Top 10 Controversies in Peripheral Artery Disease Management

The term peripheral artery disease (PAD) has been used broadly to refer to stenotic/occlusive disease involving arterial beds outside of the coronary circulation. An estimated 8.5 million Americans have PAD, with a global prevalence of PAD reaching approximately 202 million people during the period from 2000-2010.^1,2

Although atherosclerosis is by far the most common cause of PAD, other inflammatory and non-inflammatory arteriopathies contributing to PAD include vasculitis and fibromuscular dysplasia.

Smoking, severity of disease, and type 2 diabetes (T2D) are associated with a higher mortality in patients with PAD.³ A healthy lifestyle including regular physical activity, not smoking, moderate alcohol intake, and adherence to a Mediterranean diet are all factors that can reduce the risk of PAD.⁴

Although the conventional risk factors for atherosclerotic cardiovascular disease are also consistently associated with PAD, smoking may be a more powerful risk factor for PAD than coronary heart disease.^5,6 Elevated C-reactive protein, homocysteine, and lipoprotein(a) have been associated with a greater risk of PAD as well.^7-9 Chronic kidney disease is not only associated with a risk of PAD, but also a higher likelihood of adverse events including limb loss and mortality.⁶

Despite all that we know about PAD, numerous questions and controversies remain: Should we screen for PAD? How aggressively should we treat patients with diabetes who were also diagnosed with PAD? Should clopidogrel be the first line antiplatelet in symptomatic PAD? Our review will examine these questions and tackle even more controversies surrounding the treatment and management of patients with PAD.

Controversy #1 - Should we screen for PAD?

Screening and assessment of PAD begins with a detailed history and physical examination to identify signs, symptoms, and functional status in those at risk. Patients with PAD may be asymptomatic or have atypical pain.¹⁰ The classic symptom of claudication (pain that is brought on by walking and relieved in less than 10 minutes of rest) is uncommon in this patient population. This may be related to the overall poor activity status or physical impairment precluding symptom precipitation.  

While the US Preventive Services Task Force does not support screening for PAD, both the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) guidelines agree on ankle-brachial index (ABI) measurement screening in high-risk individuals (Table 1).^11-14 All patients at risk of PAD should undergo a complete physical examination to detect any discrepancy in systolic blood pressure in the upper extremities, diminished or absent pulses, arterial bruits and any skin breakdown, non-healing ulcers, or gangrene.

Table 1. Current PAD guideline recommendations on when screening is recommended.

For further evaluation of clinically suspected PAD, additional diagnostic testing can be pursued as outlined below.

Non-invasive arterial testing

In patients with symptoms suggestive of PAD, a resting ABI assessment is recommended given that it is non-invasive and easy to perform with minimal risk to the patient. Standards for measurement and criteria for staging have been well established, with an ABI less than 0.9 being abnormal and diagnostic of PAD.¹⁵ Segmental pressures and Doppler waveform assessment are often performed to localize the disease.^15,16 Treadmill exercise testing is recommended for those with normal or borderline ABI (between 0.9-0.99) with non-joint related exertional leg symptoms and for functional assessment of those with ABI less than 0.9. Toe brachial index measurement with waveforms is useful in patients with poorly compressible vessels (defined by ABI greater than 1.4) and in situations of non-healing ulcers and gangrene with any ABI. Transcutaneous oxygen assessment has shown to be predictive of wound healing potential in patients with ulcers and those being considered for amputation.¹⁷

Duplex ultrasonography can serve as an adjunct to ABI assessment to localize the disease and is recommended when revascularization is planned or to assess prior stent or graft patency. It is safe, non-invasive, easily available, and can be used in patients with renal insufficiency.¹²

Angiography

Computed tomography (CT) or magnetic resonance (MR) angiography have better spatial resolution than ultrasound and are used when revascularization is being considered for anatomic assessment of lesion severity and procedure planning. Conventional angiography is used when planning for revascularization or when non-invasive angiography does not yield optimal assessment. The risk of ionizing radiation must be kept in mind for both CT and conventional angiography. The use of iodinated contrast during conventional and CT angiography in patients with chronic kidney disease may not be feasible due to the risk of contrast-induced nephropathy. However, low dose protocols and rapid image acquisition times may reduce risk. MR angiography has a longer procedural time compared with CT angiography and is associated with significant motion artifacts in the presence of implantable cardiac devices, pacemakers, and other metallic implants. Gadolinium used for MR angiography is associated with a risk of nephrogenic systemic fibrosis in patients with chronic kidney disease stage 3 and greater.¹²

Screening of other arterial beds in patients with PAD

Patients with PAD often have atherosclerotic disease in other vascular beds, but the ACC/AHA or ESC guidelines do not recommend screening of other vascular territories. However, abdominal duplex ultrasound to screen for asymptomatic abdominal aortic aneurysm is recommended as clinically reasonable by the ACC/AHA. Aggressive risk factor reduction with guideline-directed medical therapy is indicated to reduce major adverse limb and cardiac events and improve functional status.^11,12

Medical management of PAD

The overarching goals of PAD management include risk factor modification through lifestyle-based interventions and guideline-directed medical therapy to improve functional status, slow/prevent the progression of disease, and ultimately reduce the risk of major adverse limb and cardiac events, including mortality. Patients with PAD are less likely to receive optimal guideline-recommended treatment compared with those with CHD. The potential reasons for this include lack of physician knowledge and awareness about PAD and its consequences, under-reporting of symptoms by patients, and also lack of clinical decision support in electronic health records to help physicians optimize PAD care.^18,19

Smoking cessation

Smoking cessation is the cornerstone of secondary prevention in PAD. Counseling for cessation is underutilized, as shown in a recent registry study.²⁰ All patients with PAD who smoke tobacco products should be counselled to quit at every visit and provided with cessation resources including pharmacotherapy and referral to smoking cessation programs. Secondhand smoke may be associated with a risk of PAD and counselling to avoid exposure should be provided.²¹

Controversy #2 - Should we aim for a target LDL?

Moderate- to high-intensity statin therapy with the intent to lower low-density lipoprotein cholesterol (LDL-C) to 70 mg/dL or less has been recommended by both the AHA/ACC and ESC guidelines based on improvement in major cardiovascular and limb outcomes noted in randomized controlled trials and large registry data.^22,23 Statins have also shown to reduce all-cause mortality and stroke and improve walking distance in these patients.^24,25 Amongst patients undergoing endovascular or surgical revascularization, reduced rates of restenosis, major adverse limb events, and mortality benefit has been noted with statin therapy.^26,27 Mortality benefit was also observed in patients undergoing knee amputations when treated with statin therapy.²⁸

The 2018 cholesterol clinical practice guidelines recommend consideration of non-statin therapy (ezetimibe followed by proprotein convertase subtilisin/kecxin type 9 (PCSK-9) inhibitors) added on to maximally tolerated statin therapy for patients with “very high risk” of atherosclerotic cardiovascular disease (ASCVD). Symptomatic PAD, prior revascularization, or amputation is considered a major vascular event.²⁹

The FOURIER trial showed that LDL-C reduction with PCSK-9 inhibitor evolocumab added to background statin or fibrate therapy significantly decreased the primary composite endpoint and major adverse cardiac and limb events. Effects were consistent amongst patients with and without known polyvascular disease. The average LDL-C level achieved was 31 mg/dL and no safety concerns were reported. There was a 59% mean reduction in LDL-C with evolocumab compared with placebo.^30,31

Despite evidence of benefit, patients with PAD are less likely to receive statin therapy compared with those with CHD or a combination of CHD and PAD^32,33 and less likely to be discharged on statins after peripheral intervention.³⁴ With newer evidence pointing toward the benefit of more aggressive LDL reduction in terms of both major adverse limb and cardiac events in patients with PAD specifically, it is important to initiate and maximize lipid lowering therapy.

Controversy #3 - What is the target blood pressure and how low do we go?

Treating hypertension in patients with PAD should be aligned with the standard hypertension guidelines for a goal blood pressure of less than 130/80 mm Hg.³⁵ Angiotensin-converting enzyme inhibitors (ACE-I) lowered adverse cardiovascular events in patients with PAD in the Heart Outcomes Prevention Evaluation trial. However, the impact on maximal and pain free walking distance were inconclusive.^36-39 Beta blockers are not contraindicated in patients with PAD.⁴⁰ Amlodipine has comparable effects to valsartan.⁴¹

While treatment of hypertension is central to the medical management of PAD, no particular agent gets preference over the other. ACE-I and angiotensin receptor blockers get a Class IIa mention in the American and European guidelines as a reasonable first choice.

Controversy #4 - Should diabetes mellitus be treated aggressively in patients with PAD?

Diabetes is an important risk factor for PAD. Patients with diabetes are more likely to have worse outcomes, including higher likelihood of amputation and higher mortality, when compared with patients without diabetes.^42,43 Poor glycemic control and higher incidence of infections associated with diabetes contribute to worse outcomes. Patients with diabetes undergoing surgical revascularization have been shown to have worse outcomes with higher incidence of adverse cardiovascular events compared with individuals without diabetes in one study.⁴⁴ A target hemoglobin A1C of less than 6.5 is recommended with a team-based approach to management.

Recent clinical trials demonstrated an all-cause and cardiovascular mortality benefit of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists use in patients with T2D. SGLT2 inhibitors were additionally associated with a reduction in cardiovascular events including heart failure hospitalizations and myocardial infarction.⁴⁵ Two SGLT2 inhibitors, empaglifozin and canaglifozin, were approved by the FDA for cardiovascular risk reduction in patients who have T2D and established cardiovascular disease. Amongst the GLP-1 receptor agonists, liraglutide was approved for the same indication.⁴⁶ However, increased risk of all fractures and a two-fold increase in toe-metatarsal amputations was observed with canaglifozin.⁴⁷ This limits the use of canaglifozin to secondary prevention amongst patients with T2D and PAD.

Controversy #5 – Should clopidogrel be the first line antiplatelet in symptomatic PAD?

Despite a paucity of evidence in other studies,^48,49 single antiplatelet therapy with low dose aspirin (75 to 100 mg/day) was recommended as a first-line treatment in all symptomatic patients in a major meta-analysis, which showed a 22% reduction in myocardial infarction, stroke, and vascular death.⁵⁰

Overall, aspirin was associated with a significant reduction in non-fatal stroke.^49,51The ESC guidelines favor clopidogrel over aspirin. This is likely based on the greater reduction in stroke, myocardial infarction, and vascular death in patients with ASCVD treated with clopidogrel in the CAPRIE trial. Adenosine diphosphate antagonists were noted to be superior to aspirin monotherapy in reducing major cardiovascular events and major leg amputations. Among the adenosine diphosphate antagonists, clopidogrel had the most favorable profile in terms of a safety endpoint for severe major bleeding.⁴⁸ Ticagrelor monotherapy did not show superiority to clopidogrel with respect to cardiovascular event reduction in patients with PAD in the recent EUCLID trial.⁵²

However, patients with PAD are less likely to receive any guideline directed antiplatelet therapy when compared with patients with CAD.^32,33 

Controversy #6 – Should we use dual antiplatelet therapy?

Dual antiplatelet therapy is recommended post revascularization for PAD. In patients with established PAD, the CHARISMA trial showed significant benefit of adding clopidogrel to aspirin for reduction in myocardial infarction and hospitalizations with an increase in minor bleeding but comparable rates of major bleeding with aspirin alone.^53,54 Clopidogrel in combination with aspirin was also shown to lower the risk of major amputations but at the cost of a slightly higher severe bleeding risk in a meta-analysis.⁴⁶ 

The addition of ticagrelor to aspirin was associated with a reduction in major adverse cardiovascular and limb events, with higher rates of major bleeding observed in the ticagrelor groups compared with aspirin alone in one major randomized clinical trial. The rates of intracranial and fatal bleeding were not significantly higher.⁵⁵

A more recent meta-analysis revealed that dual antiplatelet therapy is linked to a reduction in all-cause mortality and a reduced risk of repeat revascularization with a non-significant increase in major bleeding. The benefit was consistent across patients with symptomatic PAD and those with and without revascularization.⁵⁶

Cilostazol and vorapaxar as a dual antiplatelet strategy when added to aspirin and picotamide monotherapy have been ineffective in reducing cardiovascular events.⁴⁸

Controversy #7 – Should asymptomatic patients receive antiplatelet therapy?

While the ACC/AHA guidelines consider single antiplatelet therapy a reasonable option for asymptomatic patients with an ABI less than 0.9, the ESC does not recommend the use of antiplatelet therapy in asymptomatic patients. Randomized controlled trials in patients both with and without diabetes and with an ABI less than 0.99 have not shown a reduction of cardiovascular events.^57,58

Controversy #8 - Should we anticoagulate patients with PAD?

In the WAVE trial, which evaluated patients with symptomatic PAD, warfarin added to antiplatelet therapy did not show benefit compared with antiplatelet therapy alone in reducing major adverse cardiac events. Bleeding was higher in the warfarin group.⁵⁹ Current guidelines are not up to date with newer data on anticoagulation in PAD and presently the ACC/AHA does not recommend anticoagulation to reduce the risk of ischemic events. The ESC/ESVS guidelines outline an algorithm for guidance on anticoagulation management in patients who need it.

The recent COMPASS trial demonstrated the benefit of adding low dose rivaroxaban to aspirin in symptomatic patients with clinically manifest vascular disease in coronary and cerebrovascular beds. There was a significant reduction in mortality and major adverse cardiovascular events in the group receiving low dose rivaroxaban added to aspirin when compared with the other treatment groups. Analyses of PAD-specific outcomes showed a reduction of major adverse limb events by 43%, amputations by 58%, and peripheral vascular interventions by 24%. While major bleeding was higher when compared with aspirin alone, there was no increase in intracranial or critical organ bleeding and 2% of the patients had major gastrointestinal bleeding. No benefit was seen in the group with a higher dose rivaroxaban alone in terms of primary outcome or mortality.⁶⁰ Findings of the COMPASS trial also support the use of low dose rivaroxaban in addition to low dose aspirin for long term management of patients with PAD, especially those with severe disease, to reduce major adverse limb events.

Edoxaban added to aspirin was compared with dual antiplatelet therapy with clopidogrel and aspirin following femoro-popliteal endovascular interventions in the ePAD trial.⁶¹ Although lower rates of restenosis were observed in the edoxaban group, this did not reach statistical significance. Rates of major or life-threatening bleeding were similar in both groups.

The VOYAGER PAD trial recently added to the evidence regarding the addition of low dose rivaroxaban to antiplatelet therapy in patients undergoing surgical or endovascular revascularization.⁶² At 3 years, patients treated with rivaroxaban in addition to aspirin post-revascularization had a 17.3% lower risk of major adverse cardiac events, acute limb ischemia, or amputation (p = 0.009). However, no significant mortality benefit was noted amongst the rivaroxaban group. Half of the patients in this study were on clopidogrel in addition to aspirin for the first 6 months following revascularization. The benefit of rivaroxaban was noted regardless of clopidogrel use. Although the incidence of thrombolysis in myocardial infarction major bleeding did not differ significantly between groups, there was significantly more International Society of Thrombosis and Hemostasis (ISTH) major bleeding in the rivaroxaban group. Clopidogrel use for more than 30 days was linked to a higher incidence of ISTH bleeding.⁶³ A more recent analysis of VOYAGER PAD revealed that rivaroxaban was consistently effective in reducing total (initial and subsequent) vascular events at 3 years amongst patients undergoing lower extremity revascularization when compared with aspirin alone.⁶⁴

Controversy #9 – Should we also use medical therapy to improve walking distance?

Supervised exercise therapy (SET) has been recommended by the AHA/ACC guidelines for patients with PAD and intermittent claudication to improve functional status and quality of life and decrease symptoms (Class I, LOE A). It has consistently shown to improve maximal and pain free walking distance.^12,65 SET has also shown to positively impact modifiable cardiovascular risk factors including blood pressure and cholesterol levels.⁶⁶ Endovascular revascularization showed no significant difference in terms of peak walking time when compared with SET after 18 months of therapy in the CLEVER trial.⁶⁷ Treadmill exercise training is the form widely studied for PAD.

Due to lack of insurance coverage, SET has been underutilized in patients with PAD. However, in 2017 the Centers for Medicare and Medicaid Services began to cover limited SET sessions for patients with PAD.⁶⁸ A recent study over a 10-year period reported that patients with PAD were less likely to initiate and complete cardiac rehabilitation than those without PAD.⁶⁹ Compliance with supervised exercise has been variable with possible reasons for non-compliance being lack of insurance coverage, lack of interest in or difficulty with prescribed exercise program, perceived lack of benefit, transport, or social issues.⁷⁰ Most studies have focused on walking exercise programs for PAD with very few studies looking at upper and lower body ergometry. Such exercise has also shown benefit with respect to total and pain free walking distance, thought to be due to cardiorespiratory fitness improvement.^71,72 Individualized exercise prescription for PAD may improve compliance.

While SET has shown to be superior to non-supervised structured exercise therapy, benefits are still seen with non-supervised exercise therapy in terms of overall functional capacity and quality of life.^73-75

Several medications have been studied with respect to impact on mean walking distance and the greatest benefit has been noted with antiplatelets, phosphodiesterase inhibitors, statins, and vasodilators in one meta-analysis. Statins were associated with the most improvement in mean walking distance.⁷⁶ Among the phosphodiesterase inhibitors, cilostazol has consistently shown to improve walking distance and is recommended by the ACC/AHA.⁷⁷ Frequent adverse effects, including headache, diarrhea, and flushing, limit its tolerability and usage. Pentoxyfylline did not show any benefit.⁷⁸ Naftridrofuryl oxalate, a 5-hydroxytryptamine 2 receptor antagonist with vasodilating properties, has shown to improve both walking distance and quality of life.^79-81

Controversy #10 - Antiplatelet or anticoagulants after revascularization in PAD: how long and what agent?

Endovascular or surgical revascularization is reserved for those patients with PAD who experience lifestyle limiting claudication despite optimal medical and exercise therapy. Other factors to be considered include pre-procedural patient risk profile, lesion length and characteristics, available expertise, patient preference, and goals of care. There was no difference in amputation free survival and overall survival at 3 years between endovascular and surgical revascularization in the BASIL trial, where patients with infra-inguinal disease were randomized to balloon angioplasty first vs bypass first approach. Health-related quality of life did not differ between the two strategies but there was higher failure rate in the balloon angioplasty group requiring secondary bypass surgery.^82,83

While guidelines provide recommendations for endovascular revascularization in aortoiliac and femoro-popliteal arterial occlusive disease, the benefit of this strategy for infra-popliteal disease is not known. Recent meta-analyses have revealed that endovascular revascularization added to SET was associated with a significant improvement in total walking distance and quality of life compared with either therapy alone.^84-86 Drug eluting balloon angioplasty was superior to uncoated angioplasty in terms of primary patency, restenosis rates, and target lesion revascularization.⁸⁷ The 5-year primary patency rate for endovascular revascularization was 62.5% in one study of patients with PAD who underwent the procedure for claudication; 61% of these patients underwent stent placement which was protective of loss of primary patency.⁸⁸ The 12-month primary patency for femoro-popliteal intervention with nitinol stent was observed to be 69.8% in a meta-analysis.⁸⁹ Dual antiplatelet therapy is recommended for at least a month following endovascular strategy by guidelines.

For candidates with an acceptable pre-operative risk profile, in situations where a surgical approach provides a clear advantage over endovascular technique, autologous vein grafts are preferred over prosthetic grafts given greater observed 5 year primary patency.⁹⁰ Surgical revascularization has been associated with a longer length of stay but also higher primary patency compared with percutaneous transluminal angioplasty as well as nitinol self-expanding stents.^91,92 The 30-day risk of major adverse limb events was similar when surgical and infra-inguinal endovascular revascularization were compared in a national cohort. However, major adverse cardiac events were higher in the surgical treatment group, noted mainly in higher risk patients including those with diabetes, COPD, and end stage renal disease. The 30-day mortality was similar in the two groups.⁹³ Hybrid procedures with endovascular revascularization combined with bypass vs bypass alone for femoro-popliteal lesions had better perioperative outcomes in terms of length of stay, reoperation, and readmission rates.⁹⁴ Dual antiplatelet therapy is considered reasonable following surgery in these patients to reduce limb events. Data on the benefit of anticoagulation therapy following lower extremity bypass surgery continue to evolve with the most recent evidence from VOYAGER PAD. Of note, approximately 35% in each group underwent surgical revascularization with majority undergoing endovascular revascularization. A 32% lower incidence of acute limb ischemia was the main driver of the primary composite endpoint reduction in VOYAGER PAD. There was no significant difference in the risk of amputation or other individual primary endpoints. More detailed analyses of these results may be needed to outline benefits of adding rivaroxaban based on the modality of revascularization.⁶²

Ongoing clinical trials on antithrombotic therapy in PAD

While the optimal antithrombotic regimen for these patients remains a challenge, there are several clinical trials underway to address ongoing questions. ASPIRE is seeking to study the addition of clopidogrel to background aspirin therapy in patients undergoing endovascular revascularization. Rivaroxaban is also being compared with clopidogrel when added to background therapy for patients with critical limb ischemia undergoing percutaneous transluminal angioplasty in the RIVAL-PAD trial.

Conclusions

In summary, management of a patient with PAD revolves around goals of improving symptoms, slowing disease progression, preventing limb complications, improving functional status, and ultimately improving quality of life. These goals should be achieved in collaboration with patients through shared decision making through education, counselling, and motivation so they can take ownership of their preventive and medical management of the disease. Frequent follow-up care to evaluate symptoms, compliance with recommended therapy, and progress is important.

AFFILIATIONS:
¹Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL
²Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL

CITATION:
Halkar M, Kullo IJ. Top ten controversies in peripheral artery disease management. Consultant. 2023;63(10):e1. doi:10.25270/con.2023.10.000001

Received May 27, 2022. Accepted February 21, 2023. Published online October 11, 2023.

DISCLOSURES:
The authors report no relevant financial relationships.

ACKNOWLEDGEMENTS:
None.

CORRESPONDENCE:
Meghana Halkar, MD, 4500 San Pablo Road S, Jacksonville, FL 32246 (meghanahalkar@gmail.com)

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