorapaxar (HR, 1.62; 95% CI, 1.21–2.18; P = .001), which has in part limited the use of this drug.³⁵

Dual antiplatelet therapy

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial (n = 15,603) evaluated the effect of low-dose aspirin plus clopidogrel versus aspirin plus placebo in individuals with stable cardiovascular disease or multiple risk factors. In subgroup analyses (n = 3096) of patients with symptomatic (92%) and asymptomatic PAD (8%), there was similarly no decrease in MACE with dual antiplatelet therapy (DAPT) compared with aspirin (HR, 0.85; 95% CI, 0.66–1.08; P = .18).³⁶ Similar results were seen in the Clopidogrel and Acetylsalicylic Acid in Bypass Surgery trial in PAD patients undergoing unilateral surgical bypass grafting. Although there was no benefit to DAPT in decreasing mortality, the trial did suggest a benefit in decreasing prosthetic graft occlusions.³⁷

Antithrombotic Therapy

Vitamin K antagonism

Until recently, data on antithrombotic therapy in PAD were largely limited to the Warfarin Antiplatelet Vascular Evaluation trial. In this study, 2161 patients with PAD were randomized to warfarin (international normalized ratio of 2–3) plus aspirin versus aspirin alone.³⁸ There was no significant reduction in MACE (relative risk, 0.92; 95% CI, 0.73–1.16; P = .48) with warfarin, although there was a significant increase in life-threatening bleeding (relative risk, 3.41; 95% CI, 1.84–6.35; P<.001). Accordingly, professional guidelines do not support the use of warfarin in treating PAD.¹⁰

Factor Xa inhibition

After the development of numerous oral factor Xa inhibitors, several trials has assessed their efficacy in reducing atherosclerotic events in conjunction with antiplatelet therapy. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, 27,396 patients with stable CAD, PAD, or carotid disease were randomized to 1 of 3 drug regimens: the factor Xa inhibitor rivaroxaban 5 mg twice daily plus placebo, rivaroxaban 2.5 mg twice daily plus aspirin, or aspirin monotherapy plus placebo. The trial was terminated early after a mean follow-up period of 23 months owing to the decrease in MACE in the rivaroxaban plus aspirin versus the aspirin monotherapy group (HR, 0.76; 95% CI, 0.66–0.86; P<.001).³⁹

The PAD subanalysis of COMPASS (n = 7470) included 4129 with symptomatic lower extremity PAD, 1422 patients with CAD and an ABI of less than 0.90, and 1919 patients with CAD and carotid disease. The combination of rivaroxaban plus aspirin compared with aspirin monotherapy showed significantly decreased rates of MACE (HR, 0.72; 95%CI, 0.57–0.90; P = .0047) and major adverse limb event (HR, 0.54; 95% CI, 0.35–0.82; P = .0037).40 Similarly, this regimen led to decreases in ALI (HR, 0.56; 95% CI, 0.32–0.99; P = .04), vascular amputations (HR, 0.40; 95% CI, 0.20–0.79; P = .007), and peripheral vascular interventions (HR, 0.76; 95% CI, 0.60–0.97; P = .03).40,41 Major bleeding was more common with the combination of low-dose rivaroxaban and aspirin (3.1% vs 1.9%, P = .009), but there was no increased risk in intracranial hemorrhage.⁴⁰

To further evaluate the role of factor Xa inhibition in patients with PAD, the Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial randomized 6564 patients with PAD who had undergone recent revascularization to rivaroxaban 2.5 mg twice daily plus aspirin versus aspirin alone. The addition of rivaroxaban led to a decrease in the primary outcome of MACE, ALI, or major amputation (HR, 0.85; 95% CI, 0.76–0.96; P = .009). The benefit for rivaroxaban was similar for endovascular and surgical revascularization and for revascularization for CLTI and non-CLTI. Bleeding risk was modestly increased (5.94% vs 4.06%; HR, 1.42; 95% CI, 1.10–1.84; P = .007) with no differences in life-threatening and intracranial hemorrhage.⁴²

Antiplatelet and Antithrombotic Recommendations

The use of antiplatelet and antithrombotic in patients with PAD is based on multiple considerations including additional comorbidities, such as diabetes, the presence of polyvascular atherosclerotic disease, prior arterial revascularization, indications for therapeutic anticoagulation (eg, atrial fibrillation or venous thromboembolism), and other conditions that may further increase one’s bleeding risk. This is an evolving field that is, not fully addressed in current professional guidelines. Our typical approach is as follows.

• For PAD without polyvascular disease or other risk factors, such as diabetes or prior revascularization, use single antiplatelet therapy. Data suggest clopidogrel is more effective than aspirin.³³ Ticagrelor is a reasonable alternative to clopidogrel, particularly in poor metabolizers of clopidogrel.³⁴

• In patients with symptomatic PAD and polyvascular disease, use aspirin plus low-dose rivaroxaban 2.5mg twice daily.⁴⁰

• After revascularization, DAPT to decrease instent thrombosis remains common practice, although data within a PAD population are limited.⁴³ Recent trial data support the use of aspirin plus low-dose rivaroxaban 2.5 mg twice daily after revascularization.⁴² Additional studies are needed to compare DAPT to aspirin plus low-dose rivaroxaban after lower extremity percutaneous revascularization.

• In patients with lower extremity PAD but no attributable symptoms and no history of symptomatic atherosclerosis in other arterial beds, defer antiplatelet therapy.

OTHER THERAPIES

Cilostazol

Cilostazol is a selective inhibitor of phosphodiesterase III with antiplatelet, antithrombotic, and vasodilating properties. A meta-analysis (n = 2702) examining patients with stable, moderate to severe claudication from 8 randomized controlled trials found an increase in maximum walking distance by 50% and pain-free walking distance by 67% with cilostazol therapy.⁴⁴ Another meta-analysis (n = 1258) then compared cilostazol with placebo resulting in an improved maximum walking distance (50.7% vs 24.3%, P = .001) and pain-free walking distance (67.8% vs 42.6%, P = .0001).⁴⁵ Cilostazol is contraindicated in patients with heart failure owing to concerns of increased ventricular arrhythmias. Side effects of gastrointestinal intolerance, dizziness, and headaches may limit its use.^46,47

Pentoxifylline

Pentoxifylline is a theophylline derivative initially studied to improve claudication symptoms. A randomized controlled trial comparing cilostazol, pentoxifylline, and placebo in patients with moderate to severe claudication found no difference in walking distance between pentoxifylline and placebo.⁴⁸ Current guidelines do not recommend the use of pentoxifylline for intermittent claudication.¹⁰

Recommendations

Cilostazol remains the only drug that has demonstrated efficacy in improving claudication symptoms with benefits seen 4 weeks after initiation, and guidelines recommend its use to improve walking distance and claudication symptoms.^10,45,49

FUTURE DIRECTIONS

Given the results of COMPASS and VOYAGER PAD, we will likely have additional data for other factor Xa inhibitors as well as novel antithrombotic agents in the near future. There is ongoing work on new therapies to improve walking distance and claudication metrics. A pilot study of daily cocoa supplementation, which contains flavanols that may promote vascular growth and function, demonstrated improved walking distance and increased calf muscle perfusion on biopsy.^50,51 Anti-inflammatory drugs are also being explored as modulators of the proinflammatory pathways involved in the development and progression of atherosclerosis.⁵² A small study exploring the effect of canakinumab, an interleukin 1β antagonist, in patients with PAD demonstrated improved pain free walking distance as early as 3 months after treatment.⁵¹ We hopefully will have more cardiovascular outcome trial data, including limb events, of anti-inflammatory therapies in the coming years.

SUMMARY

The medical management options for PAD has improved markedly over the last 2 decades. In addition to standard risk modification therapies, advances have been made in improving lipid therapy with the addition of ezetimibe and PCSK9 inhibitors. More recently, this complex patient population has finally established an antiplatelet and antithrombic regimen that improves both MACE and major adverse limb event outcomes. We hope that the recent attention to PAD and limb outcomes leads to the development of novel therapies for this high risk patient population. Regardless, undertreatment remains a critical issue for patients with PAD, and an emphasis on both patient and provider awareness remains paramount.

KEY POINTS.

• Peripheral artery disease is a progressive atherosclerotic disease that remains underappreciated and poorly optimized.

• The target low-density lipoprotein cholesterol for this patient population is <70 mg/dL (1.8 mmol/L).

• Lipid-lowering therapy improves both cardiovascular and limb outcomes in peripheral artery disease.

• Angiotensin-converting enzyme inhibitors and aldosterone receptor antagonists remain the only antihypertensive therapies with a mortality benefit in peripheral artery disease.

• Aspirin plus low-dose rivaroxaban (2.5 mg twice daily) should be considered in high-risk patients with peripheral artery disease, such as those with a prior history of lower extremity revascularization or with atherosclerosis in other vascular territories.

CLINICS CARE POINTS.

• Smoking cessation remains paramount in PAD, and varenicline should be used as a first-line therapy to help patients attain and maintain cessation.

• Statin therapy in PAD remains underused despite a lower risk of mortality and limb-related events regardless of baseline LDL-C levels. High-intensity statins are recommend in individuals with PAD.

• Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are first-line antihypertensive therapies in patients with PAD.

• A regimen of low-dose rivaroxaban 2.5 mg twice daily plus aspirin has both mortality and limb-related benefits in stable patients with PAD patients and following lower extremity revascularization.

• Cilostazol remains the only PAD therapy to improve walking distance and claudication symptoms.