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 the reduction of confounding variables that attribute to the disease process, progress, and eventual outcome. Specific goals should include increasing maximal walking distance, duration, and pain-free walking, improving control of comorbid conditions contributing to the morbidity of the condition (eg, HTN, hyperlipidemia, and diabetes), improvement in overall quality of life, and reduction in cardiovascular complications and death.
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 with the help of various nonpharmacologic and pharmacologic interventions.
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.4,21,22 As a result, providers must advise patients to quit and should offer nonpharmacologic and pharmacologic means to aid the patient in that goal. 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. Varenicline has demonstrated superior quit rates compared with nicotine replacement therapy and bupropion.3 Other forms of tobacco use should be discouraged as well. Reassessment of smoking status and progress encouragement at each encounter can help to reemphasize to the patient the vital importance of this lifestyle change.
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%.3,23 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.24 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.25 examined patients with normal ABI (≥0.90) and impaired ABI (less than 0.90) in relation to walking distance. It was demonstrated that walking impairment in conjunction with impaired ABI was associated with higher cardiovascular events, including death. Other studies have likewise observed a link between impaired exercise/walking distance and negative long-term outcomes in patients with PAD.26,27
The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Management of PAD recommend supervised exercise training for patients with IC, for a minimum of 30 to 45 minutes, to be 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. The patient should stop walking when the symptoms become moderate in intensity, wait for the symptoms to resolve, and then resume walking, thus repeating the cycle for the duration of the session.13 A prospective, observational study performed by Gardner et al.28 concluded that PAD patients with higher physical activity (as measured with a vertical accelerometer) have reduced mortality and cardiovascular events compared with those with low physical activity, regardless of confounders. Exercise treadmill walking testing should be repeated at regular intervals (eg, quarterly to biannually) to assess improvement or decline in walking duration and distance, as well as time to assess pain onset while performing this activity. 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.
Various procedures are available for patients with severe, debilitating claudication who have attempted, and failed, other means of nonpharmacologic and pharmacologic therapy. The TASC document on PAD provides clear recommendations for invasive therapy.13 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 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.3,23 A randomized controlled clinical trial performed by Whyman et al.30 determined that in a 2-year post inter vention, 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 or femoral popliteal bypass 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, bypass surgery–first approach improved survival by 7.3 months (95% confidence interval [CI]: 1.2-13.4 months; P 0.02) in those patients who survived at least 2 years after randomization.3
HTN is a major risk factor for PAD and can lead to AMI, stroke, heart failure (HF), and death.31 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 140/90 mm Hg in nondiabetics or less than 130/80 mm Hg in diabetics to reduce risk factors for PAD. β-Blockers are effective and safe for treatment of HTN in patients with PAD. The safety of β-blockers with PAD was evaluated in a meta-analysis of six randomized controlled trials32 suggesting no evidence of harm in patients with PAD. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are also 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. 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.34 For example, patients with concomitant Raynaud phenomenon may benefit from calcium channel blockers while patients with documented CAD may receive a dual benefit by the selection of a β-blocker.34 Dosing, monitoring guidelines, and contraindications for specific agents used in the treatment of HTN may be found in Chapter 13.
Although it has been shown that a reduction in lipid levels can reduce the progression of PAD and the severity of claudication, the current recommendations for the management of hyperlipidemia in PAD are based on only a few small studies and sub-hoc analyses from larger trials.3,9 The 2013 ACC/AHA cholesterol guideline9 classifies PAD as a coronary heart disease (CHD) risk equivalent and at highest risk for recurrent atherosclerotic cardiovascular disease (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. Atovastatin 80 mg and rosuvastatin 20 mg daily have been shown to reduce ASCVD events and are recommended in PAD patients. However, patients older than 75 years and the risk of adverse effects and tolerability are also important factors when weighing risk versus benefit of therapy. Specific recommendations can be found in Chapter 21.
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.35 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.36 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% (less than 0.07; less than 53 mmol/mol hemoglobin [Hb]).3,36 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% [greater than 0.075; greater than 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% (less than 0.06; less than 42 mmol/mol Hb).37 Despite this, a study of 365 patients with known PAD and concomitant diabetes done by Rehring et al.38 showed that only 45.8% of these patients had a Hb A-1c les than 7% (less than 0.07; less than 53 mmol/mol Hb). 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 74.
Antiplatelet Drug Therapy
TABLE e22-3Pharmacotherapy Options for Patients with Peripheral Arterial Disease |Favorite Table|Download (.pdf) TABLE e22-3 Pharmacotherapy Options for Patients with Peripheral Arterial Disease
|Agent ||Daily Dose (Oral) ||Mechanism of Action (MOA) ||Side Effects ||Contraindications ||Level of Evidencea |
|Aspirin ||81-325 mg ||Irreversibly inhibits prostaglandin cyclooxygenase in platelets, prevents formation of thromboxane A2 ||GI upset and/or bleeding ||Active bleeding; hemophilia; thrombocytopenia ||With coronary or cerebrovascular (Grade 1A), without (Grade 1C+) |
|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”) ||Recommendation for use not specified in report |
|Cilostazol (Pletal)b ||100 mg twice daily ||Phosphodiesterase inhibitor, suppresses platelet aggregation; direct artery vasodilator ||Fever: infection; tachycardia ||All CHF patients (decreased survival) ||With IC (Grade 2A) |
|Clopidogrel (Plavix) ||75 mg ||Inhibits binding of ADP analogues to its platelet receptor causing irreversible inhibition of platelets ||Chest pain; purpura generalized pain; rash ||Active pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage) ||Recommend clopidogrel over no antiplatelet therapy (Grade 1C+) |
|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 ||Not recommended in patients with IC (Grade 1B) |
|Ticlopidine (Ticlid) ||500 mg ||Inhibits binding of ADP analogues to its platelet receptor causing irreversible inhibition of platelets ||Leukopenia; rash; thrombocytopenia; neutropenia; agranulocytosis; aplastic anemia ||Active bleeding; hemophilia; thrombocytopenia ||Clopidogrel recommended over ticlopidine (Grade 1C+) |
By far, the most compelling evidence for the use of any pharmacologic agent in PAD can be found for ASA. The Antithrombotic Trialists’ Collaboration (ATC)39 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/day) 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.
Tran and Anand40 conducted a systematic review of the literature in an effort to summarize the best evidence for oral antiplatelet therapy in patients with cerebrovascular disease, CAD, and PAD. This review included 111 trials (42 of which included patients with PAD, n = 9,214) and concluded that patients with PAD should use ASA (160-325 mg/day) or clopidogrel (75 mg/day) when ASA is not tolerated or contraindicated. This is in concordance with the recommendations of the Ninth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy that recommends lifelong ASA (75-325 mg/day) over clopidogrel and ticlopidine, and no antithrombotic therapy in patients with PAD.41,42 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 (6%); however, this reduction was unable to reach statistical significance (P = 0.32).39,40 It should also be taken into consideration that most of the reduction in nonfatal stroke in this analysis came from one trial, and these data are not replicated in the other studies. The addition of dipyridamole to ASA may cause an increased risk of bleeding and gastrointestinal (GI) side effects when compared with placebo and should not be used with CAD.43
Clopidogrel, a P2Y12 adenosine diphosphate (ADP)-receptor antagonists can be used an alternate to ASA. 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%, P = 0.03) described previously.39 Included in this meta-analysis was the report from the Clopidogrel versus ASA in Patients at Risk of Ischemic Events (CAPRIE) trial44 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 reduction in ischemic stroke, myocardial infarction (MI), or vascular death from 5.83% to 5.32% (P = 0.043). This difference was even more pronounced in the subgroup analysis of PAD patients, in which clopidogrel therapy led to a significant reduction of 4.86% versus 3.71% in the ASA group (P = 0.0028). Although a generic clopidogrel product is now available, it remains significantly more expensive than ASA therapy and may be less accessible by prescription than ASA, an over-the-counter (OTC) product. For this reason and established safety and efficacy with ASA in the PAD population, clopidogrel is recommended only when ASA therapy is not tolerated or contraindicated.39
Although ticlopidine causes ADP inhibition 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)45 demonstrated that ticlopidine therapy (500 mg/day) was able to reduce total mortality in comparison to placebo in patients with IC (P = 0.015). However, the once promising results seen with ticlopidine therapy have now been overshadowed by the severe hematologic side effects unique to this agent. Ticlopidine is not currently available in the United States and has a “boxed” warning from the Food and Drug Administration (FDA) warning providers that use of this agent can cause neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura, and aplastic anemia. Other agents, namely, clopidogrel, are now used recommended over ticlopidine.3
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.46 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 54% mean increase in distance compared to a 30% mean increase with pentoxifylline (P less than 0.001) which was similar to placebo. Similarly, a meta-analysis of eight randomized, double-blind, placebo-controlled, parallel-design trials supported this conclusion with a reported increase in maximal walking distance and pain-free walking distance with cilostazol at doses of 50 and 100 mg twice daily (P less than 0.05 for all) over placebo. 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.47 However, the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy does suggest a potential use of this agent in refractory patients with PAD without HF who are not candidates for surgical interventions.39
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,46 cilostazol outperformed pentoxifylline in improvement in walking distance; any improvement with pentoxifylline was not found to be different from placebo (P = 0.82). Likewise, other meta-analyses have shown minimal improvements with pentoxifylline over placebo.48 For these reasons, the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy does not recommend the use of this agent for PAD.