Antiplatelet Therapy for Peripheral Arterial Disease and Critical Limb Ischemia

Abstract

Antiplatelet therapy is invariably prescribed for patients with peripheral arterial disease and critical limb ischemia, and numerous major society guidelines espouse their use, but high-quality data in this high-risk and challenging patient population are often lacking. This article summarizes the major guidelines for antiplatelet therapy, reviews the major studies of antiplatelet therapy in peripheral arterial disease (including data for aspirin, clopidogrel, dipyridamole, cilostazol, and prostanoids), and offers perspective on the potential benefits of ticagrelor, vorapaxar, and rivaroxaban. The review concludes with a discussion of the relative lack of efficacy that antiplatelet therapy has shown in regard to peripheral vascular outcomes.

Keywords

peripheral arterial disease heart disease critical limb ischemia antiplatelet therapy aspirin clopidogrel

Introduction

Lower extremity peripheral arterial disease (PAD) encompasses a wide range of vascular diseases caused by atherosclerotic, thromboembolic, and inflammatory processes that alter the structure and function of the lower extremity arteries.¹ The primary cause of lower extremity PAD, however, is atherosclerosis. Symptomatic lower extremity PAD arises from inadequate blood flow, causing oxygen supply and demand mismatch. Critical limb ischemia (CLI) is the most severe form of lower extremity PAD. It is defined as lower extremity pain that occurs at rest or in the presence of ulcers or gangrene, secondary to severe compromise of blood flow.² Critical limb ischemia generally refers to Rutherford categories 4, 5, and 6 (ischemic rest pain, minor tissue loss, and major tissue loss, respectively). Acute limb ischemia, a subset of patients with CLI, is defined as a sudden decrease in limb perfusion that threatens limb viability.

The scope of PAD in the United States is considerable. The National Health and Nutrition Examination Survey estimated the prevalence of PAD in adults aged 40 years or older, defined as an ankle–brachial index (ABI) of ≤0.90, at 4.3%; this represents approximately 5 million individuals in the United States.³ A cross-sectional study of primary care patients, using the same definition, showed an even higher prevalence of 29%.⁴ Historically, the incidence of CLI was reported to be much lower: only 2% of patients with symptomatic PAD would progress to CLI. This would account for about 500 to 1000 incident cases per million population each year in the United States.² Recent data, however, suggest that CLI may be more common than previously realized. The Reduction of Atherothrombosis for Continued Health (REACH) registry showed that among patients with symptomatic PAD, 15% will eventually have a lower limb amputation.⁵ And patients with symptomatic PAD in a recent clinical trial, at a median of 2 years of follow-up, progressed to acute limb ischemia in 2.9% of cases.⁶

Patients with PAD are at increased risk of myocardial infarction (MI), stroke, and cardiovascular death. Among elderly populations with PAD, the incidence of coronary artery disease and stroke may be as high as 68% and 42%, respectively.⁷ In addition, the relative risk (RR) of cardiovascular death in patients with PAD is increased almost 6-fold.^1,8 The prognosis of patients with CLI, however, is even more grave. Only 1 year after the onset of symptoms, 25% of patients with CLI will be dead and 25% will have a major amputation.²

Given the markedly elevated cardiovascular risk among patients with PAD, antiplatelet therapy would be expected to be of great benefit. Surprisingly, however, there is very little evidence that antiplatelet therapy alters the natural history of PAD and CLI. This article reviews the existing evidence and offers a framework for the pharmacologic therapy of PAD and CLI, both present and future.

Antiplatelet Therapy for PAD and CLI

There is consensus among major society guidelines that antiplatelet therapy with aspirin 75 to 325 mg is indicated for secondary prevention of cardiovascular events in patients with symptomatic PAD or PAD associated with coronary or cervicocerebral atherosclerotic disease. The same guidelines, however, are inconsistent and often contradictory in regard to asymptomatic PAD, CLI, or the addition of clopidogrel.^1,2,9
-11 Tables 1 and 2 summarize existing guideline recommendations for antiplatelet therapy in patients with PAD and CLI, respectively. Table 3 outlines commonly used antiplatelet agents in the treatment of PAD and CLI.

Table 1.

Guidelines for Antiplatelet Therapy in Patients With Lower Extremity Peripheral Arterial Disease.

Professional Society	Guideline Recommendations
ACC/AHA 2005, 2011^1,9	Asymptomatic If ABI less than 0.9: antiplatelet therapy can be useful to reduce the risk of MI, stroke, CLI, or vascular death (IIa, C). If ABI 0.91 to 0.99: usefulness of antiplatelet therapy not well established (IIb, A).
ACC/AHA 2005, 2011^1,9	Symptomatic (intermittent claudication, critical limb ischemia, prior lower extremity revascularization, prior amputation for lower extremity ischemia): Antiplatelet therapy is recommended to reduce cardiovascular risk. (I, A) Aspirin 75 to 325 mg daily or clopidogrel 75 mg daily (I, B) If patient is at high risk of cardiovascular events and not at high risk of bleeding: dual antiplatelet therapy with aspirin and clopidogrel may be considered (IIb, B). No indication for adding warfarin to antiplatelet therapy (III, B).
CHEST 2012¹⁰	Asymptomatic: Aspirin 75 to 100 mg daily (2B)
CHEST 2012¹⁰	Symptomatic: Aspirin 75 to 100 mg daily or clopidogrel 75 mg daily (IA) No indication for dual antiplatelet therapy (2B) No indication for an antiplatelet with moderate intensity warfarin (IB) Intermittent claudication refractory to exercise therapy (and smoking cessation): add cilostazol to aspirin 75 to 100 mg daily or clopidogrel 75 mg daily (2C) No indication for pentoxifylline, heparinoids, or prostanoids (2C)
TASC II 2007²	Symptomatic with or without a history of other cardiovascular disease (A): Clopidogrel 75 mg daily (B) or Aspirin 75 to 160 mg daily long term (A)
	PAD with clinical evidence of other forms of cardiovascular disease (coronary or carotid): Aspirin 75 to 160 mg daily long term (A) or Clopidogrel 75 mg daily (B) No indication for combination therapy with aspirin and clopidogrel
	PAD without clinical evidence of other forms of cardiovascular disease (coronary or carotid): Aspirin 75 to 160 mg daily long term can be considered (C)
European Society of Cardiology 2011¹¹	Symptomatic lower extremity PAD: Clopidogrel 75 mg daily (I, C) or Aspirin 75 to 150 mg daily (I, C) In patients with lower extremity PAD and stable CAD, clopidogrel should be considered as an alternative to aspirin for long-term antiplatelet therapy (IIa, B) Dual antiplatelet therapy NOT recommended

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; ABI, ankle–brachial index; MI, myocardial infarction; CLI, critical limb ischemia; CAD, coronary artery disease; PAD, peripheral arterial disease; TASC, TransAtlantic InterSociety.

Table 2.

Guidelines for Antiplatelet Therapy in Patients With Critical Limb Ischemia.

Professional Society	Guideline Recommendations
ACC/AHA, 2005, 2011^1,9	Aspirin 75 to 325 mg daily or clopidogrel 75 mg daily (I, B) If patient is at high risk of cardiovascular events and not at high risk of bleeding: dual antiplatelet therapy with aspirin and clopidogrel may be considered (II, B) No indication for adding warfarin to the antiplatelet agent (III, B)
CHEST 2012¹⁰	For patients with symptomatic PAD and CLI/rest pain who are not candidates for vascular intervention, the addition of prostanoids is suggested in addition to antiplatelet therapy (aspirin 75-100 mg daily or clopidogrel 75 mg daily; 2C)
TASC II 2007²	Antiplatelet drugs should be started preoperatively and continued indefinitely as adjuvant pharmacotherapy after an endovascular or surgical procedure, unless subsequently contraindicated (A) Although there is no evidence that these drugs would improve outcomes in CLI, as in all patients with PAD they do reduce the risk of systemic vascular events (A)
European Society of Cardiology 2011¹¹	Antiplatelet and anticoagulant therapy after revascularization: Aspirin is recommended in all patients with angioplasty for lower extremity arterial disease (I, C)
	Infrainguinal bare-metal-stent implantation: Aspirin and a thienopyridine for at least 1 month (I, C)
	Infrainguinal bypass surgery: Aspirin (I, A) or Aspirin and dipyridamole (I, A)
	Autogenous vein infrainguinal bypass: Antithrombotic treatment with vitamin K antagonists may be considered (IIb, B)
	Below-knee bypass with a prosthetic graft: Dual antiplatelet therapy combining aspirin and clopidogrel may be considered (IIb, B)

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; CLI, critical limb ischemia; PAD, peripheral arterial disease; TASC, TransAtlantic InterSociety.

Table 3.

Commonly Used Antiplatelet Agents in the Treatment of PAD and CLI.

Antiplatelet Agent	Dose	Indication	Major Trials	Outcomes Data
Aspirin	75-325 mg/d	Secondary prevention of cardiovascular events in symptomatic PAD or PAD associated with coronary or cervicocerebral atherosclerotic disease	Antithrombotic Trialists’ Collaboration meta-analysis, 2002²⁷ Aspirin for Asymptomatic Atherosclerosis (AAA) trial, 2010²⁹	9214 patients with PAD treated with aspirin in 42 trials 23% reduction in serious vascular events (nonfatal myocardial infarction, CVA, or vascular death; P = .004) Similar benefits in patients with intermittent claudication, peripheral grafting, and peripheral angioplasty Aspirin 100 mg daily versus placebo in patients with no known cardiovascular disease and ABI ≤ 0.95 No difference in the primary end point of nonfatal coronary event, CVA, or revascularization at mean follow-up of 8.2 years Nonsignificant trend for increased bleeding in the aspirin group
Clopidogrel	75 mg/d	Adjunctive antiplatelet agent with aspirin for dual antiplatelet therapy in high-cardiovascular risk patients, below-knee bypass with a prosthetic graft, and patients undergoing stent implantation or drug eluting angioplasty of femoropopliteal or infrapopliteal arteries	CAPRIE, 1996²⁵ CHARISMA, 2006²⁶ Cacoub et al²⁷ CASPAR, 2010³⁰	Compared to aspirin 325 mg in patients with symptomatic atherosclerosis, including recent MI, ischemic CVA and symptomatic PAD RRR of 8.7% (95% CI 0.3-16.5, P = .043) in ischemic stroke, myocardial infarction, or vascular death. Highest reduction of risk in patients with PAD (RRR 23.8%, 95% CI 8.9-36.2; P = .003) Clopidogrel 75 mg versus placebo, with background therapy of aspirin 75 to 162 mg, in high-risk patients with stable CAD. No benefit of clopidogrel in regard to primary end point of cardiovascular death, MI, or CVA. Among patients with PAD in CHARISMA, no significant difference between clopidogrel and aspirin versus placebo and aspirin in regards to the primary end point Clopidogrel plus aspirin, compared to placebo plus aspirin, did not improve limb or systemic outcomes in patients with PAD requiring below-knee bypass grafting. Subgroup of patients receiving prosthetic grafts showed improved outcomes with clopidogrel plus aspirin (HR 0.65, 95% CI 0.45-0.95; P = .025)
Ticagrelor	180 mg loading dose, 90 mg twice daily maintenance dose	Patients with STEMI undergoing primary PCI and moderate to high risk NSTEMI/UA (both invasive and medical management)	PLATO, 2009⁶³ Patel et al⁶⁴	Compared to clopidogrel on background of aspirin therapy Significant reduction in primary end point of cardiovascular death, MI, and CVA: 9.0% versus 10.7%, HR 0.84, 95% CI 0.75-0.94 (P = .0025). Increase in non-CABG related total major bleeding with ticagrelor Post hoc analysis of patients with PAD in PLATO trial 19.8% cardiovascular and total deaths, MI, and stent thrombosis in patients with PAD versus 10.2% in patients without PAD (P < .001). Lower rates of vascular death or myocardial infarction in patients with PAD treated with ticagrelor compared to clopidogrel (16.7% vs 21.5%, P = .045) with similar bleeding rates
Dipyridamole	200 mg/d	Combination therapy with high-dose aspirin after infrainguinal bypass	Brown et al²⁶	Cochrane review of 6 trials Increase in infrainguinal primary graft patency for aspirin or aspirin plus dipyridamole at 1 year (OR 0.61, 95% CI 0.43-0.86; P = .005). More benefit for prosthetic versus venous grafts
Cilostazol	100 mg twice daily	Patients with PAD and intermittent claudication; after endovascular treatment for infrainguinal disease in critical limb ischemia	Robless et al⁴⁵ Soga et al, 2011⁴⁷	Cochrane review of 7 randomized trials showed significant increase in maximum walking distance Prospective registry of patients undergoing SFA stenting Lower rates of binary restenosis at 5 years with cilostazol (31.2% vs 42.9%, P = .02)
Prostanoids	Intra-arterial alprostadil (PGE1) for 21 days or intravenous iloprost (PGI2) for 14 to 28 days	As additional therapy in patients with critical leg ischemia who are not candidates for revascularization	Creutzig et al⁴⁰ Ruffolo et al⁴¹	Meta-analysis of 7 randomized trials in patients with CLI PGE1 therapy had significant benefit in regard to ulcer healing and pain relief (47.8% vs 25.2%, P = .029) and increased rate of patients surviving with both legs after 6 months (22.6% vs 36.2%, P = .015) Cochrane review of 13 trials Prostanoids effective for relief of rest pain (RR 1.32, 95% CI 1.10-1.57), and ulcer healing (RR 1.54, 95% CI 1.22-1.96); no effect upon amputation
Vorapaxar	2.5 mg/d	Secondary prevention of cardiovascular events, including patients with symptomatic PAD	TRA2P-TIMI 50, 2012⁶⁷ Bonaca et al, 2013⁶⁸	Compared to placebo in patients with cardiovascular disease Significant reduction in cardiovascular death/MI/CVA: 9.3% vs 10.5%, P < .001 Increase in moderate or severe bleeding: 4.2% vs 2.5%, P < .001 Subgroup analysis of TRA2P TIMI 50 with symptomatic PAD Significant reduction in acute limb ischemia (2.3% vs 3.9%, P = .006) and peripheral revascularization (18.4% vs 22.2%, P = .02)

Abbreviations: ABI, ankle–brachial index; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CASPAR, Clopidogrel and Acetylsalicylic acid in Bypass Surgery for Peripheral Arterial Disease; MI, myocardial infarction; RRR, relative risk reduction; CI, confidence interval; CAD, coronary artery disease; HR, hazard ratio; STEMI, ST-segment elevation myocardial infarction; NSTEMI/UA, non-ST-segment elevation myocardial infarction/unstable angina; PLATO, The phase III PLATelet inhibition and patient Outcomes; SFA, superficial femoral artery; PG, prostaglandin; RR, relative risk; CLI, critical limb ischemia; PAD, peripheral arterial disease; CVA, cerebrovascular accident.

Aspirin

The Antithrombotic Trialists’ Collaboration performed a meta-analysis of 287 studies involving 135 000 patients at high risk of vascular disease, examining the effect of antiplatelet therapy (primarily aspirin) upon the primary end point of vascular death, nonfatal MI, and nonfatal stroke. In the overall population, there was a significant reduction in the primary end point by one-fourth (10.7% vs 13.2%, P < .0001.) Among the subset of 9214 patients with PAD across 42 trials, there was a similar reduction in serious vascular events of 23% (5.8% vs 7.1%, P = .004), with similar trends observed among patients with intermittent claudication (IC), those who underwent peripheral grafting, and those who underwent peripheral angioplasty.¹² A subsequent meta-analysis by the same group examined 16 trials of aspirin for secondary prevention, showing a significant reduction in vascular death, nonfatal MI, and nonfatal stroke (6.7% vs 8.2% per year, P < .0001). Outcomes in the subgroup of patients with PAD, however, were not reported.¹³ A subsequent meta-analysis by Berger et al, however, specifically examined aspirin therapy (with or without dipyridamole) in 5269 patients with PAD. Although aspirin therapy was associated with a significant reduction in nonfatal stroke (RR 0.66, 95% confidence interval [CI] 0.47-0.94, P = .02), there was no significant effect upon cardiovascular or all-cause mortality, MI, or major bleeding. Results were similar for the subgroup of 3019 patients taking aspirin alone versus control.¹⁴

The Aspirin for Asymptomatic Atherosclerosis (AAA) trial was a double-blind, randomized controlled trial of aspirin 100 mg daily versus placebo in patients with no known cardiovascular disease and an ABI ≤0.95.¹⁵ At a mean follow-up of 8.2 years, there was no difference in the primary end point of nonfatal coronary event, stroke, or revascularization; there was a trend for increased bleeding in the aspirin group which was borderline significant (hazard ratio [HR] 1.71; 95% CI 0.99-2.97). A major limitation of the AAA study is its relatively low-risk PAD population, as patients were required to be asymptomatic and without a clinical history of PAD for inclusion. In addition, compliance with aspirin was suboptimal, with study drug taken for only 60% of trial person-years. Finally, the ABI for study inclusion was calculated using the lower pedal pulse; this differs from clinical practice, in which the higher pedal pulse is used.

Although there remains some controversy regarding effective aspirin dose, there is no question that low-dose aspirin (<100 mg) is effective for the prevention of vascular events in patients with cardiovascular disease.^12,16 Furthermore, the relatively recent The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT -OASIS 7) randomized trial showed no benefit to high-dose versus low-dose aspirin in patients with acute coronary syndromes but did show a small increase in gastrointestinal bleeding with high-dose aspirin.¹⁷

Data regarding high- versus low-dose aspirin for patients with PAD, however, are more limited. The strategy of high-dose aspirin after peripheral vascular intervention to prevent restenosis or reocclusion was investigated in 4 randomized studies: Heiss et al, Minar et al, Ranke et al, and Weichert et al.^18

-21 High-dose aspirin was given as 900 to 1000 mg (combined with dipyridamole in the Heiss et al trial); low-dose aspirin ranged from 50 to 300 mg daily. A subsequent Cochrane review of the 4 trials by Robertson et al showed that there was no effect of high-dose aspirin upon reocclusion within 1 month of intervention (odds ratio [OR] 1.45, 95% CI 0.63-3.36; P = .38). Similarly, at 6 months after intervention, there was still no benefit of high-dose aspirin (OR 0.99, 95% CI 0.71-1.38; P = .96). Gastrointestinal side effects, however, were more common with high- versus low-dose aspirin (OR 1.85, 95% CI 1.15-2.98; P = .01).²²

Thienopyridines

The thienopyridines (ticlopidine, clopidogrel, and prasugrel) selectively inhibit ADP-induced platelet aggregation by irreversibly blocking the P2Y12 adenosine diphosphate (ADP) receptor on the surface of platelets.²³ All thienopyridines are prodrugs that require metabolism by the hepatic cytochrome P450 (CYP) enzymatic system to acquire activity; however, prasugrel has a more rapid onset of action and produces greater and more predictable inhibition of ADP-induced platelet aggregation. These characteristics reflect the rapid and complete absorption of prasugrel from the gut and its more efficient hepatic activation.²⁴

The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared aspirin 325 mg to clopidogrel 75 mg in 19 185 patients with symptomatic atherosclerotic disease, including recent MI, ischemic stroke, and symptomatic PAD. Clopidogrel significantly reduced the combined primary end point of stroke, MI, and vascular death in the overall population, with a RR reduction of 8.7% (95% CI 0.3%-16.5%, P = .043). The CAPRIE trial included 6452 patients with PAD; this subgroup showed a more impressive RR reduction of 23.8% (95% CI 8.9%-36.2%, P = .003) and similar adverse event rates compared to ischemic stroke and MI subgroups. Gastrointestinal bleeding was marginally less frequent with clopidogrel versus aspirin (2.0% vs 2.7%, P = .05).²⁵

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial was a randomized, double-blind trial comparing clopidogrel 75 mg daily versus placebo, in addition to background therapy with aspirin 75 to 162 mg. The primary end point of cardiovascular death, MI, or stroke was investigated in a total of 7802 high-risk patients with stable coronary artery disease. At 2 years, there was a somewhat surprising finding of no benefit from clopidogrel in regard to the primary end point. Clopidogrel was of marginal benefit in the subgroup of patients with clinically evident (ie, symptomatic) cardiovascular disease (RR 0.88; 95% CI 0.77-0.998; P = .046).²⁶ Cacoub et al subsequently reported a post hoc analysis of 3096 patients with symptomatic (2338) and asymptomatic (258) PAD from the CHARISMA trial. The primary end point of cardiovascular death, MI, or stroke in the overall trial was higher in patients with PAD than in those without PAD: 8.2% versus 6.8% (HR 1.25, 95% CI 1.08-1.44; P = .002). Among the subgroup of patients with PAD, there was no significant difference between clopidogrel and aspirin versus placebo and aspirin in regard to the primary end point (7.6% vs 8.9%, P = .18). Dual antiplatelet therapy, however, was associated with a lower rate of MI (2.3% vs 3.7%, P = .029) and hospitalization for ischemic events (16.5% vs 20.1%, P = .011). There was no difference in severe or fatal bleeding between the 2 groups.²⁷

The Clopidogrel for Atherothrombotic Event Management in Patients with Peripheral Arterial Disease (COOPER) study investigated the safety profile (ie, bleeding, blood disorders, and hepatic dysfunction) of clopidogrel (75 mg/d) compared to ticlopidine (200 mg/d) in 431 patients with PAD. The study demonstrated that clopidogrel has a better safety profile than ticlopidine, with an adverse event rate of 2.4% versus 13.6%, respectively (adjusted HR 0.16; 95% CI 0.06-0.42; P < .0001).²⁸

Linnemann et al demonstrated that in the absence of background aspirin antiplatelet therapy, patients with PAD treated with clopidogrel as the sole antiplatelet drug have high variability of residual platelet function as measured by light transmittance aggregometry. High residual platelet reactivity was observed in 35.2% of patients at baseline and in 17.6% at a mean of 18 months of follow-up. During the observation period, 26.6% switched from responders to nonresponders or vice versa, thus suggesting unpredictable platelet inhibition with clopidogrel monotherapy in patients with PAD. Among nonresponders, clopidogrel or its metabolites was detected in 89.5% of patients; this suggests the findings were not related to medication compliance.²⁹

The Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial investigated the effect of dual antiplatelet therapy (clopidogrel 75 mg/d plus aspirin 75 to 100 mg/d) versus placebo plus aspirin 75 to 100 mg/d in patients undergoing unilateral, below-knee bypass grafting for atherosclerotic PAD. Study medications were started 2 to 4 days after surgery and continued for 6 to 24 months. The primary end point was a composite of graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety end point was severe bleeding. The CASPAR trial showed that the combination of clopidogrel plus aspirin did not improve limb or systemic outcomes in the overall population of patients with PAD requiring below-knee bypass grafting. Subgroup analysis of patients receiving prosthetic grafts, however, showed improved outcomes with clopidogrel plus aspirin (HR 0.65, 95% CI 0.45-0.95; P = .025) without a significant increase in major bleeding risk.³⁰

Dipyridamole

Dipyridamole inhibits the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides, and cyclic adenosine monophosphate (AMP); these mediators then inhibit platelet aggregation, cause vasodilation, and stimulate release of prostacyclin or prostaglandin (PG) D2 that cause coronary vasodilation.³¹

The effect of dipyridamole plus aspirin has been studied in a number of randomized controlled trials for evaluation of graft patency in patients who have undergone infrainguinal bypass surgery.^32
-37 Brown et al utilized data from 6 such randomized controlled trials, with a total of 966 patients, in a Cochrane review examining the effect of aspirin or aspirin plus dipyridamole versus placebo upon primary graft patency. Overall, the studies included fairly high-risk patients, with 60% to 80% having CLI. In all trials, the study medication was started prior to bypass surgery, usually 48 hours before the operation. Total daily doses ranged between 900 and 975 mg aspirin and 150 and 225 mg dipyridamole. Duration of treatment was 6 weeks in 1 trial but at least 12 to 24 months in the other trials. The results showed a statistically significant increase in infrainguinal primary graft patency for aspirin or aspirin plus dipyridamole at 1 year (OR 0.61, 95% CI 0.43-0.86; P = .005). Interestingly, there was a more profound impact upon prosthetic graft patency at 1 year (OR 0.22, 95% CI 0.12-0.38); the impact upon venous graft patency at 2 years, however, was marginal (OR 0.71, 95% CI 0.51-1.00). Both major bleeding and gastrointestinal side effects were not more frequent in participants receiving aspirin or aspirin and dipyridamole.³⁸

Prostanoids

Prostaglandins (PGE1, PGI2, and their derivatives) are potent inhibitors of platelet activation, adhesion, and aggregation and have vasodilatory and antithrombotic effects. In patients with CLI who are not candidates for arterial revascularization, prostanoids are the only vasoactive drugs with potential efficacy. The currently available data support the use of prostanoids in patients unsuitable for lower limb revascularization or in patients in whom revascularization attempts have failed.³⁹

In a meta-analysis of 7 randomized, placebo-controlled trials including 643 patients, Creutzig et al concluded that for patients with Fontaine PAD stage III (rest pain) or IV (ischemic ulcers or gangrene), PGE1 therapy not only had significant beneficial effects over placebo on ulcer healing and pain relief (47.8% vs 25.2%, P = .029) but also increased the rate of patients surviving with both legs after 6 months follow-up (22.6% vs 36.2%, P = .015).⁴⁰ A subsequent Cochrane review of prostanoids for CLI by Ruffolo et al included 13 trials that compared prostanoids to placebo. Prostanoids appeared to be effective for relief of rest pain (RR 1.32, 95% CI 1.10-1.57) and ulcer healing (RR 1.54, 95% CI 1.22-1.96). There was no significant impact, however, upon either amputation or mortality. In addition, there was a significant increase in side effects like headache, nausea, vomiting, and diarrhea (RR 2.35, 95% CI 1.99-2.78). The authors concluded that overall the evidence base for prostanoids was poor, however, and that better quality studies with longer periods of follow-up were required.⁴¹

Cilostazol

Cilostazol selectively inhibits phosphodiesterase III and therefore decreases the degradation of cyclic AMP, resulting in reversible inhibition of platelet activation and aggregation. It also improves endothelial cell function, thereby decreasing platelet activation caused by interaction with activated endothelial cells.⁴² Additionally, cilostazol has been shown to decrease endothelial smooth muscle proliferation, delay the formation of atherosclerosis, and promote vasodilation.^43,44

In symptomatic patients with PAD, cilostazol has been shown to improve maximal walking distance (MWD) and overall physical function. Robless et al pooled data from 7 randomized controlled trials comparing cilostazol with placebo to determine the effect of cilostazol on improving walking distance and in reducing vascular mortality and cardiovascular events in patients with stable IC. The weighted mean difference (WMD) for the initial claudication distance (ICD) was improved following treatment with cilostazol 100 mg twice daily (WMD 31.1 m; 95% CI 21.3-40.9 m) compared to placebo. In addition, the absolute claudication distance (ACD; also known as the maximum walking distance) was improved in patients receiving cilostazol 100 mg twice daily (WMD 49.7 m; 95% CI 24.2-75.2 m) and 50 mg twice daily (WMD 31.9 m; 95% CI 12.4-51.5 m) compared to placebo. Participants receiving cilostazol 150 mg twice daily did not have a significant improvement in either the ICD or ACD. There was no impact upon cardiovascular events or mortality in patients receiving cilostazol compared with placebo.⁴⁵

Furthermore, in a multicenter, double-blind, randomized, placebo-controlled parallel study, a total of 394 patients 40 years of age or older with chronic, stable, symptomatic IC received cilostazol 100 mg twice daily, 50 mg twice daily, or placebo for 24 weeks. Patients receiving cilostazol 100 mg twice daily experienced a 21% improvement in MWD compared with placebo (P = .0003) and a 22% improvement in distance walked to the onset of symptoms (P = .0015). Patients who received cilostazol 50 mg twice daily, however, did not have a significant improvement in their MWD (P = .18). Quality of life and functional status assessments supported these objective results. The authors concluded that cilostazol 100 mg twice daily significantly improves symptoms in patients with IC.⁴⁶

In a multicenter, prospective registry of 861 patients who underwent superficial femoral artery (SFA) stenting with a self-expanding nitinol stent, Soga et al investigated the effect of cilostazol 200 mg/d on restenosis, reocclusion, all-cause mortality, and limb salvage in patients with CLI. Patients in both the study group and comparison group received dual antiplatelet therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) before the procedure. After the procedure, all patients were prescribed lifelong aspirin (100-200 mg day), and at least 1 month of clopidogrel was recommended. Patients who had taken cilostazol before the procedure continued to receive cilostazol after the procedure. They demonstrated that at 5 years, the binary restenosis rate was significantly lower in patients who received cilostazol 200 mg/d (31.2% vs 42.9% at 5 years, P = .02). In addition, in-stent reocclusion tended to be lower in patients who received cilostazol, but this did not reach statistical significance (10.8% vs 18.2% at 5 years, P = .09). No significant difference was found between the 2 groups in terms of all-cause mortality and limb salvage rate.⁴⁷

Miyashita et al, in a small prospective trial involving 20 lower limbs of 14 patients, investigated the effect of 1 month of cilostazol 100 mg twice daily in patients with Rutherford class 3 or 4 symptoms and whose skin perfusion pressure (SPP) was less than 40 mm Hg. In patients who experienced side effects, the dosage was decreased to 50 mg twice a day. After 1 month, they found that cilostazol did not increase the ABI, but it did significantly increase the SPP (24.5 ± 8.9 to 42.8 ± 21.0 mm Hg, P < .01).⁴⁸

Antiplatelet Therapy After Peripheral Endovascular Intervention

The effect of antiplatelet therapy on patency after endovascular revascularization was investigated in 2 randomized trials. In a rather small and somewhat dated study, Heiss et al randomized 199 patients after femoropopliteal balloon angioplasty to placebo, dipyridamole 225 mg and aspirin 990 mg, or dipyridamole 225 mg and aspirin 300 mg. Evaluation of the combined angiographic and clinical results showed improvement or no deterioration in 37% of patients in the placebo group compared with 49% in the low-dose and 61% in the high-dose aspirin groups, respectively. The only statistically significant difference observed was between the placebo group and the group treated with dipyridamole and high-dose aspirin (P = .01); thus, the authors concluded, counter to much of the recent literature, that high-dose aspirin is of benefit.³³ In a similarly small and dated study after femoropopliteal or iliac angioplasty, 223 patients were randomized to placebo versus 50 mg aspirin and dipyridamole 400 mg. The study did not find any difference in primary patency between the groups, although the study was limited by the low aspirin dose and a higher number of iliac angioplasties in the placebo group.⁴⁹

Mazur et al demonstrated that stent thrombosis in patients with PAD after peripheral angioplasty is associated with impaired platelet response to aspirin and clopidogrel, as defined by increased platelet aggregation by light transmission aggregometry with ADP. Additionally, patients with stent thrombosis had higher serum arachidonic acid and thromboxane B2 levels.⁵⁰

Feiring et al reported the Preventing Amputations using Drug Eluting Stents (PARADISE) trial, in which 106 patients with CLI were treated with tibioperoneal drug-eluting stents (DESs). Unlike previously published CLI studies, 90% of patients were maintained on dual antiplatelet therapy (clopidogrel 75 mg and aspirin 81 mg daily) and close to 75% on statin therapy. The rationale for dual antiplatelet therapy was based on extensive coronary DES experience demonstrating improved stent patency with combined aspirin and thienopyridine therapy and recent evidence suggesting that survival and limb salvage are higher in vascular patients treated with thienopyridines and statins.^1,51,52 Despite intensive medical therapy with dual antiplatelet therapy and statins, the reported mortality rates in the PARADISE trial were 13% at 1 year and 29% at 3 years.⁵³

Although dual antiplatelet therapy with aspirin and clopidogrel is generally recommended after peripheral vascular intervention, this is largely based upon extrapolation of coronary percutaneous intervention data. In short, there are no dedicated studies that have shown convincing benefit of dual antiplatelet therapy following peripheral vascular intervention. Nevertheless, recent studies comparing drug-eluting stenting to balloon angioplasty or bare-metal stenting for symptomatic PAD have shown impressive benefit. In the randomized Zilver PTX trial of 479 patients, sirolimus-eluting stenting for femoropopliteal disease proved superior to balloon angioplasty. More specifically, drug-eluting stenting had higher rates of event-free survival at 1 year (primarily driven by target lesion revascularization) than balloon angioplasty (90.4% vs 82.6%, P = .004). Both arms were treated for a minimum of 60 days of aspirin and clopidogrel.⁵⁴ Similarly, Rastan et al randomized 161 patients with infrapopliteal PAD to sirolimus-eluting versus bare-metal stenting. Event-free survival was higher with sirolimus-eluting stenting (65.8% vs 44.6%, P = .02), in addition to an improvement in Rutherford class and a reduction in target limb amputation. Both arms received aspirin and clopidogrel for at least 6 months.⁵⁵ Given the relative success of these trials studying drug-eluting stenting for symptomatic PAD and the fact that both trials recommended relatively lengthy courses of dual antiplatelet therapy, clopidogrel and aspirin are likely to remain standard following femoropopliteal and infrapopliteal stenting.

Antiplatelet Therapy After Surgical Bypass

As noted previously, the CASPAR trial showed benefit of clopidogrel in addition to aspirin for patients undergoing below-knee bypass with a prosthetic graft; there was no benefit of clopidogrel, however, in the overall population undergoing lower extremity bypass surgery. Similarly, the Cochrane review by Brown et al referenced previously showed a benefit of aspirin or aspirin plus dipyridamole versus placebo in regard to prosthetic graft patency; there was only a borderline benefit in regard to venous grafts.²⁶ Otherwise, there are very few dedicated trials of antiplatelet therapy in such patients.

Burdess et al demonstrated that in patients with CLI undergoing surgery (infrainguinal revascularization or amputation), the use of perioperative dual antiplatelet therapy with aspirin 75 mg and clopidogrel 75 mg decreased biomarkers of atherothrombosis (troponin and plasma monocyte aggregation) compared to aspirin and placebo. Patients in the clopidogrel arm received clopidogrel 600 mg between 4 and 28 hours prior to surgery and dual antiplatelet therapy for 5 days after surgery without increasing major life-threatening or minor bleeding, although blood transfusions were increased.⁵⁶

The effect of statins, β-blockers, and aspirin upon survival, graft patency, and major adverse cardiovascular events was investigated in 1404 patients with CLI treated with infrainguinal vein bypass in a post hoc analysis of the Project or Ex-Vivo Vein Graft Engineering Via Transfection (PREVENT) III trial. Statin use was associated with a significant survival advantage at 1 year of 86% versus 81% (HR 0.71, 95% CI 0.52-0.98; P = .03), but there was no difference with aspirin or β-blockers. None of the medications was associated with improved graft patency. Clinical predictors of increased 1-year mortality by Cox regression modeling included age >75, coronary artery disease, chronic renal insufficiency stages 4 and 5, and tissue loss.⁵⁷

Current Status of Antiplatelet Therapy in CLI

There is a paucity of randomized trials for antiplatelet therapy in PAD, but well-designed trials of antiplatelet therapy in CLI are virtually nonexistent. Aspirin 81 to 325 mg daily is recommended by all major professional societies for secondary prevention of cardiovascular events in patients with symptomatic PAD and by extension to patients with CLI. This is not an unreasonable strategy, as many of the trials referenced in this review included both patients with IC and patients with CLI. Yet the efficacy of aspirin in patients with CLI remains to be proven, and available data suggest that aspirin does not decrease cardiovascular end points in patients with CLI. There are multiple potential reasons for the lack of aspirin efficacy in patients with CLI, including underrepresentation in clinical trials, inefficient aspirin metabolism and so-called “aspirin resistance”, and inappropriate dosing.⁵⁸ In addition, this failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance.⁵⁹

Similarly, although dual antiplatelet therapy with aspirin and clopidogrel is frequently used in patients with CLI after endovascular or surgical revascularization, there is sparse evidence for the efficacy of this strategy. Perioperative MI occurs in 6% to 20% of patients undergoing surgery for CLI, and small studies suggest that dual antiplatelet therapy with aspirin and clopidogrel may decrease the risk. Despite medical therapy with statins and dual antiplatelet therapy with aspirin and clopidogrel, recent studies report on overall survival of 87% at 1 year and 71% at 3 years.^53,56 Preliminary data suggest that high on-treatment platelet reactivity may be a factor; the incidence among patients with CLI is 78.5% for clopidogrel, 28.5% for aspirin, and 14% for both.⁶⁰

Future Directions for Antiplatelet Therapy in PAD

The role that inadequate platelet inhibition might play in the progression of PAD and CLI remains obscure. It is a reasonable hypothesis, however, that more potent platelet inhibition with newer agents would improve overall cardiovascular, procedure-specific (stent and graft patency), and limb salvage outcomes in patients with PAD.

Ticagrelor

Ticagrelor is an orally active, direct-acting, and reversible inhibitor of P2Y12. The drug is given twice daily, and it not only has a more rapid onset and offset of action than clopidogrel but also produces greater and more predictable inhibition of ADP-induced platelet aggregation.⁶¹

Gurbel et al investigated the effect of switching patients with stable coronary artery disease (CAD) from clopidogrel to ticagrelor for 2 weeks in the RESPOND study, demonstrating that ticagrelor overcomes high on-treatment platelet reactivity in patients taking clopidogrel. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P < .05). Furthermore, treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59% ± 9% to 35 ± 11% in patients switched from clopidogrel to ticagrelor and increased from 36% ± 14% to 56 ± 9% in patients switched from ticagrelor to clopidogrel (P < .0001 for both). In addition, the antiplatelet effect of ticagrelor was equivalent in clopidogrel responders and nonresponders.⁶²

The Platelet Inhibition and Patient Outcomes (PLATO) trial was a double-blind, randomized trial comparing ticagrelor to clopidogrel in 18 624 patients with acute coronary syndromes. At 12 months, the primary combined end point of vascular death, MI, or stroke occurred in 9.8% of the ticagrelor group versus 11.7% of the clopidogrel group (HR 0.84, 95% CI 0.77-0.92, P < .001).⁶³ Patel et al conducted a post hoc analysis of 1144 patients with PAD from the PLATO study and found that the primary end point occurred in 19.8% of patients with PAD versus 10.2% of patients without PAD (P < .001). Among patients with PAD, those treated with ticagrelor had lower rates of vascular death or MI than those treated with clopidogrel: 16.7% versus 21.5%, P = .045. Bleeding rates were similar in patients with PAD treated with ticagrelor or clopidogrel.⁶⁴

The recently launched EUCLID study is a randomized, double-blind, multicenter trial comparing ticagrelor with clopidogrel in regard to the risk of cardiovascular death, MI, and ischemic stroke in patients with established PAD. The study population includes approximately 11 500 male and female patients at least 50 years of age with symptomatic PAD, including CLI. The primary end point is a composite of cardiovascular death, MI, and ischemic stroke, with results anticipated in 2016.⁶⁵

Vorapaxar

Vorapaxar is an oral, reversible antagonist of the protease-activated receptor 1 (PAR-1), the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Vorapaxar competitively and selectively interferes with the interaction of PAR-1 and thrombin, thereby inhibiting thrombin-induced platelet activation. Vorapaxar does not, however, interfere with thrombin-mediated cleavage of fibrinogen; it thus does not affect the coagulation cascade.^66,67

The Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRA2P-TIMI 50) trial evaluated the efficacy and safety of vorapaxar 2.5 mg versus placebo for secondary prevention in 26 449 patients with a history of prior MI, ischemic stroke, or PAD. At 3 years, the primary end point of cardiovascular death, MI, or stroke had occurred in 9.3% of patients in the vorapaxar group compared to 10.5% in the placebo group (HR 0.87, 95% CI 0.80-0.94; P < .001). Moderate or severe bleeding, however, was more common with vorapaxar (4.2% versus 2.5%, P < .001) as was intracranial hemorrhage (1.0% vs 0.5%; P < .001); the latter was especially pronounced among patients with a history of stroke.⁶⁷

In the TRA2P-TIMI 50 trial, the PAD cohort consisted of 3787 patients with a history of IC and either an ABI <0.85 or previous revascularization for limb ischemia. In contrast to the overall study population, vorapaxar did not significantly reduce the composite of cardiovascular death, MI, or stroke in the PAD cohort (11.3% vs 11.9%; P = .53). Importantly, however, vorapaxar significantly reduced the risk of limb ischemic events; this included hospitalization for acute limb ischemia (2.3% vs 3.9%; HR 0.58, 95% CI 0.39-0.86; P = .006) and peripheral revascularization (18.4% vs 22.2%; HR 0.84, 95% CI 0.73-0.97; P = .017). Moderate or severe bleeding was more common with vorapaxar (7.4% vs 4.5%, P < .001), although there was no difference in the rates of intracranial or fatal hemorrhages in the PAD cohort.⁶⁸

Rivaroxaban

Rivaroxaban is an oral, direct-acting factor Xa inhibitor. Although rivaroxaban is an anticoagulant, inhibition of factor Xa decreases the production of thrombin and thereby decreases platelet activation as well.⁶⁹ Rivaroxaban has shown similar efficacy to warfarin for the treatment of acute venous thromboembolism.^70,71 In addition, among patients with atrial fibrillation, it was noninferior to warfarin in regard to the reduction in stroke and systemic embolism.⁷¹ Rivaroxaban has also been studied, however, in patients on dual antiplatelet therapy with an acute coronary syndrome. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) trial showed that very low-dose rivaroxaban (2.5 mg/d) decreased the composite of cardiovascular death, MI, and stroke but with a significant increase in major bleeding events.⁶⁸ Rivaroxaban has subsequently been approved in Europe for patients with acute coronary syndromes, but the US Food and Drug Administration rejected rivaroxaban for this indication.

The utility of an oral anticoagulant in patients with PAD, however, remains unclear. This was previously studied in the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial, which compared warfarin and aspirin versus aspirin alone in patients with symptomatic PAD. In regards to cardiovascular death, MI, and stroke, there was no benefit to warfarin; there was, however, a dramatic increase in life-threatening bleeding (4.0% vs 1.2%, P < .001).⁷² This question is being readdressed in the ongoing Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) randomized controlled trial, which will compare rivaroxaban and aspirin versus aspirin alone in patients with coronary or peripheral artery disease. The primary end point is a composite of cardiovascular death, MI, and stroke, with a goal enrollment of 19 500 patients; results are anticipated in 2018.⁷³

Conclusion

Given the impressive benefit of antiplatelet therapy for coronary artery disease and acute coronary syndromes, it would seem intuitive that the same pharmacotherapy would have similar effects in patients with PAD and CLI. Indeed, current guidelines would appear to support this conjecture. Antiplatelet therapy, however, does not appear to significantly impact the natural history of PAD. Mortality rates remain astonishingly high, and antiplatelet therapy has at best only modest effects upon limb salvage and long-term patency rates following endovascular and surgical interventions. Although disappointing, this is not entirely surprising; the peripheral vasculature is not an extension of the coronary tree. It also points to the need for novel approaches, in regard to antiplatelet therapy, revascularization, antiproliferative compounds, and risk modification. Acknowledging the paucity of high-quality data for antiplatelet therapy in this high-risk and difficult patient population is perhaps the first step.

Footnotes

Authors’ Contribution

Azarbal contributed to acquisition, drafted manuscript, gave final approval, and agrees to be accountable; Clavijo contributed to design, drafted manuscript, gave final approval, and agrees to be accountable; Gaglia contributed to design, contributed to acquisition, drafted manuscript, critically revised manuscript, gave final approval, and agrees to be accountable.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Gaglia, speakers bureau, AstraZeneca.

Funding

The author(s) received the following financial support for the research, authorship, and/or publication of this article: Dr. Clavijo: grant support, AstraZeneca.

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