Overview of Pharmacological Treatment in Peripheral Artery Disease

Peripheral artery disease (PAD) is a condition that affects more than 230 million individuals worldwide. The incidence increases up to 20% in patients older than 60 years, and it is more common in Black individuals. PAD is characterized by progressive reduction of blood flow to the extremities, typically the legs, due to narrowing of the arteries. An estimated 30% to 50% of patients with coronary artery disease will have comorbid PAD.^1-3

Symptoms vary among patients. Some may be asymptomatic, whereas others may present with lower extremity pain, claudication, cold extremities, numbness, or weakness. As the disease progresses, it may lead to complications including decreased or absent pulse in the feet, infections/gangrene, thromboses, limb ischemia, or amputation.¹ Diagnosis of lower extremity PAD is enhanced with the use of an ankle-brachial index (ABI). The measurement evaluates systolic blood pressure in both brachial arteries and the blood pressure in the ankles. It is highly sensitive and specific, and the normal range is greater than 0.9 to less than 1.3. An ABI lower than 0.9 is considered diagnostic of PAD.^2,4

The main goal of treatment of PAD is to minimize symptoms, increase walking ability, and reduce cardiovascular risk. Options are usually centered around lifestyle modifications and pharmacologic therapy. Surgical intervention may be necessary in advanced cases.^1,3

Patients with PAD are at an inherently increased risk of stroke, myocardial infarction (MI), and thrombosis; therefore, lifestyle modifications are an important piece of the puzzle. Lifestyle modifications should be centered on implementation of a structured exercise program to improve functional status and quality of life and to reduce leg symptoms. Management of risk factors including diabetes, hyperlipidemia, and hypertension should be taken into consideration prior to the discussion of revascularization, and smoking cessation should always be encouraged.^1,3

Medications with atherosclerotic cardiovascular disease (ASCVD) risk reduction should be a priority in patients with PAD. For those with concomitant diabetes (regardless of baseline and target hemoglobin A1c), agents include a glucagon-like peptide-1 receptor agonist and/or an SGLT2 inhibitor with proven ASCVD benefit. Hyperlipidemia should be managed with a high-intensity statin to reduce low-density lipoprotein (LDL) by 50% or greater. If further LDL reduction is warranted, ezetimibe (Zetia; Merck) and/or a PCSK9 inhibitor can be considered to optimize therapy. Current hypertension guidelines recommend a goal blood pressure of less than 130/80 mm Hg in patients with concurrent PAD, with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers being first-line therapy.^1,3

Another aspect of ASCVD prevention that should be emphasized is antiplatelet therapy. Monotherapy with aspirin at 75 to 325 mg daily or clopidogrel 75 mg daily is recommended by guidelines to reduce MI, stroke, and vascular death in symptomatic patients. If a patient is asymptomatic, monotherapy with either agent remains reasonable. Dual antiplatelet therapy (DAPT) may be reasonable in symptomatic patients after lower extremity revascularization.5 However, in asymptomatic patients who have not undergone revascularization, the benefit of DAPT is unknown. The phase 3 CHARISMA trial (NCT00050817) showed some benefit of clopidogrel (Plavix; Bristol Myers Squibb and Sanofi Pharmaceuticals) for patients at high risk of ASCVD, such as those with multiple interventions in the past.⁶

The usefulness of anticoagulants in PAD is also not fully understood, but they should not be used to reduce the risk of cardiovascular ischemic events. Rivaroxaban (Xarelto; Janssen Pharmaceuticals), a direct oral anticoagulant, is FDA approved for use in PAD at a dose of 2.5 mg twice daily and is given in combination with low-dose aspirin. This recommendation is not in the 2016 American Heart Association/American College of Cardiology (AHA/ACC) guidelines due to rivaroxaban being approved for use in PAD in October 2018. Pharmacists should also monitor dual antiplatelet and anticoagulant therapy combination therapy (triple therapy) in this patient population due to very high risk of gastrointestinal bleeds with uncertain benefit.^3,5

The phase 3 VOYAGER PAD trial (NCT02504216) looked at the risk and benefit of rivaroxaban in patients with symptomatic PAD after revascularization. The data showed that rivaroxaban at a dose of 2.5 mg twice daily plus aspirin in patients who had undergone lower extremity revascularization was associated with a significantly lower incidence of limb and atherosclerotic events but a significantly increased risk of bleeding.⁷

Historically, pharmacological treatment in PAD has been targeted toward claudication, which is defined as limping or walking with difficulty. Standard of care is cilostazol (Pletal; Otsuka Pharmaceutical), a PDE3 inhibitor that causes vasodilation. Its role in improving symptoms of claudication and improving walking ability is unknown. It should be noted that cilostazol is associated with decreased survival in patients with heart failure and should not be used in patients with reduced ejection fraction. Per 2016 AHA/ACC guidelines, pentoxifylline, which is another medication approved for the treatment of PAD because of its believed ability to improve oxygen delivery, is not an effective agent for managing claudication and should not be recommended at this time.³

PAD is a complex disease with many opportunities for pharmacist intervention to improve outcomes. Pharmacists should routinely monitor for antiplatelet and statin therapy in all patients with PAD (or reasons against) and counsel on tobacco cessation as well as the importance of a structured exercise program for this patient population.

References

1. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(12):e686-e725. doi:10.1161/CIR.0000000000000470

2. Criqui MH, Matsushita K, Aboyans V, et al. Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American Heart Association. Circulation. 2021;144(9):e171-e191. doi:10.1161/CIR.0000000000001005

3. Davies MG. Management of claudication due to peripheral artery disease. Updated May 31, 2022. Accessed February 3, 2024. https://www.uptodate.com/contents/management-ofclaudication-due-to-peripheral-artery-disease

4. Measuring and understanding the Ankle Brachial Index (ABI). Stanford Medicine. 2023. Accessed September 10, 2023. https://stanfordmedicine25.stanford.edu/the25/anklebrachial-index.html

5. Watson K, Anderson S. Peripheral arterial disease. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey LM, eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. McGraw Hill; 2023. Accessed February 3, 2024. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=269070061

6. Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA; CHARISMA Investigators. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J. 2009;30(2):192-201. doi:10.1093/eurheartj/ehn534

7. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004. doi:10.1056/NEJMoa2000052