Ischemic Events in Peripheral Artery Disease

58

Antiplatelet Drugs in the Management of Thrombotic/ Ischemic Events in Peripheral Artery Disease Stefania Basili and Francesco Violi I Clinica Medica, Department of Internal Medicine and Medical Specialties, SAPIENZA-University of Rome, Rome, Italy

EPIDEMIOLOGY 1059 RISK FACTORS OF PERIPHERAL ARTERY DISEASE 1059 MANAGEMENT OF PAD 1059 ANTIPLATELET DRUGS IN PAD 1059 Aspirin 1060 Nonaspirin Drugs Inhibiting the Platelet Arachidonic Acid Pathway 1061 Drugs Inhibiting the Platelet P2Y12 Receptors for ADP 1062 Antagonists of Protease-activated Receptor-1 1063 Cilostazol 1063 Comparison of Efficacy of Antiplatelet Treatments in PAD 1063 CONCLUSIONS 1064 REFERENCES 1064

EPIDEMIOLOGY In this chapter, the term “peripheral arterial disease” (PAD) is used for lower extremity artery disease secondary to atherosclerosis. PAD is very much an issue for clinicians in the 21st century, because it is estimated to affect 10%–20% of individuals aged 60 years or more. Thus, the prevalence of PAD will certainly escalate in response to changing population demographics and lifestyle. Already in 2010, more than 202 million individuals were affected by PAD, of whom almost 40 million are living in Europe.1–3

RISK FACTORS OF PERIPHERAL ARTERY DISEASE PAD carries high morbidity and mortality usually in association with atherosclerotic complications in other vascular beds. It is an important hallmark of generalized atherosclerosis involving, in particular, coronary and cerebral circulation.4 Patients with PAD are at high risk of suffering from myocardial infarction, stroke and vascular death with an annual incidence of about 5%.5 Nevertheless, perception of the specific risk associated with PAD is generally poor. In fact, PAD represents a growing problem for internists since it is not just a localized disease, but it has serious systemic complications6,7 (Fig. 58.1). The Walking and Leg Circulation Study8 underlined that this disease is under-diagnosed because it often presents with atypical symptoms or no ischemic symptoms related to the legs. In fact, up to 50% of all patients with PAD had asymptomatic disease.9) For example, the Rotterdam Study showed that there was a 19.1% prevalence of PAD in the study population, but claudication was reported in only 6.3% of patients.10 Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00058-8 Copyright © 2019 Elsevier Inc. All rights reserved.

The ankle-brachial-index (ABI) is a noninvasive tool that is useful for the diagnosis and surveillance of PAD. It is the ratio of the ankle to brachial systolic blood pressure.11–13 The ABI is also validated to be useful in the assessment of vascular risk in asymptomatic and symptomatic patients.14 A lot of studies demonstrated a significant relationship between abnormal ABI and risk of vascular events15–19 (Fig. 58.2). Nevertheless, an ABI
0.90 in population-based cohorts studies seems to have high specificity but not enough sensitivity for predicting vascular events; thus, ABI cannot be used as a generic screening test16 but must be used in a focused manner, choosing individuals for whom the yield of the test is expected to be higher. Thus, a metaanalysis including 16 population cohort studies15 showed that ABI provided independent risk information compared with the Framingham Risk Score (FRS). A low ABI (< 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category confirming that screening for PAD in asymptomatic individuals should be considered in terms of cardiovascular risk and not merely of limb outcomes.

MANAGEMENT OF PAD The main goals of treatment of patients with PAD are to reduce cardiovascular risk and improve functional capacity. The risk factors for PAD are common risk factors for atherosclerosis. Thus, age, cigarette smoking, arterial hypertension, dyslipidemia, and diabetes mellitus (DM) are the factors that are most strongly associated with PAD.20–22 It is recommended to implement the treatment of these concomitant diseases.23 Nevertheless, the association between PAD and smoking persists after smoking cessation, although it is considerably diminished beyond 10 years of cessation.24 Exercise rehabilitation programs increase walking distance in patients with intermittent claudication and help to relieve symptoms.22,25

ANTIPLATELET DRUGS IN PAD Platelets play an important role in the process of atherothrombosis and there is evidence indicating that platelets are activated in patients with PAD, based on the finding of elevated markers of platelet activation. In particular, a significant association between high levels of soluble CD40 ligand and P-selectin and PAD have been reported.26,27 However, it is still unclear whether platelet activation reflects PAD or the coexistence of risk factors that activate platelet function per se, such as DM, dyslipidemia and smoking. It is well known that antiplatelet agents are a therapeutic cornerstone in the secondary prevention of cardiovascular events in patients with established atherosclerosis.28 The metaanalysis of the Antithrombotic Trialist’s Collaboration (ATC) including over 130,000 patients and 50 trials28 clearly demonstrates a cardio-protective benefit of antiplatelet

1059

1060

PART V Antiplatelet Therapy

Fig. 58.1 Natural history of patients with PAD.

Panel A Anterior tibial artery

Doppler

Doppler

Posterior tibial artery

Doppler

Brachial artery

Fig. 58.2 The Ankle-Brachial Index (ABI). Panel A: After 5–10 min rest in supine position systolic blood pressure (SBP) is measured on the posterior and anterior tibial artery of each foot and on brachial artery of each arm. The ABI of each leg is calculated by dividing the highest ankle SBP by the highest arm SBP. Panel B: for diagnosis of lower extremity artery disease perform one ABI per leg and interpret each leg separately.

Panel B

Aspirin

vasoconstrictor molecule.29 Aspirin is the most used antiplatelet drug to prevent vascular events in the secondary prevention in patients with coronary or cerebral ischemic vascular disease (Chapter 50). Conversely, the effect of aspirin in peripheral arterial atherosclerosis has provided inconclusive results. In a post hoc analysis of the Physicians’ Health Study, aspirin was ineffective in preventing claudication deterioration, whereas it seemed to reduce the need of peripheral surgical interventions.30 Moreover, three randomized controlled trials (RCTs) compared antiplatelet therapy versus placebo for cardiovascular risk reduction among patients with PAD specifically examined the role of aspirin in PAD.

Aspirin inhibits platelet COX1, thereby preventing the formation of thromboxane (Tx) A2, a potent aggregating and

(1) The Critical Leg Ischaemia Prevention Study (CLIPS)31 randomized PAD patients to placebo or 100 mg aspirin and

therapy in patients who have had ischemic events or were at high-risk for vascular events. In particular, analyzing 42 randomized studies including 9706 patients with PAD, the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke at follow-up was significantly decreased 23% by antiplatelet drugs (including aspirin, ticlopidine, clopidogrel, picotamide, and dipyridamole). Thus, in the following sections the impact of the different antiplatelet agents in the primary and in the secondary prevention of PAD patients will be analyzed.

Antiplatelet Drugs in the Management of Thrombotic/Ischemic Events in Peripheral Artery Disease

followed-up them for 2 years. Throughout the study major cardiovascular events such as cerebral ischemia, myocardial infarction and critical leg ischemia were monitored. The aim of the study was to explore the efficacy of aspirin in 2000 PAD patients but the enrolment was discontinued prematurely after including only 210 PAD patients. The reasons for stopping early were feasibility and not due to encountering any predefined stopping rule. During the follow-up, there were seven major cardiovascular events (all fatal) in the aspirin-treated group and 20 (four deaths) in the placebo-treated group, with a hazard ratio of 0.35, 95% CI 0.15–0.82. Despite such interesting findings, the relatively few number of events and imbalance in deaths did not permit to reach definite conclusions on the clinical efficacy of aspirin in the PAD population. (2) The prevention of progression of arterial disease and DM (POPADAD) trial was a multicenter, randomized, double-blind, placebo-controlled study designed to examine the efficacy and safety of aspirin plus antioxidant (αtocopherol 200 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulphate 10 mg, nicotinamide 10 mg, lecithin 9.4 mg, and sodium selenite 0.8 mg) compared with aspirin alone, antioxidant alone, and placebo.32 Belch et al. included in the study 1276 patients over 40 years of age with type 1 or type 2 DM who were determined as having asymptomatic PAD as detected by a lower than normal ABI (
0.99). Patients were randomized to receive either aspirin 100 mg or placebo, an antioxidant or placebo, or aspirin and an antioxidant or double placebo and followed over 8 years. There were two hierarchical composite primary endpoints: (i) death from coronary heart disease or stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia; (ii) death from CHD or stroke. No evidence of benefit from either aspirin or antioxidant treatment on the composite hierarchical primary end points of cardiovascular events and cardiovascular mortality was found. In fact, patients in the aspirin groups had 116 (18.2%) primary events compared with 117 (18.3%) in the placebo group [HR: 0.98 (95% CI: 0.76–1.26), P ¼ 0.86]. There were 43 deaths from coronary heart disease or stroke in the aspirin group compared with 35 in the no-aspirin group [HR 1.23 (0.79– 1.93); P ¼ 0.36]. No evidence was found of any interaction between aspirin and antioxidant. It is important to recognize that POPADAD is smaller than most of the other aspirin trials, with fewer events and includes patients in primary prevention of cardiovascular events and mortality. (3) The Aspirin for Asymptomatic Atherosclerosis (AAA) trial was an intention-to-treat, double-blind, RCT of once daily low-dose (100 mg) enteric-coated aspirin vs. placebo.33 The Authors screened 28,980 men and women aged 50–75 years in the general population, all of whom were assumed to be healthy at the time of ABI screening, identifying 3350 with a low ABI (defined as an ABI value equal to or less than 0.95). All patients were free of clinical cardiovascular disease and were recruited from a community Scottish health registry. Enrolled patients were randomly assigned in 1:1 ratio to low dose aspirin (100 mg/daily) or placebo. The primary end-point of this study was a composite of fatal or nonfatal coronary events or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; (2) all-cause mortality. After a mean follow-up of 8.2 years, no statistically significant difference was found in event rates over time between the groups (aspirin, 13.7; 95% CI, 11.8–15.9 vs. placebo, 13.3; 95% CI, 11.4– 15.4, events per 1000 person-years; HR, 1.03; 95% CI,

1061

0.84–1.27). Moreover, aspirin treatment had no significant effect on any of the secondary end points (aspirin, 22.8; 95% CI, 20.2–25.6 vs. placebo, 22.9; 95% CI, 20.3–25.7 events per 1000 person-years; HR, 1.00; 95% CI, 0.85– 1.17). All-cause mortality did not differ significantly between the aspirin group and the placebo group. However, aspirin therapy was associated with a nonsignificant increased risk of major hemorrhage (2.0% vs. 1.2%; HR ¼ 1.71, 95% CI: 0.99–2.97). Intracranial hemorrhage occurred in 11 participants in the aspirin group and 7 in the placebo group. Based on these findings, the authors concluded that in asymptomatic PAD patients aspirin had no clinical benefit and may be harmful. Accordingly, a metaanalysis of 18 randomized trials achieved additional findings.34 Eligible studies were prospective, RCTs of aspirin therapy, with or without dipyridamole, that reported cardiovascular event rates. To investigate the effect of aspirin on cardiovascular event rates in patients with PAD, Berger et al. included 5269 participants. Cardiovascular events were experienced in 8.9% of 2823 patients taking aspirin (alone or with dipyridamole) and in 11.0% of 2446 in the control group. The pooled RR reduction of 12% in cardiovascular event rates was not statistically significant. Furthermore, in the subset of 1516 participants taking aspirin mono-therapy compared to control, aspirin was associated with a nonsignificant reduction in cardiovascular events (8.2% vs. 9.6%; RR ¼ 0.75 [95% CI, 0.48–1.18]) and in all-cause or cardiovascular mortality, MI, or major bleeding. Results of this metaanalysis demonstrated that for patients with PAD, aspirin therapy alone or in combination with dipyridamole did not significantly decrease the primary endpoint of cardiovascular events, results that may reflect limited statistical power. Recently, the results of a landmark trial that compared three antithrombotic regimens in patients with stable ischemic heart disease or symptomatic PAD were published.35 A total of 7470 patients with PAD had a median duration of treatment of 21 months. The rate of the primary endpoint (a composite of cardiovascular death, myocardial infarction, or stroke) was significantly reduced in aspirin (aspirin 100 mg once a day) plus low-dose rivaroxaban (rivaroxaban 2.5 mg twice a day) combination group (HR ¼ 072, 95% CI: 0.57–0.90, P ¼ 0.0047) compared with the aspirin alone group. Nevertheless, anticoagulation therapy (rivaroxaban 5 mg twice a day) alone group was not superior to aspirin alone group (aspirin 100 mg once a day) (HR ¼ 0.86, 95% CI: 0.69–1.08, P ¼ 0.19). Moreover, the rates of acute limb ischemia and major adverse limb events were significantly reduced in both groups receiving rivaroxaban versus the aspirin alone group, and there was a reduction in the rate of major amputation in the low-dose rivaroxaban plus aspirin group versus the aspirin alone group (major adverse limb events including major amputation 32 [1%] vs. 60 [2%]; HR 0.54, 95% CI 0.35–0.82, P ¼ 0.0037). The COMPASS trail did not include patients without coronary artery disease and without PAD symptoms who were diagnosed with PAD via screening ABI and receiving a score of less than 0.90; thus, the results are not likely to be applicable to nonsymptomatic PAD without concomitant vascular disease in another arterial bed.36

Nonaspirin Drugs Inhibiting the Platelet Arachidonic Acid Pathway Picotamide, a derivative of methoxy-isophtalic acid, is an antiplatelet drug (not approved in the U.S. by the Food and Drug Administration) whose pharmacological properties are inhibition of both TxA2 receptors and TxA2 synthase. Picotamide may exert a dual pharmacological action in vivo

58

1062

PART V Antiplatelet Therapy

and be potentially useful in various clinical settings characterized by atherosclerotic disease.37–40 In PAD patients, with different risks for cardiovascular events, picotamide was analyzed in two prospective studies. (1) The ADEP (Atherosclerotic Disease Evolution by Picotamide) study was the first large randomized trial on picotamide investigating its clinical usefulness in patients with PAD.41 Patients (n ¼ 2304) were consecutively enrolled, allocated to either placebo or picotamide (300 mg t.i.d.), and followed for 18 months to assess the efficacy on prevention of major (cardiovascular death, myocardial infarction, stroke or amputation) or minor events (unstable angina, transient ischemic attack, hypertension, renal failure, deterioration of PAD). The results were analyzed with the “intention to treat analysis.” A risk reduction (18.9%) in the combined endpoints (major and minor events) in the picotamide group compared to controls was observed; nevertheless, this difference did not reach statistical significance. Thus, analyzing the results using “on treatment analysis” a higher and statistically significant reduction (22.8%) in the same endpoints was observed in the picotamide group. The two groups did not differ for side effects occurrence such as bleeding. The low occurrence of major events during the follow-up as well as the short observation period could be responsible of the lack of statistically significant beneficial effects of picotamide. However, the capacity of picotamide to prevent vascular complications was magnified when claudicant patients affected by DM were taken into account. Accordingly, a retrospective analysis of the results obtained in diabetic patients only (n ¼ 438) revealed a risk reduction of 45.2% of combined major and minor events in picotamide-treated patients compared to placebo-treated patients.42 (2) The DAVID trial was the second RCT testing picotamide as an antiplatelet agent in PAD. It was a randomized trial specifically designed for PAD patients, 40 and 75 years of age, with a 5-year history of type 2 DM.43 PAD was defined as the presence of two or more of the following: (1) history of intermittent claudication lasting more than 2 months, (2) loss of posterior tibial pulse in the foot, (3) ABI <0.90 or >1.30, (4) amputation or reconstructive surgery in patients with previous history of intermittent claudication, and (5) angioplasty with no persisting complication from intervention. The study enrolled 1209 patients. The primary endpoint was overall mortality and the secondary end-point was the combined incidence of death and major cardiovascular events. Patients were randomly assigned to picotamide (600 mg/bid) or aspirin (320 mg/day) and followed for 2 years. Mortality was significantly lower in picotamide-treated patients than in those treated with aspirin, showing a relative risk of reduction of 45%. The secondary endpoint did not show any statistically significant difference between the two populations, showing only a trend in favor of patients taking picotamide. Additionally, the incidence of gastrointestinal bleeding was much lower in the picotamide group than in the aspirin group. As pointed out by the authors, a possible bias relative to the high proportion of patients who discontinued the trial because of nonfatal events (about 20% in each group) may have underestimated the real incidence of the secondary endpoints. Besides, the little sample size of the study was probably insufficient to detect any difference in vascular events between the two groups. Evaluation and comparison of ADEP and DAVID trials results raises the questions as to whether (i) the differences seen are dependent on the fact that TxA2 production is more relevant for atherosclerotic progression in PAD patients with DM

compared with PAD without DM, or (ii) the different daily dosage of picotamide (900 mg in ADEP and 1200 mg in DAVID, respectively) had a different impact on clinical outcomes. Finally, activation of platelet arachidonic plays an important role in the pathogenesis of cardiovascular events in PAD, but the clinical trials with picotamide should be considered inconclusive and warrant further investigation. Further studies are therefore necessary to explore the relationship between picotamide dosage and TxA2 inhibition in vivo.

Drugs Inhibiting the Platelet P2Y12 Receptors for ADP Thienopyridines are drugs that inhibits platelet aggregation by interfering with the platelet ADP receptor P2Y12 (Chapter 51). The first drug of this class investigated in patients with PAD was ticlopidine. A prospective Italian study performed in 151 patients with claudication demonstrated that ticlopidine (250 mg/bid) increased walking distance compared to placebo-treated patients.44 Moreover, in ticlopidine-treated patients ABI did not worsen compared to placebo-treated patients, indicating that ticlopidine may favorably influence atherosclerotic progression. Subsequently a Swedish trial45 investigated whether ticlopidine (250 mg/bid), compared to placebo, was able to reduce cerebrovascular and cardiovascular events in a population with PAD-associated claudication. A total of 687 patients were included in the trial and followedup for 5 years. There was no difference in cerebrovascular and cardiovascular events between the two groups during the follow-up period. Conversely, the secondary endpoint of mortality was lower in the ticlopidine group, and in an ontreatment analysis, there were fewer ischemic events in the ticlopidine-treated group. The effect of thienopyridines on cardiovascular events was later examined in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which compared the clinical efficacy of clopidogrel (75 mg/day), a secondgeneration thienopyridine, with aspirin (325 mg/day) in a population at different risks of cardiovascular events.46 The study enrolled 19,185 patients, with more than 6300 in each of the clinical subgroups (ischemic stroke, recent myocardial infarction, or symptomatic PAD). During 3 years of follow-up, clopidogrel was marginally significantly superior to aspirin in reducing cardiovascular events in the entire population. Specifically, an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (P ¼ 0.043) relative-risk reduction of 8.7% in favor of clopidogrel. An analysis of the CAPRIE trial performed only in the PAD population showed a statistically significant risk reduction of 24% for cardiovascular events in the clopidogrel-treated group compared to the aspirin group, suggesting that the inhibitors of P2Y12 receptors may be particularly efficacious in PAD patients. The combination of aspirin and clopidogrel therapy versus aspirin alone was subsequently tested in the CHARISMA (Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events) trial, a multicenter, randomized placebo-controlled, double-blind trial of over 15,000 patients.47 The study enrolled a broad group of patients, with a large percentage at lower risk for atherothrombotic events who did not have established cardiovascular disease. Overall, no benefit was seen when clopidogrel was added to aspirin versus aspirin alone in reducing the primary efficacy endpoint of MI, CVA, or vascular death in the overall population of patients. In 2007, a post hoc analysis of the CHARISMA trial48 included 2838 patients who had symptomatic PAD. After a

Antiplatelet Drugs in the Management of Thrombotic/Ischemic Events in Peripheral Artery Disease

mean follow-up of 23.6 months the overall rate of cardiovascular death, MI, or stroke in PAD cohort was 8.7% in the placebo plus aspirin arm and 7.6% in the clopidogrel plus aspirin arm (HR ¼ 0.869; 95% CI: 0.671–1.125). Although the risk reduction in the PAD subgroup appeared similar to that observed in patients with prior MI or prior stroke, it did not reach statistical significance. Ticagrelor is a novel class of oral platelet P2Y12 receptor inhibitors (Chapter 51). It has the theoretical advantage over thienopyridines that it does not require biotransformation to an active metabolite. In a post hoc analysis of PLatelet inhibition And patienT Outcomes (PLATO) trial, patients with PAD (n ¼ 1144) treated with ticagrelor showed numerically lower death from vascular cause, MI or stroke when compared to clopidogrel-treated patients. The Kaplan-Meier 1-year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs. 20.6% (HR: 0.85, 95% CI 0.64–1.11; for PAD status by treatment interaction, P ¼ 0.99) and for death from any cause 8.7% vs. 11.9% (HR: 0.74, 95% CI 0.50–1.08; interaction P ¼ 0.73).49 Recently, a large randomized, double-blind, parallel group, multicenter Phase IIIb study, Examining Use of ticagreLor In paD (EUCLID), enrolled 13,885 patients with symptomatic PAD to compare ticagrelor monotherapy against clopidogrel monotherapy for the reduction of cardiovascular death, MI and ischemic stroke.50 Patients were eligible if they were at least 50 years and had an ABI of 0.80 or less or had undergone previous revascularization of the lower limbs more than 30 days before randomization. Patients underwent randomization to receive either ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). The median follow-up was approximately 30 months. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. Ticagrelor was not shown to be superior to clopidogrel for the reduction of the primary efficacy end point (HR ¼ 1.02; 95% CI ¼ 0.92–1.13; P ¼ 0.65). The only statistically significant between-group difference was in the rate of ischemic stroke, which occurred in 1.9% of the patients in the ticagrelor group versus 2.4% in the clopidogrel group (HR ¼ 0.78; 95% CI ¼ 0.62–0.98; P ¼ 0.03). The rates of bleeding were similar in the two groups (HR ¼ 1.10; 95% CI ¼ 0.84–1.43; P ¼ 0.49). Nevertheless, ticagrelor was prematurely discontinued more often than clopidogrel during the study (in 30.1% of patients vs. in 25.9%; hazard ratio, 1.21; 95% CI, 1.14–1.29; P <0.001), mainly in association with the occurrence of dyspnea and minor bleeding.50 Together these data indicate that ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events but suggested the clinical usefulness of all P2Y12 antagonists in PAD to prevent major cardiovascular events.

Antagonists of Protease-activated Receptor-1 Vorapaxar is an oral, protease-activated receptor [PAR]-1 antagonist that inhibits thrombin-induced platelet aggregation (Chapter 53). The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA2°P)TIMI 50 study, a randomized, double-blind, placebocontrolled trial of vorapaxar in 24 449 patients with stable atherosclerosis.51 A subgroup analysis of the study showed that in PAD patients (n ¼ 3787) vorapaxar did not significantly reduce the risk of cardiovascular death, MI, or stroke (11.3% vs. 11.9%; HR ¼ 0.94; 95% CI ¼ 0.78–1.14; P ¼ 0.53), whilst the occurrence of acute leg ischemia (2.3% vs. 3.9%; HR ¼ 0.58; 95% CI ¼ 0.39–0.86; P ¼ 0.006) and the need for peripheral

1063

revascularization (18.4% vs. 22.2%; HR ¼ 0.84; 95% CI ¼ 0.73–0.97; P ¼ 0.017) were significantly reduced. Vorapaxar therapy was, however, associated with increased the risk of bleeding (7.4% vs. 4.5%; HR ¼ 1.62; 95% CI ¼ 1.21–2.18; P ¼ 0.001). These findings highlight a potential therapeutic approach to reduce acute limb ischemia and the need for peripheral revascularization in patients with symptomatic PAD. Moreover, further analyzing this population of patients, Bonaca et al. showed that vorapaxar significantly reduced the risk for peripheral revascularization at 3 years (19.3% for placebo, 15.4% for vorapaxar; HR, 0.82; 95% CI: 0.72–0.93; P ¼ 0.003) and that this effect appeared consistent across indications for peripheral revascularization and types, although surgical revascularization showed the greatest magnitude of reduction (41%).52

Cilostazol Cilostazol is an inhibitor of phosphodiesterase type 3 (PDE3), which hinders platelet aggregation by modifying intracellular cAMP accumulation (Chapter 54). It improves the symptoms and walking distance in PAD. Accordingly, a Cochrane review, that included 15 double-blind RCTs with a total of 3718 patients with intermittent claudication secondary to PAD, absolute claudication distance was significantly increased in participants taking cilostazol 100 and 50 mg twice daily, compared with placebo. Nevertheless, there were insufficient data on whether taking cilostazol results in a reduction of all-cause mortality and cardiovascular events.53 Moreover, cilostazol has several side effects including headache, diarrhea, dizziness, and palpitations. Thus, the American Heart Association (AHA)/ American College of Cardiology (ACC)54 recommended cilostazol only as an effective therapy to improve symptoms and increase walking distance in patients with claudication (level IA recommendation).

Comparison of Efficacy of Antiplatelet Treatments in PAD Although symptomatic patients with PAD warrant life-long antiplatelet therapy, an important issue relates to the potentially different impact of antiplatelet drug categories in the clinical progression of PAD. To investigate whether specific antiplatelet treatment had a different impact on clinical outcomes a metaanalysis has been performed in patients with claudication and/or ABI
0.99.55 A total of 29 RCTs on antiplatelet therapy for prevention of vascular death, myocardial infarction or stroke were included in the metaanalysis (10,735 patients with PAD). The authors found 1900 (17.7%) patients in trials with aspirin, 5326 (49.6%), thienopyridines, 2324 (21.6%), picotamide or other antiplatelet drugs, 1185 (11%) (including three studies where the active drugs were aspirin and/or dipyridamole). Antiplatelet treatment showed a vascular outcomes risk reduction of 17%. Analyzing separately each drug category conclusive results were achieved by trials with thienopyridines, that reduced the risk of cardiovascular events by 22% (P ¼ 0.014). Moreover, a trend to a reduction was observed with aspirin (15%, P ¼ 0.208) or picotamide (21%, P ¼ 0.302) but these changes were not statistically significant. One of the limitations of this metaanalysis is the fact that it has been done in patients with stable PAD and, as a consequence, its results cannot be extrapolated to nonmedical PAD patients. Another limitation of the study was the lack of a direct comparison between two antiplatelet treatments that should require more interventional trials.

58

1064

PART V Antiplatelet Therapy

CONCLUSIONS

TABLE 58.2 Recommendations for Antiplatelet Agents

Antiplatelet therapy is indicated in patients with PAD to reduce the risk of major cardiovascular events. However, remains an open issue why PAD represents an atherosclerotic clinical model where aspirin, differently from coronary heart disease, is less effective in reducing atherosclerotic progression. In fact, the recently published European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines23 suggest that single antiplatelet therapy is indicated only if lower extremity artery disease patients are symptomatic or have undergone revascularization and that clopidogrel is the preferred antiplatelet drug in these patients (Table 58.1). Moreover, the AHA/ ACC54 revised the management of patients with PAD and recommended antiplatelet therapy with aspirin alone (range 75–325 mg/day) or clopidogrel alone (75 mg/day) to reduce MI, stroke, and vascular death in patients with symptomatic PAD (Table 58.2). Data supporting the use of antiplatelet drugs in patients with PAD, who do not have a history of other cardiovascular disorders, are still inconclusive. Indeed, the ESC/ESVS guidelines23 state that, because of a lack of proven benefit, antiplatelet therapy is not routinely indicated in patients with isolated asymptomatic PAD (ABI
0.90) and the AHA/ACC guidelines,54 based on consensus of expert opinion, suggested that in these patients antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. Thus, the efficacy of antiplatelet treatment for primary prevention in symptomatic or asymptomatic PAD patients is less evident and future interventional trials should analyze its cost-effectiveness in this clinical setting.

COR

LOE

I

Aa

IIa

C-EOa

IIb

B-Ra

IIb

B-Ra

IIb

C-LDa

IIb

B-Ra

TABLE 58.1 Recommendations on antithrombotic therapy in patients with peripheral arterial diseases. Recommendations Lower extremities artery disease Long-term SAPT is recommended in symptomatic patients. Long-term SAPT is recommended in all patients who have undergone revascularization. SAPT is recommended after infra-inguinal bypass surgery. In patients requiring antiplatelet therapy, clopidogrel may be preferred over aspirin. Vitamin K antagonists may be considered after autologous vein infra-inguinal bypass. DAPT with aspirin and clopidogrel for at least 1 month should be considered after infra-inguinal stent implantation. DAPT with aspirin and clopidogrel may be considered in below-the-knee bypass with a prosthetic graft. Because of a lack of proven benefit, antiplatelet therapy is not routinely indicated in patients with isolatedc asymptomatic LEAD.

Classa

Levelb

I

A

I

C

I

A

IIb

B

IIb

B

IIa

C

IIb

B

III

A

DAPT, dual antiplatelet therapy; LEAD, lower extremity artery disease; SAPT, single antiplatelet therapy. a Class of recommendation. bLevel of evidence. cWithout any other clinical cardiovascular condition requiring antiplatelet therapy (e.g. coronary artery disease or other multisite artery diseases). From Aboyans et al.23, reproduced by permission of Oxford University Press on behalf of the European Society of Cardiology. All rights reserved in respect of European Heart Journal, © European Society of Cardiology 2017.

Recommendations Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. In asymptomatic patients with PAD (ABI
0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization. The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain.

B-R = Moderate-quality evidence from 1 or more RCTs; Meta-analyses of moderate-quality RCTs. C-LD = Randomized or non-randomized observational or registry studies with limitations of design or execution; Meta-analyses of such studies; Physiological or mechanistic studies in human subjects. C-EO = Consensus of expert opinion based on clinical experience. COR, class of recommendation; LOE, level of evidence. a A = High-quality evidence from more than 1 randomized controlled trail (RCT); Meta-analysis of high-quality RCTs; One or more RCTs corroborated by high-quality registry studies. From Gerhard-Herman et al.54, reprinted with permission. © 2017 American Heart Association, Inc.

REFERENCES 1. Hiatt WR, Goldstone J, Smith Jr SC, McDermott M, Moneta G, Oka R, Newman AB, Pearce WH, American Heart Association Writing Group 1. Atherosclerotic peripheral vascular disease symposium II: nomenclature for vascular diseases. Circulation 2008;118:2826–9. 2. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jim
enez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O’Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, UKA S, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018;137:e67–e492. 3. Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, Creager MA, Easton JD, Gavin 3rd JR, Greenland P, Hankey G, Hanrath P, Hirsch AT, Meyer J, Smith SC, Sullivan F, Weber MA, Prevention of Atherothrombotic Disease Network. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003;163:884–92. 4. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, Goto S, Liau CS, Richard AJ, R€ other J, Wilson PW, REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–9. 5. Steg PG, Bhatt DL, Wilson PW, D’Agostino Sr R, Ohman EM, R€ other J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, Registry Investigators REACH. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–206.

Antiplatelet Drugs in the Management of Thrombotic/Ischemic Events in Peripheral Artery Disease 6. Stehouwer CD, Clement D, Davidson C, Diehm C, Elte JW, Lambert M, Sereni D, EFIM Vascular Medicine Working Group. Peripheral arterial disease: a growing problem for the internist. Eur J Intern Med 2009;20:132–8. 7. Pande RL, Perlstein TS, Beckman JA, Creager MA. Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004. Circulation 2011;124:17–23. 8. McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med 2002;136:873–83. 9. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor Jr LM, White CJ, White J, White RA, Antman EM, Smith Jr SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B, American Association for Vascular Surgery; Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease, American Association of Cardiovascular and Pulmonary Rehabilitation, National Heart, Lung, and Blood Institute, Society for Vascular Nursing, TransAtlantic Inter-Society Consensus, Vascular Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113:e463–654. 10. Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler Thromb Vasc Biol 1998;18:185–92. 11. Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, J€ onsson 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, Council on Epidemiology and Prevention, Council on Clinical Cardiology, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation 2012;126:2890–909. 12. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45:S5–S67. 13. Criqui MH, Alberts MJ, Fowkes FG, Hirsch AT, O’Gara PT, Olin JW, American Heart Association Writing Group 2. Atherosclerotic Peripheral Vascular Disease Symposium II: screening for atherosclerotic vascular diseases: should nationwide programs be instituted? Circulation 2008;118:2830–6. 14. Beckman JA, Jaff MR, Creager MA. The United States Preventive Services Task Force recommendation statement on screening for peripheral arterial disease: more harm than benefit? Circulation 2006;114:861–6. 15. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, Folsom AR, Hirsch AT, Dramaix M, deBacker G, Wautrecht JC, Kornitzer M, Newman AB, Cushman M, Sutton-Tyrrell K, Fowkes FG, Lee AJ, Price JF, d’Agostino RB, Murabito JM, Norman PE, Jamrozik K, Curb JD, Masaki KH, Rodríguez BL, Dekker JM, Bouter LM,

16. 17.

18. 19.

20.

21. 22. 23.

24.

25. 26.

27.

28.

29. 30.

31.

32.

1065

Heine RJ, Nijpels G, Stehouwer CD, Ferrucci L, McDermott MM, Stoffers HE, Hooi JD, Knottnerus JA, Ogren M, Hedblad B, Witteman JC, Breteler MM, Hunink MG, Hofman A, Criqui MH, Langer RD, Fronek A, Hiatt WR, Hamman R, Resnick HE, Guralnik J, McDermott MM. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197–208. Doobay AV, Anand SS. Sensitivity and specificity of the anklebrachial index to predict future cardiovascular outcome: a systematic review. Arterioscler Thromb Vasc Biol 2005;25:1463–9. Resnick HE, Lindsay RS, McDermott MM, Devereux RB, Jones KL, Fabsitz RR, Howard BV. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004;109:733–9. O’Hare AM, Katz R, Shlipak MG, Cushman M, Newman AB. Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. Circulation 2006;113:388–93. McDermott MM, Liu K, Criqui MH, Ruth K, Goff D, Saad MF, Wu C, Homma S, Sharrett AR. Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis. Am J Epidemiol 2005;162:33–41. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, Rutherford RB, TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease. Int Angiol 2007;26:81–157. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;116:1509–26. Aronow WS. Office management of peripheral arterial disease. Am J Med 2010;123:790–2. Aboyans V, Ricco JB, Bartelink MEL, Bj€ orck M, Brodmann M, Cohnert T, Collet JP, Czerny M, De Carlo M, Debus S, EspinolaKlein C, Kahan T, Kownator S, Mazzolai L, Naylor AR, Roffi M, R€ other J, Sprynger M, Tendera M, Tepe G, Venermo M, Vlachopoulos C, Desormais I, ESC Scientific Document Group. 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018;39:763–816. Joosten MM, Pai JK, Bertoia ML, Rimm EB, Spiegelman D, Mittleman MA, Mukamal KJ. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA 2012;308:1660–7. McDermott MM. Exercise training for intermittent claudication. J Vasc Surg 2017;66:1612–20. Berger JS, Eraso LH, Xie D, Sha D, Mohler 3rd ER. Mean platelet volume and prevalence of peripheral artery disease, the National Health and Nutrition Examination Survey, 1999–2004. Atherosclerosis 2010;213:586–91. Blann AD, Tan KT, Tayebjee MH, Davagnanam I, Moss M, Lip GY. Soluble CD40L in peripheral artery disease. Relationship with disease severity, platelet markers and the effects of angioplasty. Thromb Haemost 2005;93:578–83. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. FitzGerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991;68: 11B–15B. Goldhaber SZ, Manson JE, Stampfer MJ, LaMotte F, Rosner B, Buring JE, Hennekens CH. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians’ Health Study. Lancet 1992;340:143–5. Critical Leg Ischaemia Prevention Study (CLIPS) Group, Catalano M, Born G, Peto R. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med 2007;261:276–84. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J, Macfarlane P,

58

1066

33.

34. 35.

36. 37. 38. 39.

40. 41. 42.

43.

44.

PART V Antiplatelet Therapy

Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O’Brien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R, Prevention of Progression of Arterial Disease and Diabetes Study Group, Diabetes Registry Group, Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840. Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, Sandercock PA, Fox KA, Lowe GD, Murray GD, Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010;303:841–8. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301:1909–19. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, Aboyans V, Alings M, Kakkar AK, Keltai K, Maggioni AP, Lewis BS, St€ ork S, Zhu J, Lopez-Jaramillo P, O’Donnell M, Commerford PJ, Vinereanu D, Pogosova N, Ryden L, Fox KAA, Bhatt DL, Misselwitz F, Varigos JD, Vanassche T, Avezum AA, Chen E, Branch K, Leong DP, Bangdiwala SI, Hart RG, Yusuf S, COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219–29. Berger JS. Antithrombotic therapy in peripheral artery disease. Lancet 2018;391:183–4. Modesti PA, Cecioni I, Colella A, Costoli A, Paniccia R, Neri Serneri GG. Binding kinetics and antiplatelet activities of picotamide, a thromboxane A2 receptor antagonist. Br J Pharmacol 1994;112:81–6. Violi F, Ghiselli A, Iuliano L, Praticò D, Alessandri C, Balsano F. Inhibition by picotamide of thromboxane production in vitro and ex vivo. Eur J Clin Pharmacol 1988;33:599–602. Gresele P, Deckmyn H, Arnout J, Nenci GG, Vermylen J. Characterization of N,N0 -bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. Thromb Haemost 1989;61:479–84. Cattaneo M, Tenconi PM, Lecchi A, Mannucci PM. In vitro effects of picotamide on human platelet aggregation, the release reaction and thromboxane B2 production. Thromb Res 1991;717–24. Balsano F, Violi F. Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study. The ADEP Group. Circulation 1993;87:1563–9. Milani M, Longoni A, Maderna M. Effects of picotamide, an antiplatelet agent, on cardiovascular, events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study. Br J Clin Pharmacol 1996;42:782–5. Neri Serneri GG, Coccheri S, Marubini E, Violi F. Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur Heart J 2004; 25:1845–52. Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violi F, Hellemans H, Vanhove P. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med 1989;114:84–91.

45. Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindg€arde F, Persson G. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990;227:301–8. 46. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329–39. 47. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17. 48. Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KA, Investigators CHARISMA. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982–8. 49. Patel MR, Becker RC, Wojdyla DM, Emanuelsson H, Hiatt WR, Horrow J, Husted S, Mahaffey KW, Steg PG, Storey RF, Wallentin L, James SK. Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: data from the PLATO Trial. Eur J Prev Cardiol 2015;22:734–42. 50. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, Katona BG, Mahaffey KW, Norgren L, Jones WS, Blomster J, Millegård M, Reist C, Patel MR, EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017;376:32–40. 51. Bonaca MP, Scirica BM, Creager MA, Olin J, Bounameaux H, Dellborg M, Lamp JM, Murphy SA, Braunwald E, Morrow DA. Vorapaxar in patients with peripheral artery disease: results from TRA2P-TIMI 50. Circulation 2013;127:1522–9. 52. Bonaca MP, Gutierrez JA, Creager MA, Scirica BM, Olin J, Murphy SA, Braunwald E, Morrow DA. Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery disease: results from the trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosisthrombolysis in myocardial infarction 50 (TRA2P-TIMI 50). Circulation 2016;133:997–1005. 53. Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cocrane Database Syst Rev 2014;CD003748. 54. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RA, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135:e726–79. 55. Basili S, Raparelli V, Vestri A, Di Tanna GL, Violi F. Comparison of efficacy of antiplatelet treatments for patients with claudication. A meta-analysis. Thromb Haemost 2010;103:766–73.