PAD is the result of atherosclerotic plaque formation in the arteries that results in decreased blood flow to the legs. Several of the treatment goals for these patients involve address the cardiovascular risk factors that contribute to the development of PAD, it's progression, and patient outcomes. Specific goals include increasing maximum walking distance, walking duration, and pain-free walking; optimizing risk factor management (eg, HTN, dyslipidemia, and diabetes); improving the overall quality of life; and reducing cardiovascular complications and death.3
General Approach to Treatment
As with any atherosclerotic condition, several risk factors play an important role in the morbidity and mortality of PAD. Many of these risk factors are modifiable using various nonpharmacologic and pharmacologic interventions. Optimization of all modifiable risk factors, except high serum levels of homocysteine, have demonstrated improvements in either morbidity and/or mortality.
Not only does cigarette smoking increase the risk of developing PAD and other cardiovascular disorders, but the duration and quantity smoked can negatively impact disease progression (eg, increase the risk of amputation) and increase mortality.5,23 As a result, patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit.3 Providers should offer nonpharmacologic and pharmacologic options to aid the patient in achieving smoking cessation. Individual or group behavior modification therapy with or without the addition of certain antidepressants (eg, bupropion), varenicline, or nicotine replacement therapy (eg, gum or patches) has been proven effective in numerous studies. Dosing, monitoring, and contraindications for specific smoking cessation agents may be found in Chapter 44, Chronic Obstructive Pulmonary Disease.
Walking exercise programs for patients with PAD have been proven to result in an increase in walking duration and distance, an increase in pain-free walking, and a delayed onset of claudication by 179%.3,24 Walking, or any aerobic exercise program conducted under the supervision of a healthcare provider, has the ability to positively impact several of the pathophysiologic abnormalities present in patients with PAD. Benefits of exercise programs include improving diabetes and lipid management, reducing weight, improving blood viscosity and flow, and reducing blood pressure.25 Walking distance can also be used as a prognostic tool for future outcomes in patients with normal and impaired ABIs. A study conducted by de Liefde et al.26 demonstrated that walking impairment in conjunction with impaired ABI was associated with higher cardiovascular events, including death. Similarly, other studies have observed a link between impaired exercise/walking distance and negative long-term outcomes in patients with PAD.27,28 Finally, walking distances can be used as a monitoring tool for claudication medications by comparing their current walking distance to their baseline walking distance.
In patients with claudication, a supervised exercise program is recommended to improve functional status and quality of life and reduce leg symptoms. The guidelines recommend an exercise prescription consisting of a minimum of 30 to 45 minutes of activity performed at least three times per week for a minimum of 12 weeks.3 During exercise sessions, walking should be performed at a speed and grade of incline to produce the symptoms of IC within 3 to 5 minutes. Unstructured community-based or home-based walking programs that consist of providing general recommendations to patients with claudication to simply walk more are not effective.16 More recently, studies supporting structured community- or home-based programs for patients with symptomatic PAD have demonstrated improvement in claudication and should be considered as an alternative.3,24 The type of aerobic activity recommended, as well as the duration and frequency of the activity, should be individually designed on a patient-to-patient basis (Table e34-2).
TABLE e34-2Guideline Recommended Definitions for PAD Exercise Programs |Favorite Table|Download (.pdf) TABLE e34-2 Guideline Recommended Definitions for PAD Exercise Programs
|Supervised Exercise Program ||Structured-Community or Home-Based Exercise Program |
Program takes place in a hospital or outpatient facility directly supervised by a qualified healthcare provider(s).
Program uses intermittent walking exercise as the treatment modality.
Program can be standalone or within a cardiac rehabilitation program.
Training is performed for a minimum of 30-45 minutes per session; sessions are performed at least 3 times/week for a minimum of 12 weeks.
Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest.
Warm-up and cool-down periods precede and follow each session of walking.
Program takes place in the personal setting of the patient rather than in a clinical setting.
Program is self-directed with the guidance of healthcare providers.
Healthcare providers prescribe an exercise regimen similar to that of a supervised program.
Patient counseling ensures understanding of how to begin and maintain the program and how to progress the difficulty of the walking (by increasing distance or speed).
Program may incorporate behavioral change techniques, such as health coaching or use of activity monitors.
Several surgical procedures are available for patients with severe, debilitating claudication who have attempted, and failed, nonpharmacologic and pharmacologic therapy. The TASC guidelines make clear recommendations for invasive therapy.17 First, there must be a lack of adequate response to exercise therapy and risk factor modification. Second, the patient must have severe disability from IC resulting in impairment of daily activities. Third, there must be a thorough evaluation of the risks versus benefits of intervention including the probability of success, the anticipated future course of the disease if an intervention is not performed, and an evaluation of concomitant disease states.29
The decision to attempt percutaneous revascularization is often made with the guidance of diagnostic angiography. Percutaneous transluminal angioplasty (PTA) is an example of a minimally invasive procedure for PAD. PTA typically is reserved for patients whose lifestyle and/or job performance are compromised secondary to claudication despite adequate pharmacologic interventions and exercise.3,30 A randomized controlled clinical trial performed by Whyman et al.30 determined that in a 2-year post-intervention, PTA outcomes on maximum walking distance and ABI were not significantly different than in patients who had only received daily low-dose aspirin (acetylsalicylic acid [ASA]).
For patients with severe IC resulting in critical leg ischemia, more invasive surgical interventions such as aortofemoral bypass surgery or femoral popliteal bypass surgery may be an equivalent, if not better option, than PTA. A large prospective study evaluating open vascular surgery versus endovascular procedures using PTA found no significant difference in amputation-free survival and overall survival between groups. However, the bypass surgery–first approach improved survival by 7.3 months in those patients who survived at least 2 years after randomization.31
HTN is a major risk factor for PAD and can lead to AMI, stroke, heart failure (HF), and death.32 Current guidelines recommend the treatment goal for blood pressure in patients with PAD to mirror those in patients with documented CVD. PAD patients with HTN should achieve a target goal of less than 130/80 mm Hg. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are reasonable antihypertensive agents for patients with symptomatic or asymptomatic PAD. The Heart Outcomes Prevention Evaluation (HOPE)33 study demonstrated that ACE inhibitors reduced not only blood pressure but also other cardiovascular events (eg, AMI, stroke, and death) in high-risk patients, including those with PAD. β-Blockers are also effective and safe for treatment of HTN in patients with PAD. Historically, the safety of β-blockers was controversial because unopposed alpha constriction may lead to a reduction of peripheral circulation resulting in claudication symptoms. However, the safety of β-blockers in PAD was evaluated in a meta-analysis of six randomized controlled trials34 that suggested no evidence of harm in patients with PAD. Further, selection of drug therapy for HTN should be made in accordance with comorbid disease states, drug costs, and availability, drug allergies, or other possible limiting factors.35 For example, patients with concomitant Raynaud phenomenon may benefit from calcium channel blockers while patients with documented CAD may receive a dual benefit from a β-blocker.35 Dosing, monitoring guidelines, and contraindications for specific agents used in the treatment of HTN may be found in Chapter 30, Hypertension.
Although it has been shown that a reduction in lipid levels can reduce the progression of PAD, the severity of claudication, and adverse limb-related events, the current recommendations for the management of dyslipidemia in PAD are based on only a few studies with most including patients with other forms of clinical atherosclerosis.3,11 The 2018 ACC/AHA Cholesterol guideline11 classifies PAD as a form of clinical atherosclerotic cardiovascular disease (ASCVD), and at the highest risk for recurrent ASCVD and ASCVD death. Therefore, high-intensity statin therapy is recommended over moderate intensity for secondary prevention of events in patients younger than or aged 75 years with PAD. Atorvastatin 80 mg and rosuvastatin 20 mg daily have been shown to reduce ASCVD events and are recommended in PAD patients to reduce the LDL by 50% or greater. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have recently been studied in patients with peripheral atherosclerosis.24,36 Early evidence suggests evolocumab reduces both major adverse cardiac events (MACE), which includes cardiovascular death, myocardial infarction, and stroke, and major adverse limb events (MALE), which includes acute limb ischemia, major amputation, and urgent revascularization. The 2018 ACC/AHA Cholesterol guidelines recommend the intitiation of ezetimibe and/or aPCSK9 inhibitor in patients who are at very high risk (multiple ASCVD events or 1 ASCVD event with multiple high risk conditions) receiving maximally tolerated LDL lowering therapy with an LDL ≥70 mg/dL (≥1.81 mmol/L) or a non-HDL ≥100 mg/dL (≥2.59 mmol/L). Specific recommendations can be found in Chapter 31, Dyslipidemia.
A meta-analysis of over 95,000 diabetic patients provided additional support for the accepted premise that glycemic control serves as a risk factor for CVD.37 The analysis demonstrated an increasing risk of death from cardiovascular events as blood glucose concentrations increased, with the same relationship observed even at levels below the threshold of clinically defined diabetes mellitus. This relationship is just one illustration of the criticality of good glycemic control. Due to the high prevalence of PAD among diabetic patients, the American Diabetes Association recommends ABI screening for PAD in all diabetics older than 50 years.3,38 Due to the presence of peripheral neuropathy, patients with diabetes may be less likely to experience or report symptoms of PAD and the first sign may be as drastic as the appearance of a gangrenous foot ulcer. Therefore, although there is currently a lack of randomized controlled studies illustrating that the degree of glycemic control is predictive of the extent of PAD present, it is widely recommended that all patients with concomitant diabetes and PAD maintain good glycemic control, and a target hemoglobin A-1c level of less than 7% (0.07; 53 mmol/mol hemoglobin [Hb]).3,38 This recommendation is supported by a prospective cohort study of 1,894 diabetic patients, which demonstrated that patients with poor glucose control (A-1c greater than 7.5% [0.075; 58 mmol/mol Hb]) were five times more likely to develop IC and also to be hospitalized for PAD compared with those with a Hb A-1c less than 6% (0.06; 42 mmol/mol Hb).39 Oral antidiabetic agents, insulin regimens, as well as other pharmacologic and nonpharmacologic strategies to reduce the risk of complications associated with diabetes mellitus are discussed at length in Chapter 91, Diabetes Mellitus.
Antiplatelet Drug Therapy
Aspirin, relatively to any other pharmacologic agent, has the most compelling evidence to support its use in PAD. The Antithrombotic Trialists’ Collaboration (ATC)40 conducted a meta-analysis of 195 randomized trials, composed of over 135,000 patients at high risk for occlusive arterial disease, and concluded that low-dose ASA (75-160 mg) and medium-dose ASA (160-325 mg) lead to a significant reduction in serious vascular events (12%) in “high-risk” patients, such as those with PAD. The ATC also noted in this analysis that the risk of major extracranial bleed was similar between the low-dose and medium-dose regimens. A systematic review of the literature which included 111 trials (42 of which included patients with PAD, n = 9,214) concluded that patients with PAD should use ASA (160-325 mg/day) or clopidogrel (75 mg/day) when ASA is not tolerated or contraindicated.41
The ACC/AHA guidelines recommend aspirin alone (range 75-325 mg/day) to reduce MI, stroke, and vascular death in patients with symptomatic PAD. In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is also reasonable to consider to reduce cardiovascular complications.3 Unfortunately, no data are currently available from large, clinical, randomized trials that ASA, or any other antiplatelet therapies, can actually prevent or delay the onset of PAD.
Aspirin + Dipyridamole Extended Release (Aggrenox)
The ATC also examined the use of aspirin-dipyridamole extended-release (Aggrenox) in combination with ASA in “high-risk” patients, such as those with PAD. The meta-analysis of 25 trials (which included greater than 10,000 patients) concluded that the addition of dipyridamole to ASA led to an additional reduction in serious vascular events over ASA alone; however, this reduction was unable to reach statistical significance.40,41 Most of the individual studies included in this meta-analysis did not find any statistically significant difference in vascular outcomes.
Clopidogrel, a P2Y12 adenosine diphosphate (ADP)-receptor antagonist, can be used as an alternative to ASA.42 The ATC meta-analysis also reviewed the effectiveness of clopidogrel (Plavix) 75 mg/day in “high-risk” patients, including those with PAD. The ATC concluded that although clopidogrel was able to reduce serious vascular events by 10%, this was significantly less than the reduction seen with ASA (12%) described previously.40 Included in this meta-analysis was the report from the Clopidogrel versus ASA in Patients at Risk of Ischemic Events (CAPRIE) trial43 that had concluded that clopidogrel (75 mg daily) was more effective than ASA (325 mg daily) in preventing vascular events in “high-risk” patients. In comparison to the ASA therapy, the clopidogrel regimen resulted in an overall significant reduction in ischemic stroke, myocardial infarction (MI), or vascular death from 5.83% to 5.32%. This difference was even more pronounced in the subgroup analysis of PAD patients, in which clopidogrel (3.71%) led to a significant reduction in the composite outcome compared to ASA (4.86%). Although a generic clopidogrel product is now available, it remains significantly more expensive than ASA therapy and may be less accessible (prescription only) compared to ASA, an over-the-counter (OTC) product. According to the ACC/AHA guidelines, clopidogrel alone (75 mg/day) is equally recommended as ASA to reduce MI, stroke, and vascular death in patients with symptomatic PAD and a reasonable alternative in asymptomatic patients.3
Although ticlopidine inhibits ADP and has the same mechanism of action as clopidogrel, results of clinical trials among the two agents are strikingly different. The Swedish Ticlopidine Multicenter Study (STIMS)44 demonstrated that ticlopidine therapy (500 mg/day) significantly reduced total mortality when compared to placebo in patients with IC. However, the once-promising results seen with ticlopidine therapy have now been overshadowed by the hematologic side effects unique to this agent. Ticlopidine is no longer available in the United States and has a “boxed” warning from the Food and Drug Administration (FDA) that warns providers about the risk of neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura, and aplastic anemia45 (Table e34-3).
Table e34-3Pharmacotherapy Options for Patients with Peripheral Arterial Disease |Favorite Table|Download (.pdf) Table e34-3 Pharmacotherapy Options for Patients with Peripheral Arterial Disease
|Agent ||Daily Dose (Oral) ||Mechanism of Action ||Side Effects ||Contraindications ||Level of Evidence3 |
|Aspirin ||81-325 mg ||Irreversibly inhibits prostaglandin cyclooxygenase in platelets, prevents the formation of thromboxane A2 ||GI upset and/or bleeding ||Active bleeding, hemophilia, thrombocytopenia ||Symptomatic PAD (COR 1 LOE A) and asymptomatic PAD (COR IIa LOE C-EO)a |
|Dipyridamole ER (Aggrenox) ||400 mg (+aspirin 50 mg) ||May act by inhibiting platelet aggregation (complete MOA unknown) ||Angina, dyspnea, hypotension, headache, dizziness ||Active bleeding, CAD (“coronary steal syndrome”) ||Not specified |
|Cilostazol (Pletal) ||100 mg twice daily ||Phosphodiesterase inhibitor, suppresses platelet aggregation, direct artery vasodilator ||Fever, infection, tachycardia ||All CHF patients (decreased survival) ||COR 1 LOE A |
|Clopidogrel (Plavix) ||75 mg ||Inhibits binding of ADP analogs to its platelet receptor causing irreversible inhibition of platelets ||Chest pain; purpura generalized pain; rash ||Active pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage) ||Symptomatic PAD (COR 1 LOE A) and asymptomatic PAD (COR IIa LOE C-EO) |
|Pentoxifylline (Trental) ||1.2 g ||Alters RBC flexibility, decreases platelet adhesion, reduces blood viscosity, decreases fibrinogen concentration ||Dyspnea, nausea, vomiting, headache, dizziness ||Recent retinal or cerebral hemorrhage, active bleeding ||COR III LOE B-R |
|Ticlopidine (Ticlid) ||500 mg ||Inhibits binding of ADP analogs to its platelet receptor causing irreversible inhibition of platelets ||Leukopenia, rash, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia ||Active bleeding, hemophilia, thrombocytopenia ||Not specified |
Despite the use of antiplatelet therapy, patients with PAD still experience high rates of cardiovascular events. Therefore, it is reasonable to expect that the addition of an anticoagulant, such as warfarin, may be more beneficial since platelet activation and thrombin generation both play important roles in the thrombus development in arterial disease. However, randomized controlled trials and observational studies have consistently demonstrated that oral anticoagulation therapy aimed at reducing cardiovascular ischemic events provide no benefit and result in increased morbidity.50,51 In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial,52 patients with atherosclerotic vascular disease, including PAD, experienced no benefit in reducing cardiovascular ischemic events with oral anticoagulation and antiplatelet therapy compared to antiplatelet therapy alone. In addition, there was an increase in bleeding events, including life-threatening and intracranial bleeding. The ACC/AHA guidelines do not recommend anticoagulation to reduce the risk of cardiovascular ischemic events in patients with PAD.3
Non-Vitamin K Oral Anticoagulants
The development of target-specific anticoagulants has led to a renewed interest in studying antithrombotic therapy in peripheral arterial disease. Rivaroxaban, a direct factor Xa inhibitor, was studied in stable cardiovascular disease, including coronary and peripheral arterial disease, with and without ASA. The PAD subgroup analysis of the COMPASS trial53,54 shows that use of rivaroxaban 2.5 mg twice a day with ASA 81 mg daily reduces cardiovascular death, myocardial infarction, stroke, and acute limb ischemia and amputation, compared with ASA alone. Although there is an increase in bleeding leading to more hospital admissions, there is no excess of fatal bleeding, intracranial bleeding, or bleeding into critical organs. This combination could replace aspirin alone as the standard of care in patients with PAD who are not at high risk for bleeding. Rivaroxaban 2.5 mg twice daily has been approved for use by the Food and Drug Administration in patients with PAD defined as patients with either a previous limb arterial surgery, bypass, or percutaneous transluminal angioplasty, previous limb or foot amputation due to arterial disease, or history of intermittent claudication with an ABI <90% or peripheral arterial stenosis ≥50%.
Cilostazol works through cyclic nucleotide phosphodiesterase (PDE3) to degrade cyclic adenosine monophosphate (cAMP) which may benefit PAD patients with IC through vasodilation and antiplatelet effects. In a head-to-head, randomized, placebo-controlled study in 698 patients with moderate-to-severe claudication, Dawson et al.55 assigned patients to cilostazol (100 mg twice a day), pentoxifylline (400 mg three times a day), or placebo in an effort to improve maximal walking distance. After 24 weeks, the cilostazol group demonstrated a statistically significant 54% mean increase in distance compared to a 30% mean increase with pentoxifylline which was similar to placebo. Similarly, a meta-analysis of eight randomized, double-blind, placebo-controlled, parallel-design trials supported this conclusion with a signifcant increase reported in maximal walking distance and pain-free walking distance with cilostazol at doses of 50 and 100 mg twice daily over placebo. While cilostazol is associated with improvement in claudication symptoms, no improvements in cardiovascular death or quality of life have been reported. Furthermore, cilostazol received a “boxed” warning from the FDA cautioning use with coexisting HF of any severity due to risk of ventricular tachyarrhythmias and reduced survival from phosphodiesterase III inhibition.46 The ACC/AHA guidelines recommend cilostazol as an effective therapy to improve symptoms and increase walking distance in patients with claudication.3
Unlike cilostazol, pentoxifylline is a xanthine derivative and improves peripheral blood flow and tissue oxygenation through its vasoactive effects. However, data have been less promising than cilostazol in clinical trials. In a randomized study,55 cilostazol outperformed pentoxifylline in improvement in walking distance. Furthermore, improvement in walking distance between pentoxifylline and placebo was not found to be different. Likewise, other meta-analyses have shown minimal improvements with pentoxifylline over placebo.56 For these reasons, the ACC/AHA guidelines do not recommend pentoxifylline for treatment of claudication.3