Antithrombotic therapy in peripheral artery disease: A review of the EUCLID trial results and current ongoing trials

Abstract

In addition to risk‐factor modification, antithrombotic therapy is the hallmark of management to reduce cardiovascular ischemic events in patients with peripheral artery disease (PAD). Currently, the guidelines recommend long‐term antiplatelet therapy with aspirin or clopidogrel in this patient population to reduce myocardial infarction, stroke, and vascular death. Past outcomes studies have shown some benefit of ticagrelor, another antiplatelet agent, as compared with clopidogrel in patients with coronary disease and concomitant PAD. However, most recently, the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial has shown no additional benefit of ticagrelor over clopidogrel. In this trial, a minority of patients had concomitant coronary artery disease, making it unique to previous studies. The EUCLID trial's evidence of neutrality between clopidogrel and ticagrelor sheds light into the complexity of studying the PAD population and the continued need to meticulously design trials to investigate the optimal therapies. The topics that will be discussed in this review include the role of antiplatelet therapy in the management of patients with PAD, a review of the EUCLID trial results and the important factors to be considered in interpreting the surprising results, and promising recent ongoing clinical trials assessing therapies in the treatment of patients with PAD.

1. INTRODUCTION

Peripheral artery disease (PAD) is a disease manifestation of atherosclerosis involving the lower extremities.1 In Europe and North America, approximately 27 million individuals are affected by PAD, with approximately 413 000 inpatient admissions occurring annually.2 Certain risk factors are associated with the development of PAD, including older age, diabetes mellitus (DM), history of smoking, hypertension, hyperlipidemia, and known atherosclerosis at other sites.3 PAD may be clinically silent or may present with signs and symptoms indicative of lower‐extremity ischemia (Figure 1). Symptomatic patients may present with atypical leg symptoms, intermittent claudication, or critical limb ischemia (severe limb ischemia characterized by ischemic rest pain and tissue loss such as skin ulceration or gangrene). Patients with early‐onset atherosclerosis, atherosclerotic disease in another vascular bed, DM, or end‐stage renal disease have a higher risk for progression of PAD and overall worse prognosis.4 PAD is associated with poor cardiovascular (CV) outcomes, including myocardial infarction (MI), ischemic stroke, and death.5 Symptomatic PAD patients carry a higher mortality rate than those with asymptomatic disease, although both carry significant risks for poor CV outcomes.6

Figure 1.

Conceptual framework of patients with PAD including symptom classification, initial treatment (exercise training and medical therapy), and revascularization options. Abbreviations: MI, myocardial infarction; PAD, peripheral artery disease

The management of PAD is aimed at alleviating symptoms and prevention of progression to poor outcomes and complications. Treatment involved in risk‐factor modification includes smoking cessation, glycemic control, the use of cardioprotective medications including antihypertensive medications and HMG‐CoA reductase inhibitors, and antithrombotics.7 In addition, patients benefit from significant lifestyle modifications, including dietary changes and increased physical activity. Patients who remain symptomatic despite medical therapy and those presenting with signs of critical limb ischemia are often considered for endovascular or surgical revascularization procedures.

Antiplatelet therapy is considered a critical part of management in the treatment of patients with PAD. Specifically, clopidogrel has been shown to be more effective than aspirin in this subset of patients in reducing CV adverse events.8 Ticagrelor has shown some evidence of additional benefit in patients with coronary artery disease (CAD) with concomitant PAD.9 Until recently, there had been no large trials specifically focusing on patients with PAD alone, as many studies have focused largely on patients with CAD. This unmet need led to the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial.10 The EUCLID trial showed no evidence of the superiority of ticagrelor monotherapy when compared with clopidogrel monotherapy in patients with PAD. In this trial, a minority of patients had concomitant CAD, making it unique compared with previous studies. Consequently, the optimal medical therapy for patients with PAD is continuously evolving. The topics that will be discussed in this review include (1) the role of antithrombotic therapy in the management of patients with PAD, (2) a review of the EUCLID trial results, and (3) recent ongoing clinical trials assessing therapies in the treatment of patients with PAD.

2. ANTIPLATELET AGENTS

2.1. Aspirin

First‐line treatment includes antiplatelet therapy with aspirin alone or clopidogrel alone. In the 2002 collaborative meta‐analysis of randomized trials of antiplatelet therapy for prevention of adverse CV events in high‐risk patients, aspirin was shown to be protective against vascular events among patients with PAD.11 In the 2007 Critical Leg Ischemia Prevention Study (CLIPS) trial to assess prevention of death, MI, or stroke and critical leg ischemia in patients with PAD, low‐dose aspirin was found to reduce the incidence of vascular events by 26%.12 In the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, aspirin was compared with placebo in reducing the development of CV events in patients with DM and asymptomatic PAD.13 The trial found no significant evidence to support the use of aspirin in the prevention of adverse CV events in patients with PAD. In a trial assessing vascular events in patients with clinical cardiovascular disease identified with a low ankle‐brachial index (ABI; Aspirin for Asymptomatic Atherosclerosis trial), aspirin was not shown to reduce vascular events when compared with placebo.14

2.2. Clopidogrel

A recommended alternative to aspirin is clopidogrel, a P2Y₁₂ inhibitor. In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, long‐term administration of clopidogrel was shown to be superior to aspirin in reducing the risk of vascular events.8 Dual antiplatelet therapy (DAPT) has also been considered in the PAD population. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, the rate of CV death, MI, or stroke occurred with similar frequency in PAD patients treated with the combination of clopidogrel and aspirin and in those treated with aspirin alone.15 And in the Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial, there was no benefit of DAPT in limb outcomes (graft occlusion, revascularization, amputations) or adverse CV events in PAD patients.16

2.3. Vorapaxar

Vorapaxar is a novel thrombin receptor antagonist (via the protease‐activated receptor 1) that has activity on platelets, vascular endothelium, and smooth muscle. The Trial to Assess the Effects of Scheme 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRA2°P‐TIMI 50) trial was a randomized, double‐blind, placebo‐controlled trial of vorapaxar in patients with stable atherosclerosis, including symptomatic PAD.17 In the cohort of patients with PAD, vorapaxar did not reduce the risk of CV death, MI, and stroke.18 However, vorapaxar was associated with a lower occurrence of acute limb ischemia and peripheral revascularization in this subset of patients, but this was offset by an increase in major bleeding compared with placebo. Therefore, the overall clinical benefit of vorapaxar monotherapy in patients with PAD is not fully certain, and its clinical use in the United States is very low. Importantly, inhibition of protease‐activated receptor 1 (PAR1) on thrombin does not exclude the effects of circulating thrombin; therefore, patients who undergo surgical procedures may proceed without stopping therapy with vorapaxar.

3. GUIDELINES IN THE MANAGEMENT OF PAD WITH ANTIPLATELET AND ANTITHROMBOTIC DRUGS

The 2005 American College of Cardiology/American Heart Association guidelines recommend antiplatelet therapy with aspirin in daily doses of 75 to 325 mg or clopidogrel as an effective alternative to aspirin to reduce the risk of MI, stroke, or vascular death in individuals with atherosclerotic lower‐extremity PAD (class 1 recommendation).19 Oral anticoagulation therapy with warfarin is not indicated to reduce risk of CV or ischemic events in patients with PAD (class 3 recommendation). The most recent guidelines in 2016 written by Dr. Marie Gerhard‐Herman and committee members also recommend antiplatelet therapy with aspirin alone (75–325 mg/d) or clopidogrel alone (75 mg/d) to reduce MI, stroke, and vascular death in patients with symptomatic PAD (class 1).20 In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death (class 2a). 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 (class 2b). The effectiveness of DAPT with aspirin and clopidogrel to reduce the risk of CV ischemic events in patients with symptomatic PAD is not well established (class 2b), although this is greatly driven by device‐related recommendations for patients receiving infrainguinal interventions.21 However, the use of DAPT may be reasonable to reduce the risk of limb‐related events in patients with symptomatic PAD after lower‐extremity revascularization (class 2b). The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain (class 2b).

4. TICAGRELOR IN THE MANAGEMENT OF PAD

Some trials have suggested that ticagrelor, a potent reversibly binding P2Y₁₂ receptor antagonist, may provide some additional benefit in the prevention of adverse CV events. This antiplatelet agent reduces CV death, MI, or stroke compared with clopidogrel in patients with acute coronary syndrome (ACS) and has proven benefits as chronic therapy in patients with prior MI.

4.1. The PLATO trial

The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial was established to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients with an ACS.22 A total of 18 624 patients were randomized to receive either ticagrelor or clopidogrel. Endpoints for the study included death from vascular causes, MI, stroke, and major bleeding. In this subset of patients, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, MI, or stroke without causing a significant increase in the rate of major bleeding.

4.2. PEGASUS‐TIMI 54

In the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54 (PEGASUS‐TIMI 54) trial, 21 162 patients with prior MI (1–3 years) were randomized to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, with all patients also on low‐dose aspirin.23 Approximately 5% of the patients had concomitant PAD. Primary efficacy endpoint was a composite of CV death, MI, or stroke. Among stable patients with prior MI with concomitant PAD, ticagrelor reduced major adverse cardiovascular events (MACE) and major adverse limb events. The benefit of ticagrelor for the relative risk reduction in CV death, MI, or stroke was consistent regardless of concomitant PAD; however, those patients with PAD had a particularly robust absolute risk reduction in this study. Among those PAD patients with prior MI, ticagrelor also significantly reduced the risk for peripheral revascularization as compared with aspirin.

4.3. The EUCLID trial

The evidence to support the efficacy of ticagrelor in vascular patients led to the EUCLID trial, which directly evaluated the efficacy and safety of ticagrelor as compared with clopidogrel.10 Prior to this trial, there were no large trials that have focused on management to reduce ischemic risk in a purely PAD population; most other trials have focused on patients with ACS and stable CAD. In some studies, PAD has been studied concomitantly with ACS, and much of the existing evidence to support the use of ticagrelor is extrapolated from these populations. On the basis of these trial results, and with the need to develop more evidence to support the use of specific therapies in patients with PAD, the EUCLID trial was developed.

4.3.1. Trial design and population

EUCLID was a double‐blind, event‐driven trial in which 13 885 symptomatic PAD patients were randomly assigned to ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily; Figure 2). The inclusion criteria included patients age ≥ 50 years with symptomatic PAD as defined by (1) PAD symptoms plus ABI ≤0.80 at the first visit and ≤0.85 at the second visit, or (2) prior lower‐extremity revascularization for symptomatic PAD >30 days ago.24 Key exclusion criteria included planned use of DAPT, requirement of aspirin, history of bleeding diathesis, treatment with anticoagulation, or poor metabolizer status for cytochrome P450 2C19 (CYP2C19). The primary endpoint of the trial was the composite of CV death, MI, or ischemic stroke. The major secondary endpoint was the composite of CV death, MI, ischemic strike, and acute limb ischemia requiring hospitalization. The primary safety endpoint was major bleeding.

Figure 2.

Overall trial design and patient flow for EUCLID. Abbreviations: ABI, ankle‐brachial index; CYP2C19, cytochrome P450 2C19; EUCLID, Examining Use of Ticagrelor in Peripheral Artery Disease; PAD, peripheral artery disease; TIMI, Thrombolysis In Myocardial Infarction

4.3.2. Study results

The primary efficacy composite endpoint of CV death, MI, or ischemic stroke occurred in 751 of 6930 patients (10.8%) in the ticagrelor group and in 740 of 6955 patients (10.6%) in the clopidogrel group (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 0.92‐1.13, P = 0.65).10 Notably, there was a significant between‐group difference in the rate of ischemic stroke, which occurred in 1.9% of the patients in the ticagrelor group vs 2.4% in the clopidogrel group (HR: 0.78, 95% CI: 0.62‐0.98, P = 0.03). Secondary endpoints including acute limb ischemia and revascularization were similar between the 2 groups. Major bleeding occurred in 1.6% of the patients in both the ticagrelor group and clopidogrel group (HR: 1.10, 95% CI: 0.84‐1.43, P = 0.49). Overall, ticagrelor was discontinued more often than clopidogrel. There were fewer fatal bleeding events in the ticagrelor group; however, there were more bleeding events in the ticagrelor group leading to discontinuation. In a subgroup analysis, patients enrolled based on prior revascularization had similar rates of composite adverse CV events but higher rates of MI and acute limb ischemia when compared with patients enrolled based on ABI criteria.25

4.4. Why was ticagrelor not superior to clopidogrel in EUCLID?

As previously stated, ticagrelor had shown some promise of benefit in patients with PAD as evidenced by prior studies. In addition, ticagrelor is a more potent P2Y₁₂ receptor antagonist than clopidogrel. With this knowledge, clopidogrel represented an effective active comparator to ticagrelor. Naturally, the field of vascular medicine expected the trial results of EUCLID to yield favorable results for ticagrelor in a PAD population. However, the EUCLID trial showed that monotherapy with ticagrelor is not superior to monotherapy with clopidogrel in reducing the rate of adverse CV events. In addition, the rate of major bleeding was also similar in the 2 groups. Why did ticagrelor, a more potent P2Y₁₂ receptor antagonist with evidenced promise of benefit in this population, not turn out to be superior to clopidogrel?

4.4.1. Unique differences in the PAD population as compared with the CAD population

One theory behind the neutral trial results of EUCLID is the possibility that CAD patients with concomitant PAD are a uniquely different population as compared with a purely PAD population in their response to antiplatelet agents. The EUCLID trial provided evidence that ticagrelor is not clearly superior to clopidogrel outside of the ACS or stable CAD populations. Previous studies in which the evidence showed benefit of ticagrelor focused on either a purely CAD population (stable CAD or ACS) or a CAD population in which PAD was concomitant. The EUCLID patient population included patients with PAD and only a minority of patients with baseline, concomitant CAD. Patients with CAD and concomitant PAD or patients with predominantly chronic CAD may have some important biological and physiological differences when compared with patients with isolated PAD that are less well understood.

Another consideration in comparing the purely PAD population with the purely CAD or CAD with concomitant PAD populations is the possibility that patients with PAD have unique risks and clinical drivers that may lead to non‐CV events. The PAD patient population presents a unique patient pool with several well‐known risk factors (eg, smoking, DM) that may have led to death from causes other than vascular‐related events. The possibility of these competing risks will be the focus of future substudies derived from the EUCLID data. It is also important to note that in the case of acute limb ischemia, there is a proportion of patients who may have central thromboembolic events unrelated to an atherosclerotic process.

4.4.2. Trial‐specific considerations

A second theory to illuminate the neutral trial results of EUCLID involves questions specific to the trial itself. The EUCLID trial was meticulously designed to thoroughly investigate whether ticagrelor was superior to clopidogrel in patients with PAD. However, perhaps different comparators could have been used for the trial to reveal different results. Aspirin was not included in the trial, and so direct conclusions about the effects of ticagrelor and/or clopidogrel as compared with aspirin could not be made. Aspirin has been well documented in the management of patients with PAD and could have been used as an alternative comparator to ticagrelor rather than clopidogrel. Aspirin was not chosen as the comparator for the trial due to the available evidence showing the superiority of clopidogrel over aspirin in the broad population of patients with atherosclerotic disease, specifically in those patients with PAD.

Another possibility for trial design that may have impacted the EUCLID results was the enrollment exclusion criterion of patients with lower‐extremity revascularization procedures <30 days before randomization. If these patients had been included in the trial, it may have augmented the event rate and enhanced the opportunity to see a difference between ticagrelor an clopidogrel, if one existed.

The EUCLID trial was designed as a superiority trial to test the hypothesis that ticagrelor is superior in effectiveness to clopidogrel in treating patients with PAD. Previous studies have clearly shown some evidence of the benefit of ticagrelor in patients with atherosclerotic disease. However, the clear evidence of ticagrelor in a purely PAD population has been less clear. In contrast, the benefit of clopidogrel in PAD patients has been clearly documented. It would have been reasonable to design the trial as a noninferiority trial to test the hypothesis that ticagrelor is not unacceptably worse than clopidogrel in treating patients with PAD.

5. THE FUTURE OF ANTITHROMBOTIC THERAPY IN PAD

Although there have been studies to investigate the best therapies to reduce the ischemic risk associated with atherosclerosis in patients with PAD, there is still more room to inform the field of vascular medicine in determining optimal therapy. Moreover, the PAD population has proven to be unique in clinical outcomes and response to therapy. In addition, many trials have not included the role of walking exercise in symptomatic patients. There are currently 5 major ongoing trials focusing on the use of other therapies in the management of PAD, which may shed more light onto the treatment of this patient population in the field of vascular medicine.

The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial is a randomized controlled trial of rivaroxaban, a selective and reversible factor Xa inhibitor, for the prevention of major CV events in patients with CAD or PAD.26 Patients were randomized to either rivaroxaban plus aspirin or rivaroxaban plus placebo, with the active comparator being aspirin plus placebo. The primary outcome measures include time from randomization to (1) the first occurrence of either MI, stroke, or CV death, and (2) the first occurrence of major bleeding. The secondary outcome measures include time from randomization to (1) the first occurrence of either coronary heart disease death, MI, ischemic stroke, or acute limb ischemia, and (2) the first occurrence of all‐cause mortality. The COMPASS trial began enrollment in 2013, was terminated early for efficacy (as announced by the sponsor), and will be presented in the fall of 2017.

VOYAGER PAD is an international, multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial investigating efficacy and safety of rivaroxaban to reduce the risk of major thrombotic vascular events in patients with symptomatic PAD undergoing lower‐extremity revascularization procedures.27 The primary outcome measure is time from randomization to the first occurrence of MI, ischemic stroke, CV death, acute limb ischemia, or major amputation. The primary safety measure is time from randomization to the first occurrence of major bleeding events. This trial began in August 2015 and the estimated primary completion date is January 2019.

The Antiplatelet Strategy for Peripheral Arterial Interventions for Revascularization of Lower Extremities (ASPIRE) trial is a randomized, parallel‐grouped, controlled trial evaluating whether clopidogrel 75 mg on a background of aspirin 75 to 100 mg/d will lead to an increased rate of primary patency, limb salvage, nonfatal MI, ischemic stroke, and survival in patients receiving endovascular treatment of PAD.28 The primary outcome measure is the first occurrence of target‐vessel occlusion, surgical revascularization, endovascular revascularization, major amputation of target limb, ischemic stroke, MI, or death. Secondary outcome measure includes first occurrence of bleeding within 12 months or at the end of study treatment. The study is currently ongoing with an estimated primary completion date of June 2018.

Edoxaban in Peripheral Artery Disease (ePAD) is a randomized, open‐label, parallel‐grouped, multicenter phase 2 study designed to evaluate the safety and potential efficacy of adding endoxaban to aspirin following femoropopliteal endovascular intervention, with or without stent placement, relative to current treatment practice with clopidogrel and aspirin.29 Primary outcomes include bleeding events and proportion of patients with restenosis/re‐occlusion. Secondary outcomes include bleeding events, any bleeding, safety assessments, MACE, amputation, and all‐cause mortality. The expected completion date was December 2014; however, trial results have not yet been posted.

The Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia (RIFLE) is a phase 2 open‐label, parallel‐grouped, randomized trial to evaluate rivaroxaban plus aspirin vs clopidogrel plus aspirin following percutaneous transluminal angioplasty for critical limb ischemia in the prevention of restenosis.30 The primary outcome is a combined outcome consisting of any re‐intervention or above‐ankle amputation and restenosis (RAS) at 1 year. Secondary outcome measures include improved Rutherford scale, event‐free survival, overall survival, target‐lesion revascularization, target‐vessel revascularization, periprocedural death, MACE, major and minor bleeding, and specific biomarkers. The trial is currently ongoing with an estimated completion date of June 2017.

6. CONCLUSION

It is clear that many knowledge gaps remain in the optimal treatment of PAD patients. Although EUCLID was a surprisingly neutral study, the field of vascular medicine is now more informed in the use of ticagrelor in the treatment of a purely PAD population in preventing events. Importantly, the EUCLID trial shed more light onto the fact that there needs to be a more clear delineation on not only how to treat patients with PAD, but also how to study this unique population effectively. Studying a purely PAD population without concomitant CAD or disease in other vascular beds or without having a recent vascular intervention may not be the best way to study the population moving forward. The recent ongoing trials will shed more light onto the use of rivaroxaban both in patients with known PAD and those patients with PAD plus recent revascularization. The possibility that rivaroxaban is more efficacious than aspirin in preventing events in patients with PAD will greatly inform opinion moving forward.

Conflicts of interest

Dr. Patel reports research grants from AstraZeneca and honorarium/other support from Bayer and Janssen Pharmaceuticals. Dr. Jones reports research grants from the Agency for Healthcare Research and Quality, AstraZeneca, American Heart Association, Bristol‐Myers Squibb, Doris Duke Charitable Foundation, and Patient‐Centered Outcomes Research Institute; and honorarium/other support from the American College of Radiology, Bayer, Bristol‐Myers Squibb, Daiichi Sankyo, and Janssen Pharmaceuticals. The authors declare no other potential conflicts of interest.

Ward R, Long C, Patel MR, Jones WS. Antithrombotic therapy in peripheral artery disease: A review of the EUCLID trial results and current ongoing trials. Clin Cardiol. 2018;41:137–143. 10.1002/clc.22839