As a resident eager to find a topic to specialize in throughout my career, the cardiovascular field was crowded with national experts and thought leaders. I loved the complexity and reputation of anticoagulation, but I struggled to find a therapeutic niche needing a fresh take. My residency director pointed me towards PAD (peripheral arterial disease) — a disease we had only discussed in medicinal chemistry when learning about phosphodiesterase inhibitors. I began to learn about a cardiovascular condition that affects more than 8 million patients in the United States. The therapeutic options for PAD aligned with my clinical interests, but more importantly, there appeared to be the need for a disease state expert or educator.
The prevalence of peripheral atherosclerosis is highly dependent on patient age, ethnicity, smoking status, diabetes, hypertension, cholesterol, and renal function.1 While 2.7% of the population are afflicted with PAD, less than 50% are aware they have the disease.2 Many patients experience no symptoms leading to a general lack of awareness and diagnosis by both patients and providers. Some patients experience pain in the calf, thigh, or buttock with exertion or other symptoms related to poor peripheral perfusion such as cold extremities, diminished peripheral pulses and extremity hair loss. Screening high-risk patients for peripheral atherosclerosis is critical as epidemiological studies have found that nearly 50% of patients with asymptomatic disease will die within 10 years.3
I think pharmacists can play an important and unique role in PAD as we are providers that possess both the knowledge in therapeutic options and skills needed to perform disease state screening. An ankle-brachial index is a simple, non-invasive, cost-effective measurement that can be used to diagnose PAD.4 A blood pressure ratio less than 0.9 between the brachial artery and a peripheral artery (dorsalis pedis or posterior tibial) is consistent with PAD. Screening high-risk patients to identify poor peripheral circulation gives clinicians an opportunity to initiate or intensify therapies targeting the underlying modifiable cardiovascular risk factors such as blood pressure, glucose, lipids, and smoking, and antiplatelet or anticoagulant therapy.
All patients with PAD require therapies that reduce cardiovascular mortality regardless of the presence of absence of peripheral exertional symptoms.2 Practitioners should identify modifiable risk factors, including hypertension, hyperlipidemia, and diabetes, that contribute to the progression of disease and cardiovascular events. The antihypertensive of choice in patients with PAD is an angiotensin converting enzyme (ACE) inhibitor titrated to achieve a blood pressure goal < 130/80 mm Hg. A beta-blocker could be used in patients with mild or moderate PAD. However, in patients with severe disease, a beta-blocker may further reduce peripheral perfusion resulting in a worsening of symptoms. A high-dose statin, or HMG Co-A reductase inhibitor, should be used as a first line agent to manage low-density lipoprotein. While no specific diabetes agent is recommended, blood glucose should be managed to achieve a hemoglobin A1c goal < 7%.
Historically, antiplatelet agents were the drug of choice to reduce the incidence of cardiovascular and cerebrovascular morbidity and mortality in patients with PAD. The clinical benefits of low dose aspirin, an irreversible cyclooxygenase inhibitor, have been well documented with most trials reporting a significant 20% reduction in vascular events.5 Clopidogrel, an ADP antagonist, was studied in the CAPRIE trial and resulted in a significant 23.8% reduction in cardiovascular events in the PAD cohort compared to aspirin.6 Interestingly, ticagrelor and prasugrel do not have an FDA-approved indication to reduce cardiovascular events in patients with peripheral arterial disease.
I think the intimate relationship between platelets and clotting factors in hemostasis is often underappreciated. Many of the complex biochemical reactions involved in activating clotting factors occur on the surface of the platelet, and many clotting factors are potent platelet activators. Historically, arterial thrombosis was seen as a platelet-rich process and antiplatelet therapies were studied and utilized to manage patients who experience a thrombotic event in an arterial bed such as the heart, brain, or periphery. We first began to appreciate the potential benefits of an antiplatelet and anticoagulant combination in the management of acute coronary syndromes – and now patients routinely receive aspirin, clopidogrel, and a heparin during the index event. The underlying disease process in peripheral vessels is no different than coronary or cerebrovascular vessels. Early investigations in patients with PAD explored warfarin with antiplatelet therapy, but this combination was not more effective than antiplatelet therapy alone with an increase in bleeding events.7 It was hypothesized that low dose rivaroxaban, an oral direct factor Xa inhibitor, combined with aspirin, would reduce the incidence of vascular events in patients with PAD.8 In the COMPASS trial, 27,395 patients were randomized to receive rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily or aspirin 100 mg once daily. The composite of myocardial infarction (MI), stroke, and cardiovascular (CV) death occurred in fewer patients receiving rivaroxaban and aspirin versus aspirin alone (4.1% vs 5.4%; p<0.001). The incidence of major bleeding events occurred in more patients receiving rivaroxaban and aspirin compared to aspirin alone (3.1% vs 1.9%; p<0.001) with no significant differences in fatal bleeding, intracranial bleeding, or symptomatic bleeding into a critical organ. These data suggest the combination of rivaroxaban and aspirin should be strongly considered in patients with peripheral atherosclerosis to reduce cardiac and vascular events.
I think we’re finally recognizing and addressing the need to provide comprehensive therapy to patients with PAD. As pharmacists, we can play a critical role in the diagnosis of the disease and optimization of life-saving therapy. Despite aggressive research and evolving therapeutic options, we need clinicians and educators to promote disease state awareness to patients and other colleagues.
- Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, Jönsson B, Lacroix P, Marin B, McDermott MM, Norgren L, Pande RL, Preux PM, Stoffers HE, Treat-Jacobson D; American Heart Association Council on Peripheral Vascular Disease Circulation. 2012 Dec 11;126(24):2890-909. doi: 10.1161/CIR.0b013e318276fbcb. Epub 2012 Nov 16. Erratum in: Circulation. 2013 Jan 1;127(1):e264. PMID: 23159553.
- 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. Circulation. 2017;135:e686-725.
- Fowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329-1340.
- McClary KN, Massey P. Ankle Brachial Index. 2020 May 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 31334946.
- Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860.
- CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.
- Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007;357(2):217-227.
- Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319-1330.