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J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 1 , N O . 2 1 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Antithrombotic Therapy forPeripheral Artery DiseaseRecent Advances

Mohamad A. Hussain, MD, PHD,a,b,c Mohammed Al-Omran, MD, MSC,b,c,d Mark A. Creager, MD,e

Sonia S. Anand, MD, PHD,f Subodh Verma, MD, PHD,b,g Deepak L. Bhatt, MD, MPHa,h

ABSTRACT

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Peripheral artery disease (PAD) affects over 200 million people globally and is a cause of significant morbidity, mortality,

and disability due to limb loss. Although secondary prevention with antithrombotic therapy is a mainstay of treatment to

prevent adverse cardiovascular events, PAD patients are often undertreated with antithrombotic agents. Furthermore,

there is a paucity of high-quality data from randomized controlled trials of PAD patients, leading to wide variations in

clinical practice and guideline recommendations. Recently, there have been important advances that have further

increased the number of antiplatelet and anticoagulant choices potentially available for patients with PAD. In this

context, this paper aims to summarize the current available evidence for the safety and efficacy of various antithrombotic

agents in PAD, and discuss how to integrate this emerging evidence into actual clinical practice. An evidenced-based

approach to PAD patients is essential to achieve optimal outcomes, weighing cardiovascular and limb benefits against

bleeding risks. (J Am Coll Cardiol 2018;71:2450–67) © 2018 by the American College of Cardiology Foundation.

N 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.03.483

m the aBrigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts; bDepartment of Surgery, University of

ronto, Toronto, Ontario, Canada; cDivision of Vascular Surgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Tor-

to, Ontario, Canada; dDepartment of Surgery, King Saud University, Riyadh, Kingdom of Saudi Arabia; eDartmouth-Hitchcock

dical Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire; fHamilton Health Sciences, McMaster Uni-

rsity, Hamilton, Ontario, Canada; gDivision of Cardiac Surgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto,

tario, Canada; and the hHarvard Medical School, Boston, Massachusetts. Dr. Anand has received speaker honoraria from Bayer

d Novartis. Dr. Verma has received speaker honoraria from Boehringer Ingelheim, Bayer, Pfizer, Sanofi, Eli Lilly, Amgen,

traZeneca, Mylan, Merck, Janssen, Novo Nordisk, and Abbott; and research support from Amgen, AstraZeneca, Boehringer

elheim, and Eli Lilly. Dr. Bhatt has served on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape

rdiology, and Regado Biosciences; has served on the board of directors of the Boston VA Research Institute and Society of

rdiovascular Patient Care; has served as the chair of American Heart Association Quality Oversight Committee; has served on

data monitoring committees of the Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute,

yo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (senior

ociate editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical

search Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP

mmunications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor;

ociate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor,

rdiology Today Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering

mmittees); has served as the deputy editor for Clinical Cardiology; has served as the chair of the NCDR-ACTION Registry

ering Committee and VA CART Research and Publications Committee; has received research funding from Abbott, Amarin,

gen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic,

zer, Roche, Sanofi, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A

mpanion to Braunwald Heart Disease); has served as a site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical

w Abbott); has served as a trustee of American College of Cardiology; and has performed unfunded research for FlowCo, PLx

arma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to

close.

nuscript received December 26, 2017; revised manuscript received March 16, 2018, accepted March 21, 2018.

https://doi.org/10.1016/j.jacc.2018.03.483

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AB BR E V I A T I O N S

AND ACRONYM S

ABI = ankle-brachial index

HR = hazard ratio

MACCE = major adverse

cardiovascular or

cerebrovascular events

MALE = major adverse limb

events

NNT = number needed to treat

OR = odds ratio

PAD = peripheral artery

disease

RR = risk ratio

SVS = Society for Vascular

Surgery

J A C C V O L . 7 1 , N O . 2 1 , 2 0 1 8 Hussain et al.M A Y 2 9 , 2 0 1 8 : 2 4 5 0 – 6 7 Antithrombotics in PAD

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P eripheral artery disease (PAD) is the third mostcommon manifestation of atherosclerosis aftercoronary artery disease and cerebrovascular

disease. Globally, 202 million people were estimatedto be living with PAD in 2010—this number hasincreased by nearly a quarter since 2000 (1). Further-more, in contrast to the declining rate of age-adjustedmortality due to cardiovascular causes (2,3), mortalitydue to PAD has increased over the last 2 decades (3,4).Coincidently, and unfortunately, the most fearedcomplication of PAD, namely amputation, has alsoremained relatively unchanged (5).

Patients with PAD have systemic atherosclerosis,and their natural history is worse than those of pa-tients with coronary or cerebrovascular disease (6–9).In the multinational REACH (Reduction of Athero-thrombosis for ContinuedHealth) registry, 40% of PADpatients experienced myocardial infarction, stroke,vascular death, or hospitalization over 3 years—thiswas considerably higher in those with coronary (30%)or cerebrovascular disease (28%) (8). Likewise, incontemporary clinical trials involving patients withdiabetes, cardiovascular event rates are higher inpatients with PAD compared with those without PAD(10). In the REACH registry, as well as contemporarycardiovascular outcome trials in diabetes, vascularevent rates were even higher among patients withpolyvascular disease (established vascular disease in 2or 3 arterial beds) (7,9,11). The majority (62%) of PADpatients enrolled in the REACH registry had poly-vascular disease (6). In addition, symptomatic PADpatients are at increased risk for adverse limb events,which include progression to debilitating claudica-tion, critical limb ischemia (rest pain, ulcers, organgrene), and ultimately amputation (12). A total of24% of symptomatic PAD patients experienced a limbevent after 4 years in the REACH registry (13).

Atherosclerotic narrowing of the infrarenal aortaand arteries of the legs is the most common cause ofPAD (14). Platelet activation plays a central role in thedevelopment of these atherosclerotic lesions, andalso contributes to acute arterial thrombosis inconjunction with the coagulation cascade (15,16);therefore, medical management of PAD includesantithrombotic therapy to reduce adverse cardiovas-cular and limb events (17,18). However, severalstudies have shown that PAD patients, who are athighest for atherothrombotic events, are also themost likely to be undertreated with antithromboticagents (19–22). Part of this care gap may be explainedby a lack of consensus around the optimal antith-rombotic strategy in PAD patients. A paucity of high-quality data has led to variations in prescribingpatterns among clinicians and some discrepancies in

guideline recommendations (23–25). In addi-tion to a paucity of original literature onantithrombotic therapy in PAD patients, thereis also a paucity of high-quality review arti-cles in this area (26). In this context, wesought to summarize the current availableevidence for the safety and efficacy of variousantithrombotic agents in PAD patients, andpropose a clinical decision-making algorithmthat may aid clinicians in selecting the mostappropriate antithrombotic treatment strat-egy in patients with PAD (Central Illustration).

ANTITHROMBOTIC THERAPY IN

STABLE PAD

Data on antithrombotic therapy for stable
PAD are largely derived from subanalyses of ran-domized trials that enrolled patients with variousmanifestations of atherosclerosis, including coronarydisease, cerebrovascular disease, and PAD. Impor-tantly, the definition of PAD employed in variousclinical trials varies. In general, these trials definedstable PAD as an ankle-brachial index (ABI) of <0.90with or without symptoms of claudication, >50%peripheral artery stenosis on duplex ultrasound orangiography, or previous intervention for PAD (pe-ripheral angioplasty, surgical bypass, or lower ex-tremity amputation). The primary efficacy outcome inthese trials was generally a composite of majoradverse cardiovascular or cerebrovascular events(MACCE), with some trials also reporting majoradverse limb events (MALE). In addition, the majorityof these trials have focused on patients with symp-tomatic PAD; few have examined the influence ofantithrombotic therapy in asymptomatic PAD. Table 1provides details and results of studies of variousantithrombotic agents in patients with stableasymptomatic and symptomatic PAD.
ASYMPTOMATIC PAD. Aspir in . Two randomized,placebo-controlled trials studied the effect of aspirinon cardiovascular outcomes in patients withasymptomatic PAD: the POPADAD (Prevention ofProgression of Arterial Disease and Diabetes) trial (27)and the AAA (Aspirin for AsymptomaticAtherosclerosis) trial (28). The POPADAD trial, whichenrolled 1,276 patients with an ABI of #0.99 anddiabetes, found no significant difference in thecomposite risk of MACCE or amputation betweenaspirin and placebo (18.2% vs. 18.3%, respectively;hazard ratio [HR]: 0.98 [95% confidence interval (CI):0.76 to 1.26). The AAA trial randomized 3,350 patientswith an ABI of #0.95 to aspirin or placebo. After amean follow-up of 8.2 years, there was no significant

CENTRAL ILLUSTRATION Clinical Decision-Making Algorithm for Patients With Peripheral Artery Disease

Approach to Antithrombotic Therapy in Peripheral Artery Disease

Asymptomatic

Consider Aspirin

Particularly if disease inanother vascular bed

All PatientsRecent CoronaryStent or Acute

Coronary SyndromeSurgical Endovascular

DAPTfor 1-6 Months

Aspirin or ClopidogrelOR

Aspirin+Rivaroxaban

High Limb Risk

Dual Antiplatelet Therapy (DAPT)

Weigh ischemic andbleeding risks for long-term use

↑ Ischemic Risk ↑ Bleeding Risk ↑ Limb Risk

Prior MIDiabetesOlder age

Chronic kidney diseaseHeart failure

Current smoker

AnticoagulationPrior bleeding

Older ageChronic kidney disease

AnemiaLow body weight

Prosthetic bypassBelow-knee bypassSuboptimal conduitPoor arterial run-off

Extensive lesionsTissue loss

Intensify Antithrombotic TherapyConsider aspirin+rivaroxaban, vitamin K

antagonist, or DAPT after bypass. Consider prolonged DAPT after endovascular

procedure. Weigh limb and bleeding risks.

Aspirin or ClopidogrelOR

Aspirin+Rivaroxaban

Rivaroxaban 2.5 mg BID addedto aspirin reduces major adverse

cardiovascular or cerebrovascularevents and major adverse limbevents but increases bleeding

Symptomatic Revascularization

Hussain, M.A. et al. J Am Coll Cardiol. 2018;71(21):2450–67.

DAPT ¼ dual antiplatelet therapy; MI ¼ myocardial infarction.

Hussain et al. J A C C V O L . 7 1 , N O . 2 1 , 2 0 1 8

Antithrombotics in PAD M A Y 2 9 , 2 0 1 8 : 2 4 5 0 – 6 7

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difference in MACCE between the 2 groups (10.8% foraspirin vs. 10.5% for placebo; HR: 1.03 [95% CI: 0.84to 1.27]). Of note, subgroup analyses of patients witha lower ABI of #0.90, which is traditionally used todefine PAD, also showed no benefit of aspirin in thesetrials. However, these trials might have beenunderpowered to detect differences in subgroups ofpatients with a lower ABI. For example, in thePOPADAD trial, there was a numerical trend toward abeneficial effect of aspirin in the subgroup of patientswith an ABI of #0.90 (HR: 0.81 [95% CI: 0.58 to 1.14]);however, this did not reach statistical significance.SYMPTOMATIC PAD. Aspi r in therapy . In 2002, theAntithrombotic Trialists’ Collaboration (ATC) reported

a meta-analysis of randomized controlled trials thatexamined the efficacy of various antiplatelet agentsin patients at high risk for vascular occlusive events(29). Meta-analysis of 42 trials comprising 9,214patients with symptomatic PAD showed thatantiplatelet therapy was associated with a 23% oddsreduction (SE 8%) in serious vascular events.However, the trials included in this analysis wereconducted over 20 years ago and they studied severaldifferent antiplatelet agents in addition to aspirin.Subsequent to the ATC meta-analysis, the CLIPS(Critical Leg Ischaemia Prevention Study) studyrandomized 366 patients with Fontaine stage I(asymptomatic) or II (intermittent claudication) PAD


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to aspirin versus placebo (30). A total of 77.6% (284 of366) of patients in the trial had claudication. Afternearly 2-year follow-up, aspirin significantly reducedthe risk of a composite of MACCE and critical limbischemia (6.5% for aspirin vs. 15.5% for placebo; HR:0.42 [95% CI: 0.21 to 0.82]). This trial was stoppedearly and well short of the 2,000 patients originallyplanned for enrollment. In 2009, Berger et al. (31)published a meta-analysis of 18 trials involving 5,269individuals, which examined the efficacy of aspirinwith or without dipyridamole compared with placeboin PAD patients (31). The majority (16 of 18) of trialsincluded patients with symptomatic PAD, whereas 1trial included asymptomatic PAD (the POPADAD trial)(27), and 1 trial included both symptomatic andasymptomatic PAD (the CLIPS study) (30). In total,74.2% (3,911 of 5,269) of patients included in thereview had symptomatic PAD. The authors observeda nonsignificant decrease in MACCE (8.9% for aspirin� dipyridamole vs. 11.0% for placebo; risk ratio [RR]:0.88 [95% CI: 0.76 to 1.04]). Similarly, a meta-analysis of trials of aspirin alone versus placebofound a nonsignificant decrease in events (RR: 0.74[95% CI: 0.48 to 1.18]). Most of the trials included inthis meta-analysis were small, of short duration, andcompleted before 1990. Based on the available data,the U.S. Food and Drug Administration has notgranted aspirin a PAD indication.Monotherapy with P2Y12 inh ib i tors . Two P2Y12

inhibitors have been studied in the context of singleantiplatelet therapy for symptomatic PAD: clopidog-rel and ticagrelor. The CAPRIE (Clopidogrel versusAspirin in Patients at Risk of Ischaemic Events) trialshowed superior efficacy of clopidogrel 75 mg dailycompared with aspirin 325 mg daily in reducingMACCE in patients with a recent ischemic stroke,myocardial infarction, or symptomatic PAD over amean follow-up period of 1.91 years (5.3% for clopi-dogrel vs. 5.8% for aspirin; RR: 0.91 [95% CI: 0.84 to0.997]) (32). The 6,452-patient PAD subgroup experi-enced the greatest risk reduction with clopidogrel inthis trial (3.7% for clopidogrel vs. 4.9% for aspirin;RR: 0.76 [95% CI: 0.64 to 0.91]). In addition, analysesof other high-risk subgroups of patients with diabetes(33) or prior ischemic events (34) from the CAPRIEstudy showed an amplified benefit of clopidogrel overaspirin, similar to the PAD subgroup. Hospitalizationfor gastrointestinal bleeding was higher with aspirinthan with clopidogrel (0.7% for clopidogrel vs. 1.1%for aspirin; RR: 0.68 [95% CI: 0.51 to 0.92]) (35). Thesedata suggest clopidogrel should be considered as analternative to aspirin in symptomatic PAD. Morerecently, the EUCLID (Examining Use of Ticagrelor inPeripheral Artery Disease) trial tested whether

ticagrelor was superior to clopidogrel in 13,885 pa-tients with PAD (36). After a mean follow-up of 2.5years, the authors found no significant difference inMACCE between ticagrelor and clopidogrel (10.8% vs.10.6%, respectively; HR: 1.02 [95% CI: 0.92 to 1.13]).Acute limb ischemia, limb revascularization, andmajor bleeding rates were also similar between the 2groups. Furthermore, a subgroup analysis of patientswith a prior lower extremity revascularizationshowed similar efficacy of ticagrelor and clopidogrel(37). Therefore, the efficacy and safety profile ofticagrelor appears similar to clopidogrel in symp-tomatic PAD. Of note, according to another recentanalysis of the EUCLID trial, w5% of patients enrolledin the trial had critical limb ischemia (defined as restpain or tissue loss) (38). The risk for MACCE (HR: 1.43[95% CI: 1.16 to 1.76]) and major amputation (HR: 3.41[95% CI: 2.39 to 4.87]) was significantly higher amongpatients with critical limb ischemia than thosewithout critical limb ischemia.Dual ant ip la te let therapy . Dual aspirin and clopi-dogrel therapy versus aspirin alone was studied in theCHARISMA (Clopidogrel for High AtherothromboticRisk and Ischemic Stabilization, Management, andAvoidance) trial (39–41). The trial included patientswith established cardiovascular disease or multipleatherothrombotic risk factors. The primary MACCEendpoint was numerically lower with aspirin plusclopidogrel, but this did not reach statistical signifi-cance in the overall trial (6.8% for aspirin plusclopidogrel vs. 7.3% for aspirin; RR: 0.93 [95% CI: 0.83to 1.05]), or in the PAD subgroup (7.6% for aspirin plusclopidogrel vs. 8.9% for aspirin; HR: 0.85 [95% CI: 0.66to 1.08]) (39,41). The risk for minor bleeding was 2-foldhigher with aspirin plus clopidogrel. However, in asubanalysis of high ischemic risk patients in theCHARISMA trial, which included those with a historyor stroke, myocardial infarction, or symptomatic PAD,MACCE was significantly lower in the aspirinplus clopidogrel arm (7.3% for aspirin plus clopidogrelvs. 8.8% for aspirin; HR: 0.83 [95% CI: 0.72 to 0.96])(40). Among the PAD group, dual antiplatelet therapyreduced the risk of myocardial infraction (HR: 0.63[95% CI: 0.42 to 0.96]) and hospitalization for ischemicevents (HR: 0.81 [95% CI: 0.68 to 0.95]) (41). Therefore,subgroup data from the CHARISMA trial suggest but donot entirely prove that there may be a benefit of dualaspirin plus clopidogrel therapy in PAD, particularly inthose patients at high risk for ischemic events and atlow risk for bleeding.

The efficacy of ticagrelor plus aspirin was exam-ined in the PLATO (Study of Platelet Inhibition andPatient Outcomes) (42,43) and PEGASUS-TIMI 54(Prevention of Cardiovascular Events in Patients with

TABLE 1 Studies of Antithrombotic Agents in Patients With Stable PAD

Study, Year (Ref. #)StudyDesign

SampleSize

PatientPopulation Treatment

MedianFollow-Up Main Results Interpretation

Asymptomatic PAD

POPADAD, 2008(27)

RCT (2 � 2) 1,276 ABI #0.99,asymptomatic,and diabetes

Aspirin 100 mg vs.placebo/antioxidant

6.7 yrs MACCE or amputation: 18.2%aspirin vs. 18.3% placebo; HR:0.98 (95% CI: 0.76–1.26)

GI bleed: 4.4% aspirin vs. 4.9%placebo; HR: 0.90 (95% CI:0.53–1.52)

Aspirin did not reduce MACCEin asymptomatic PADpatients with diabetes

AAA, 2010 (28) RCT 3,350 ABI #0.95 andasymptomatic

Aspirin 100 mg vs.placebo

8.2 yrs* MACCE or revascularization:10.8% aspirin vs. 10.5%placebo; HR: 1.03 (95% CI:0.84–1.27)

Major hemorrhage: 2.0% aspirinvs. 1.2% placebo; HR: 1.71(95% CI: 0.99–2.97)

Aspirin did not reduce MACCEin asymptomatic PAD

Symptomatic PAD

Aspirin therapy

ATC, 2002(29)

Meta-analysis ofRCTs (PADsubgroup)

9,214 Symptomatic PAD Various antiplateletsvs. placebo

— MACCE: 5.8% antiplatelets vs.7.1% placebo; 23% oddsreduction (SE 8%)

Antiplatelet agents comparedwith placebo reducedMACCE in symptomaticPAD patients

CLIPS, 2007(30)

RCT (2 � 2) 366 Fontaine stage I–IIwithABI <0.85 orTBI <0.6†

Aspirin 100 mg vs.placebo/antioxidant

1.7 yrs* MACCE or critical leg ischemia:6.5% aspirin vs. 15.5%placebo; HR: 0.42 (95% CI:0.21–0.83)

Bleeding: 2.2% aspirin vs. 0%placebo; p ¼ 0.99

Aspirin reduced MACCE/legischemia in mild-moderatePAD without increasingbleeding risk

Berger et al.,2009 (31)

Meta-analysis ofRCTs

5,269 Symptomatic andasymptomaticPAD trials†

Aspirin 100–1,500mg� dipyridamolevs. placebo

10 days to6.7 yrs‡

MACCE: 8.9% aspirin vs. 11.0%placebo; RR: 0.88 (95% CI:0.76–1.04)

Major bleeding: 1.8% aspirin vs.1.8% placebo; RR: 0.99 (95%CI: 0.66–1.50)

Statistically nonsignificantdecrease in MACCE withaspirin � dipyridamole inPAD

P2Y12 inhibitor monotherapy

CAPRIE, 1996(32–35)

RCT (PADsubgroup)

6,452 Symptomatic PAD Clopidogrel 75 mg vs.aspirin 325 mg

1.9 yrs* MACCE: 3.7% clopidogrel vs.4.9% aspirin per year; RR:0.76 (95% CI: 0.64–0.91)

GI bleed hospitalization: 0.7%clopidogrel vs. 1.1% aspirin;RR: 0.68 (95% CI: 0.51–0.92)

Clopidogrel more effectivethan aspirin in reducingMACCE in symptomaticPAD

EUCLID, 2016(36–38)

RCT 13,885 Symptomatic PAD Ticagrelor 90 mgtwice daily vs.clopidogrel 75 mg

2.5 yrs MACCE: 10.8% ticagrelor vs.10.6% clopidogrel; HR: 1.02(95% CI: 0.92–1.13)

Acute limb ischemia: 1.7% vs.1.7%; HR: 1.03 (95% CI: 0.79–1.33)

Limb revascularization: 12.2%ticagrelor vs. 12.8%clopidogrel; HR: 0.95 (95% CI:0.87–1.05)

Major bleeding: 1.6% vs. 1.6%;HR: 1.10 (95% CI: 0.84–1.43)

Ticagrelor not superior toclopidogrel in reducingMACCE or limb eventswith similar rates ofbleeding in symptomaticPAD

DAPT

CHARISMA,2009(39–41)

RCT (PADsubgroup)

3,096 SymptomaticPAD andasymptomaticPAD withABI <0.9 plusmultiple riskfactors

Clopidogrel 75 mgplus aspirin vs.aspirin

2.3 yrs MACCE: 7.6% clopidogrel þaspirin vs. 8.9% aspirin; HR:0.85 (95% CI: 0.66–1.08)

Peripheral bypass: 3.8%clopidogrel þ aspirin vs. 5.1%aspirin; p ¼ 0.070

Amputation: 0.8% clopidogrel þaspirin vs. 1.1% aspirin;p ¼ 0.36

Severe bleeding: 1.7% vs. 1.7%;HR: 0.97 (95% CI: 0.56–1.66)

Minor bleeding: 34.4%clopidogrel þ aspirin vs.20.8% aspirin; HR: 1.99(95% CI: 1.69–2.34)

Statistically nonsignificantdecrease in MACCE andlimb events withclopidogrel þ aspirin vs.aspirin alone, with higherrisk of minor bleeding inPAD

PLATO,2015(42,43)

RCT (PADsubgroup)

1,144 PAD plus ACS Ticagrelor 90 mgtwice daily plusaspirin vs.

9.1 months MACCE: 18.0% ticagrelor þ aspirinvs. 20.6% clopidogrel þaspirin; HR: 0.85 (95% CI:0.64–1.11)

Statistically nonsignificantdecrease in MACCE withticagrelor þ aspirin vs.

Continued on the next page



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TABLE 1 Continued


SampleSize



clopidogrel 75 mgplus aspirin

Major bleeding: 14.8%ticagrelor þ aspirin vs. 17.9%clopidogrelþaspirin; HR: 0.81(95% CI: 0.59–1.10)

clopidogrel þ aspirin inACS with PAD

PEGASUS-TIMI54, 2016(44–46)

RCT (PADsubgroup)

1,143 PAD plus prior MIin 1–3 yrs

Ticagrelor 90/60 mgtwice daily plusaspirin vs. aspirin

2.8 yrs MACCE: 19.3% aspirin; 16.3%ticagrelor 90 mg þ aspirin (HRvs. aspirin: 0.81 [95% CI: 0.57–1.15]);

14.1% ticagrelor 60 mg þ aspirin(HR vs. aspirin: 0.69 [95% CI:0.47–0.99])

MALE: 0.46% ticagrelor þ aspirin(pooled doses) vs. 0.71%aspirin; HR: 0.65 (95% CI:0.44–0.95)

Major bleeding: ticagrelor90 mg þ aspirin vs. aspirin HR:1.46 (95% CI: 0.39–5.43);ticagrelor 60 mg þ aspirin vs.aspirin HR: 1.18 (95% CI: 0.29–4.71)

Ticagrelor þ aspirin reducedMACCE and MALE eventscompared with aspirinalone in PAD patients withprior MI

PRODIGY,2016(47,48)

RCT (PADsubgroup)

246 Symptomatic PADpatientsundergoingcoronarystenting

Clopidogrel plusaspirin for 24 vs.6 months

2 yrs§ MACCE: 16.1% 24 months vs.27.3% 6 months; HR: 0.54(95% CI: 0.31–0.95)

Stent thrombosis: 6.0%24 months vs. 0% 6 months;HR: 0.07 (95% CI: 0–1.21)

Bleeding: 5.2% 24 months vs.6.9% 6 months; HR: 0.77(95% CI: 0.27–2.21)

Prolonged dual antiplatelettherapy decreasedischemic events withoutincreasing bleeding aftercoronary stenting insymptomatic PAD

DAPT, 2017(49,50)

RCT (PADsubgroup)

649 PAD patientsundergoingcoronarystenting

Clopidogrel orprasugrel plusaspirin for 30 vs.12 months

2.5 yrs§ MI or stent thrombosis: 4.7%30 months vs. 7.3%12 months; HR: 0.63 (95% CI:0.32–1.22)

MACCE: 12.0% 30 months vs.11.3% 12 months; HR: 1.06(95% CI: 0.67–1.67)

Moderate or severe bleeding:6.3% 30 months vs. 3.5%12 months; HR: 1.82 (95% CI:0.87–3.83)

Statistically nonsignificantdecrease in MI/stentthrombosis and increase inbleeding with prolongeddual antiplatelet therapyafter coronary stenting inPAD

PAR-1 antagonist

TRA2�P-TIMI50, 2013(57–59)

RCT (PADsubgroup)

3,787 SymptomaticPAD

Vorapaxar 2.5 mg vs.placebo

2 yrs MACCE: 11.3% vorapaxar vs. 11.9%placebo; HR: 0.94 (95% CI:0.78–1.14)

Acute limb ischemia: 2.3%vorapaxar vs. 3.9% placebo;HR: 0.58 (95% CI: 0.39–0.86)

Peripheral revascularization:18.4% vorapaxar vs. 22.2%placebo; HR: 0.84 (95% CI:0.73–0.97)

Moderate/severe bleeding: 7.4%vorapaxar vs. 4.5% placebo;HR: 1.62 (95% CI: 1.21–2.18)

No difference in MACCE butlower rates of limb eventsand higher rates ofbleeding with vorapaxar insymptomatic PAD

TRACER, 2014(60,61)

RCT (PADsubgroup)

936 SymptomaticPAD plus non–ST-segmentelevation ACS

Vorapaxar 2.5 mg vs.placebo

1.4 yrs MACCE: 21.7% vorapaxar vs.24.8% placebo; HR: 0.85(95% CI: 0.64–1.13)

Peripheral revascularization: 8.1%vorapaxar vs. 9.0% placebo;HR: 0.68 (95% CI: 0.40–1.16)

Amputation: 0.9% vorapaxar vs.1.5% placebo; HR: 0.16 (95%CI: 0.02–1.49)

Moderate-severe bleeding: 13.3%vorapaxar vs. 9.2% placebo;HR: 1.47 (95% CI: 0.89–2.45)

No significant differences inMACCE and MALE andhigher rates of bleedingwith vorapaxar in ACS withsymptomatic PAD



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TABLE 1 Continued


SampleSize



Anticoagulation

WAVE, 2007(62)

RCT 2,161 SymptomaticPAD, carotidartery disease,or subclavianartery disease

Warfarin oracenocoumarolplus antiplateletvs. antiplatelet

2.9 yrs* MACCE: 12.2% anticoagulant þantiplatelet vs. 13.3%antiplatelet; RR: 0.92 (95% CI:0.73–1.16)

Life-threatening bleeding: 4.0%anticoagulant þ antiplateletvs. 1.2% antiplatelet; RR: 3.41(95% CI: 1.84–6.35)

Warfarin/acenocoumarol plusantiplatelet was not moreeffective thanantiplatelet alone inpreventing MACCE andincreased bleeding

COMPASS,2017(63–65)

RCT (PADsubgroup)

7,470 SymptomaticPAD, carotidartery disease,or ABI <0.9with coronaryartery diseasek

Rivaroxaban 2.5 mgtwice daily plusaspirin orrivaroxaban 5 mgtwice daily vs.aspirin

1.8 yrs MACCE: 6.9% aspirin; 5.1%rivaroxaban þ aspirin (HR vs.aspirin: 0.72 [95% CI: 0.57–0.90]); 6.0% rivaroxaban (HRvs. aspirin: 0.86 [95% CI:0.69–1.08])

MALE: 1.2% rivaroxaban þ aspirinvs. 2.2% aspirin; HR: 0.54(95% CI: 0.35–0.84)

Major amputation: 0.2%rivaroxaban þ aspirin vs. 0.7%aspirin; HR: 0.30 (95% CI:0.11–0.80)

Major bleeding: 3.1%rivaroxaban þ aspirin vs. 1.9%aspirin (HR: 1.61 [95% CI: 1.12–2.31])

Net clinical benefit: 6.8%rivaroxaban þ aspirin vs. 9.3%aspirin; HR: 0.72 (95% CI:0.59–0.87)

Low-dose rivaroxaban plusaspirin was superior toaspirin alone in reducingMACCE, MALE, and majoramputations in PAD, butincreased risk of majorbleeding, with net clinicalbenefit in favor ofrivaroxaban þ aspirinstrategy

*Mean follow-up. †The CLIPS (Critical Leg Ischaemia Prevention Study) trial and Berger et al. (31) meta-analysis included 22% (82 of 366) and 26% (1,358 of 5,269) patients with asymptomatic peripheralartery disease (PAD), respectively. ‡Range of follow-up. §Maximum follow-up. kThe COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial PAD subgroup included 55% (4,129of 7,470) of patients with symptomatic PAD of the lower extremities; 26% (1,919 or 7,470) of patients with previous carotid revascularization or carotid stenosis of at least 50%; and 20% (1,422 of 7,470)patients with coronary disease and asymptomatic PAD.

AAA ¼ aspirin for Asymptomatic Atherosclerosis; ABI ¼ ankle-brachial index; ACS¼ acute coronary syndrome; ATC¼ Antithrombotic Trialists’ Collaboration; CAPRIE ¼ Clopidogrel versus Aspirin in Patientsat Risk of Ischaemic Events; CHARISMA ¼ Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI ¼ confidence interval; DAPT ¼ dual antiplatelet therapy;EUCLID ¼ Examining Use of Ticagrelor in Peripheral Artery Disease; GI ¼ gastrointestinal; HR ¼ hazard ratio; MACCE ¼ major adverse cardiovascular or cerebrovascular event; MALE ¼ major adverse limbevent; MI ¼myocardial infarction; PAR ¼ protease-activated receptor; PEGASUS-TIMI 54 ¼ Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on aBackground of Aspirin–Thrombolysis In Myocardial Infarction 54; PLATO ¼ Study of Platelet Inhibition and Patient Outcomes; POPADAD ¼ Prevention of Progression of Arterial Disease and Diabetes;PRODIGY ¼ Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study; RCT ¼ randomized controlled trial; RR ¼ risk ratio; TBI ¼ toe-brachial index; TRA2�P-TIMI50 ¼ Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis In Myocardial Infarction 50; TRACER ¼ Thrombin Receptor Antagonist for Clinical EventReduction in Acute Coronary Syndrome; WAVE ¼ Warfarin Antiplatelet Vascular Evaluation.



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Prior Heart Attack Using Ticagrelor Compared to Pla-cebo on a Background of Aspirin–Thrombolysis InMyocardial Infarction 54) (44–46) trials. The PLATOtrial showed a significantly lower rate of MACCE withticagrelor plus aspirin compared with clopidogrel plusaspirin in patients with acute coronary syndrome(9.8% vs. 11.7%, respectively; HR: 0.84 [95% CI: 0.77to 0.92]) (42). In a subgroup analysis of 1,144 PADpatients from the PLATO trial, MACCE was numeri-cally lower with ticagrelor plus aspirin, but this didnot reach statistical significance (18.0% for ticagrelorplus aspirin vs. 20.6% for clopidogrel plus aspirin;HR: 0.85 [95% CI: 0.64 to 1.11]), perhaps owing to lackof statistical power (43). The PEGASUS-TIMI 54 trialcompared ticagrelor plus aspirin with aspirin alone inpatients with a prior myocardial infarction, and foundticagrelor significantly reduced the risk of MACCEwith 90 mg (0.85 [95% CI: 0.75 to 0.96]) and 60 mg(0.84 [95% CI: 0.74 to 0.95]) twice-daily dosing (44).

In a subgroup analysis of 1,143 patients with PAD,MACCE were lower particularly in the ticagrelor60 mg twice daily plus aspirin arm (14.1% vs. 19.3%for aspirin; HR: 0.69 [95% CI: 0.47 to 0.99]), as wereMALE (0.46% vs. 0.71% for aspirin; HR: 0.65 [95% CI:0.44 to 0.95]; pooled doses) at 3 years (45). However,the overall trial showed a 2 to 3 times higher risk ofThrombolysis In Myocardial Infarction majorbleeding in the ticagrelor group, which did not reachstatistical significance in the PAD subgroup.

Subanalyses of PAD patients from 2 coronary trialsprovide data with regard to duration of dual anti-platelet therapy: the PRODIGY (Prolonging Dual An-tiplatelet Treatment After Grading Stent-InducedIntimal Hyperplasia Study) (47,48) and DAPT(Dual Antiplatelet Therapy) (49,50) trials. Both trialscompared long versus short duration of dual antith-rombotic therapy after coronary stenting. Among thetotal population of patients who underwent


2457

randomization in the PRODIGY trial, clopidogrel plusaspirin for 24 versus 6 months did not significantlyreduce MACCE (10.1% vs. 10.0%, respectively; HR:0.98 [95% CI: 0.74 to 1.29]), and increased bleeding by2-fold (47). However, a subgroup analysis from thePRODIGY trial suggested a benefit of prolonged dualantiplatelet therapy in PAD patients, in whom therewas a significant reduction in MACCE (16.1% vs. 27.3%for 6 months; HR: 0.54 [95% CI: 0.31 to 0.95]) (48).The overall results of the DAPT study showed asignificantly lower risk of MACCE with dual anti-platelet therapy when administered for 30 versus12 months in the overall trial (4.3% vs. 5.9%, respec-tively; HR: 0.71 [95% CI: 0.59 to 0.85]) (49), and anumerically lower risk of stent thrombosis ormyocardial infarction in the PAD subgroup that didnot reach statistical significance (4.7% vs. 7.3%,respectively; HR: 0.63 [95% CI: 0.32 to 1.22]) (50). Therisk of moderate or severe bleeding was significantlyhigher with prolonged dual antiplatelet therapy in theoverall trial and numerically higher in the PADsubgroup.

A meta-analysis of 6 trials comprising 33,435 pa-tients with previous myocardial infarction found thatdual antiplatelet therapy beyond 1 year decreasedMACCE (6.4% vs. 7.5%; RR: 0.78 [95% CI: 0.67 to0.90]) but increased major bleeding (1.9% vs. 1.1%;RR: 1.73 [95% CI: 1.19 to 2.50]) (51). Therefore, athoughtful approach to duration of dual antiplatelettherapy is recommended in this population, carefullyweighing ischemic and bleeding risks in individualpatients (52). Unfortunately, there are limited data onthe efficacy and safety of antithrombotic regimens inPAD patients undergoing peripheral revascularization(53,54). Contemporary trials of PAD patients typicallyrequire at least 30 to 60 days of dual antithrombotictherapy after endovascular revascularization, fol-lowed by lifelong aspirin (55,56)—this represents thecurrent standard or care in the absence of level Ievidence.Protease-activated receptor 1 antagonist. The effect ofvorapaxar when used in conjunction with other an-tiplatelet agents was examined in the TRA2�P-TIMI 50(Thrombin Receptor Antagonist in Secondary Pre-vention of Atherothrombotic Ischemic Events-Thrombolysis In Myocardial Infarction 50) (57–59)and TRACER (Thrombin Receptor Antagonist forClinical Event Reduction in Acute CoronarySyndrome) (60,61) trials. The TRA2�P-TIMI 50 trial,which included patients with a history of myocardialinfarction, ischemic stroke, or PAD, showed asignificant reduction in MACCE with vorapaxarcompared with placebo (9.3% vs. 10.5%, respectively;HR: 0.87 [95% CI: 0.80 to 0.94]) (57). In a subgroup

analysis of PAD patients, MACCE was numericallylower with vorapaxar, although this did not reachstatistical significance (11.3% for vorapaxar vs. 11.9%for placebo; HR: 0.94 [95% CI: 0.78 to 1.14]) (58).However, vorapaxar did reduce the risk of severaladverse limb events including the development ofacute limb ischemia (HR: 0.58 [95% CI: 0.39 to 0.86])and peripheral revascularization (HR: 0.84 [95% CI:0.73 to 0.97]) (59). Occurrence of moderate or severebleeding however was 1.5 times higher withvorapaxar compared with placebo in the overall trialparticipants and in the PAD subgroup. The efficacyand safety of vorapaxar in patients with acutecoronary syndrome was studied in the TRACER trial.There was a nonsignificant reduction in MACCEin the overall trial (18.5% for vorapaxar vs. 19.9%for placebo; HR: 0.92; [95% CI: 0.85 to 1.01]),and in the 936-patient PAD subgroup (21.7% forvorapaxar vs. 24.8% for placebo; HR: 0.85 [95% CI:0.64 to 1.13]) (60,61). In addition, there werenumerical but nonsignificant reductions in peripheralrevascularization procedures (8.1% for vorapaxar vs.9.0% for placebo; HR: 0.68 [95% CI: 0.40 to 1.16]) andlower-extremity amputations (0.9% for vorapaxar vs.1.5% for placebo; HR: 0.16 [95% CI: 0.02 to 1.49]). Riskfor bleeding was significantly higher in the overalltrial and numerically higher in the PAD subgroup.Anticoagulation. The efficacy of warfarin or aceno-coumarol plus antiplatelet therapy compared withantiplatelet alone was tested in the WAVE (WarfarinAntiplatelet Vascular Evaluation) trial (62). In acohort of 2,161 patients with symptomatic PAD, anti-coagulation or antiplatelet therapy compared withantiplatelet therapy alone did not reduce MACCE(12.2% vs. 13.3%, respectively; RR: 0.92 [95% CI: 0.73to 1.16]) or a composite endpoint of MACCE and se-vere ischemia of the peripheral or coronary arteries(15.9% vs. 17.4%, respectively; RR: 0.91 [95% CI: 0.74to 1.12]). Life-threating bleeding was increased withanticoagulation (4.0% vs. 1.2%; RR: 3.41 [95% CI: 1.84to 6.35]).

The recent COMPASS (Cardiovascular Outcomes forPeople Using Anticoagulation Strategies) trialcompared 3 antithrombotic strategies in patients withstable atherosclerotic cardiovascular disease: rivar-oxaban 2.5 mg twice daily plus aspirin 100 mg daily,rivaroxaban 5 mg twice daily, or aspirin 100 mg alone(63–67). Among the overall 27,395 participants in theCOMPASS trial, the risk of MACCE was significantlyreduced in the rivaroxaban plus aspirin armcompared with aspirin alone (4.1% vs. 5.4%, respec-tively; HR: 0.76 [95% CI: 0.66 to 0.86]) (63). Similarefficacy of rivaroxaban plus aspirin compared withaspirin alone was observed in the subgroup of 7,470



2458

patients with PAD or carotid artery disease (5.1% vs.6.9%, respectively; HR: 0.72 [95% CI: 0.57 to 0.90])(64). In addition, in the PAD or carotid disease sub-group, there were fewer MALE in the rivaroxabanplus aspirin arm than in the aspirin-alone arm (1.2%vs. 2.2%, respectively; HR: 0.54 [95% CI: 0.35 to 0.84])and fewer major amputations (0.2% vs. 0.7%,respectively; HR: 0.30 [95% CI: 0.11 to 0.80]). Therewas not a significant decrease in MACCE in therivaroxaban 5 mg twice daily group versus theaspirin-alone group (HR: 0.86 [95% CI: 0.69 to 1.08]),but there was a reduction in MALE (HR: 0.67 [95% CI:0.45 to 1.00]). Major bleeding was higher in therivaroxaban plus aspirin group (3.1% vs. 1.9% foraspirin; HR: 1.61 [95% CI: 1.12 to 2.31]), but there wasno significant increase in fatal or critical organbleeding. Net clinical benefit after accounting forischemic, limb, and bleeding events was in favor ofthe rivaroxaban plus aspirin strategy (6.8% for rivar-oxaban plus aspirin vs. 9.3% for aspirin; HR: 0.72[95% CI: 0.59 to 0.87]). Of note, the MACCE and MALEbenefits, and bleeding risks of the combination ther-apy, were consistent in patients with symptomaticand asymptomatic PAD, and carotid artery disease.The data from the COMPASS trial suggest that rivar-oxaban dosed at 2.5 mg plus aspirin may be apreferred treatment strategy in PAD patients in whomthe bleeding risk is deemed to be favorable.

ANTITHROMBOTIC THERAPY AFTER

PERIPHERAL ARTERY REVASCULARIZATION

Few controlled data exist on the various antith-rombotic regimens in PAD patients undergoing pe-ripheral revascularization (Table 2).

SURGICAL REVASCULARIZATION. Among a sub-group of 2,497 patients undergoing peripheral graft-ing for PAD in the ATC meta-analysis, antiplateletagents reduced the risk of MACCE by 22% (SE 16%)(29). Furthermore, a recent Cochrane review sug-gested a benefit of aspirin with or without dipyr-idamole on infrainguinal bypass graft patency at 1year (odds ratio [OR]: 0.42 [95% CI: 0.22 to 0.83]) (68).The protective effect of aspirin, however, was morepronounced in patients receiving prosthetic grafts(OR: 0.19 [95% CI: 0.10 to 0.36]) than with vein grafts(OR: 0.60 [95% CI: 0.48 to 0.99]). In the CASPAR(Clopidogrel and Acetylsalicylic acid in bypass Sur-gery for Peripheral Arterial disease) trial, the efficacyof dual antiplatelet therapy with clopidogrel plusaspirin versus aspirin alone was compared in 851 pa-tients undergoing below-the-knee bypass grafting(69). After 1-year follow-up, there was no differencein the composite rate of graft occlusion,

revascularization, amputation, or death between the2 arms (35.1% for clopidogrel plus aspirin vs. 35.4%for aspirin; HR: 0.98 [95% CI: 0.78 to 1.23]). A sub-analysis by type of graft, however, showed a benefitof clopidogrel plus aspirin in patients who receivedprosthetic grafts (HR: 0.65 [95% CI: 0.45 to 0.95]). Anybleeding was higher with clopidogrel plus aspirinthan with aspirin alone (16.7% vs. 7.1%, respectively;p < 0.001), although no significant differences wereobserved in the rates of severe bleeding between the2 arms.

The Dutch BOA (Bypass Oral anticoagulants orAspirin) trial randomized 2,690 patients undergoinginfrainguinal bypass to high intensity anticoagulation(international normalized ratio 3.0 to 4.5) withphenprocoumon or acenocoumarol versus aspirin(70). Overall rates of graft occlusion were similar be-tween the 2 arms (13.5% for anticoagulation vs. 14.2%for aspirin; HR: 0.95 [95% CI: 0.82 to 1.11]); however, asubgroup analysis indicated anticoagulation wasassociated with better vein graft patency (HR: 0.69[95% CI: 0.54 to 0.88]). Major bleeding includingintracranial hemorrhage was higher with anti-coagulation than with aspirin (8.1% vs. 4.2%,respectively; HR: 1.96 [95% CI: 1.42 to 2.71]). Saracet al. (71) conducted a randomized controlled trial ofwarfarin plus aspirin versus aspirin alone in a smallcohort of high-risk patients undergoing infrainguinalbypass with vein. Suboptimal conduit, poor runoff, orredo procedure were used as criteria to define high-risk patients. The authors observed significantlyhigher 3-year primary patency rates and limb salvagerates with warfarin plus aspirin than with aspirinalone (74% vs. 51% [p ¼ 0.04] and 81% vs. 31%[p ¼ 0.02], respectively); the risk for wound hema-toma was higher in the warfarin plus aspirin groupthan in the aspirin group (31% vs. 4%, respectively;p ¼ 0.004). Other trials examining combinations ofwarfarin plus aspirin (72), warfarin plus clopidogrel(73), and dalteparin plus aspirin (74) have not pro-vided conclusive evidence for the efficacy of anti-coagulation after surgical revascularization for PAD.ENDOVASCULAR REVASCULARIZATION. The ATCmeta-analysis reported a nonstatistically significantdecrease in MACCE with antiplatelet therapy versusplacebo (2.5% vs. 3.6%, respectively; odds reduction29%; SE 35%) in a subgroup of 946 patients who un-derwent peripheral angioplasty for PAD (29). A sub-sequent Cochrane meta-analysis identified 3 trialsthat compared high dose aspirin plus dipyridamolewith placebo in 356 patients undergoing endovascularrevascularization for PAD (75). Aspirin plus dipyr-idamole therapy was associated with superiorpatency at 6 months (OR: 0.40 [95% CI: 0.19 to 0.84]).


2459

The MIRROR (Management of Peripheral Arterial In-terventions with Mono or Dual Antiplatelet Therapy)trial randomized 80 patients undergoing peripheralangioplasty with or without stenting to clopidogrelplus aspirin for 6 months versus aspirin alone (76,77).Rate of target lesion revascularization (definedas need for repeat revascularization of a lesion thatwas initially treated with angioplasty or stenting)was lower in the clopidogrel plus aspirin group thanin the aspirin alone group at 6 months (5% vs. 8%;p ¼ 0.04), although this benefit was lost at 1 year (25%vs. 32%; p ¼ 0.35). The phosphodiesterase 3 inhibitorcilostazol, which has antiplatelet properties, hasalso been studied in small controlled trials ofPAD patients undergoing endovascular revasculari-zation; however, convincing data for its efficacy arelacking (78–80).

CLINICAL DECISION MAKING FOR

ANTITHROMBOTIC THERAPY IN PAD

The approach to antithrombotic therapy in PAD pa-tients can be broadly stratified into 3 categories basedon patient status: asymptomatic, symptomatic, orundergoing peripheral revascularization. Figure 1summarizes the major clinical trials of antith-rombotics in PAD, and the Central Illustration illus-trates a suggested approach to antithromboticselection in patients with PAD.ASYMPTOMATIC PAD. Currently, there is no defini-tive evidence for the efficacy of aspirin in patientswith asymptomatic PAD. However, given theincreased risk of adverse cardiovascular events,aspirin therapy in the context of asymptomatic PAD isreasonable, particularly if there is atheroscleroticdisease in another vascular bed.

SYMPTOMATIC PAD. Patients with symptomatic PADshould be treated with antithrombotic therapy toreduce cardiovascular risk. Single antiplatelet ther-apy with either aspirin or clopidogrel is recom-mended, although controlled data from well-poweredPAD trials are limited, and most inferences must bedrawn from subgroup findings, which are largelyconsistent with overall trial findings. Robust datafrom secondary prevention trials of patients withestablished coronary or cerebrovascular diseaseindicate a 1.5% yearly absolute reduction in seriousvascular events with aspirin, which is equivalent to anumber needed to treat (NNT) of 67 (81). In addition,smaller PAD trials (e.g., the CLIPS study) also suggesta potential benefit of aspirin specifically in thesymptomatic PAD population (30). Therefore,although the evidence is of weak quality, aspirinmonotherapy should be considered in patients with

stable symptomatic PAD. The CAPRIE trial found anincremental benefit of clopidogrel over aspirin inPAD—this benefit provided an absolute risk reductionof 1.15% per year, translating to a NNT of 87 comparedwith aspirin to prevent 1 MACCE event over 1 year(32). Based on the COMPASS trial, the addition ofrivaroxaban (2.5 mg twice daily or a quarter of its fullanticoagulation dose) to aspirin could be anotherreasonable treatment strategy to reduce ischemicevents in PAD (64). Furthermore, rivaroxaban plusaspirin reduces MALE and major amputations. Theabsolute risk reduction in the composite risk ofMACCE, MALE, or major amputations with rivarox-aban plus aspirin was 1.54% per year (NNT ¼ 65compared with aspirin alone). However, these bene-fits must be weighed against bleeding risk, as theannualized absolute major bleeding rate in theCOMPASS trial was 0.69% higher with rivaroxabanplus aspirin than with aspirin alone (number neededto harm ¼ 146), and the trial also excluded patientswho were at high risk for bleeding. The net clinicalbenefit after accounting for MACCE, MALE, majoramputation, fatal bleeding, or symptomatic bleedinginto a critical organ favored rivaroxaban plus aspirinover aspirin alone with an absolute risk reduction of1.43% per year (NNT ¼ 70) (67). As no data exist ondirect head-to-head comparisons of rivaroxaban plusaspirin with clopidogrel, both appear to be reasonablestrategies and provide more benefit than aspirinalone to reduce ischemic risk in PAD. Patients who areprescribed rivaroxaban plus aspirin, however, shouldbe carefully screened for bleeding risk. Indeed, highbleeding risk was the most common reason for pa-tients being excluded in an analysis that assessed theexternal applicability of the COMPASS trial bycomparing it with the REACH registry (66). Further-more, increased costs and twice-daily dosing ofrivaroxaban are other important considerations.

PAD patients with a recent coronary stent or acutecoronary event should receive dual antiplatelettherapy with aspirin plus clopidogrel or aspirin plusticagrelor. Ticagrelor 60 mg twice daily plus aspirinshowed a significantly reduced risk of MACCE in thesubgroup of patients with symptomatic PAD and aprior myocardial infarction (1.73% absolute riskreduction per year [NNT ¼ 58]) (45). Longer-term useof dual antiplatelet therapy requires careful consid-eration of ischemic and bleeding risks, as dual anti-platelet therapy confers a 1.5 to 2 times relativelyhigher risk of bleeding than aspirin alone (82,83). Asillustrated in the Central Illustration, some factors thatincrease bleeding risk are also associated withelevated ischemic risk, thus making risk-benefitanalysis challenging in these patients. Risk scores,

TABLE 2 Studies of Antithrombotic Agents in Patients Undergoing Peripheral Artery Revascularization

Study/First Author,Year (Ref. #) Study Design

SampleSize


MaximumFollow-Up Main Results Interpretation

Surgical revascularization

Single antiplatelet therapy

ATC, 2002(29)


2,497 Peripheralgrafting for PAD

Variousantiplateletsvs. placebo


Antiplatelet agents reducedMACCE in PAD patientsundergoing peripheralgrafting

Cochrane,2015 (68)


952 Infrainguinalperipheral bypassgrafting for PAD

Aspirin �dipyridamolevs. placebo

6 weeksto 2 yrs*

1-yr primary graft patency: OR:0.42 (95% CI: 0.22–0.83);venous grafts OR: 0.69 (95% CI:0.48–0.99); prosthetic grafts: OR:0.19 (95% CI: 0.10–0.36)

Major bleeding: OR: 1.88 (95% CI:0.85–4.16)

Aspirin � dipyridamole had abeneficial effect on primarypatency of peripheral bypassgrafts, particularlyprosthetic grafts

DAPT

CASPAR, 2010(69)

RCT 851 Below-knee bypassgraft for PAD

Clopidogrel 75 mgplus aspirin vs.aspirin

1 yr† Graft occlusion, revascularization,amputation, or death: 35.1%clopidogrel þ aspirin vs. 35.4%aspirin; HR: 0.98 (95% CI: 0.78–1.23); venous grafts HR: 1.25(95% CI: 0.94–1.67); prostheticgrafts HR: 0.65 (95% CI: 0.45–0.95)

Severe bleeding: 2.1%clopidogrel þ aspirin vs. 1.2%aspirin; p ¼ NS

Any bleeding: 16.7% clopidogrel þaspirin vs. 7.1% aspirin; p< 0.001

Aspirin þ clopidogrel notsuperior to aspirin alone inreducing limb events andmortality in PAD patientsundergoing peripheralbypass, although may bebeneficial in prosthetic graftwith higher rate ofnonsevere bleeding

Anticoagulation

Dutch BOA,2000 (70)

RCT 2,690 Infrainguinalperipheralbypass graft forPAD

Phenprocoumon oracenocoumarolvs. aspirin

1.8 yrs‡ Graft occlusion: 13.5%anticoagulants vs. 14.2%aspirin; HR: 0.95 (95% CI: 0.82–1.11); vein grafts HR: 0.69 (95%CI: 0.54–0.88); nonvenousgrafts HR: 1.26 (95% CI: 1.03–1.55)

Major bleeding: 8.1%anticoagulants vs. 4.2% aspirin;HR: 1.96 (95% CI: 1.42–2.71)

Oral anticoagulants better forprevention of infrainguinalvein graft occlusion; aspirinbetter for nonvenous graftocclusion and lower risk ofbleeding

Sarac et al.,1998 (71)

RCT 56 Infrainguinal bypasswith vein inpatients withsuboptimalconduit, poorrunoff, or redoprocedure for PAD

Warfarin plusaspirin vs.aspirin

3 yrs Primary graft patency: 74%warfarin þ aspirin vs. 51%aspirin (p ¼ 0.04)

Limb salvage: 81% warfarin þaspirin vs. 31% aspirin(p ¼ 0.02)

Wound hematoma: 32% warfarin þaspirin vs. 4% aspirin(p ¼ 0.004)

Warfarin þ aspirin improvesvenous graft patency andlimb salvage in patients athigh risk for graft failure butis associated with higher riskof wound hematoma

Johnson et al.,2002 (72)

RCT 831 Surgical bypass forPAD

Warfarin plusaspirin vs.aspirin

3 yrs‡ Graft occlusion: prosthetic 23.5%warfarin þ aspirin vs. 34.4%aspirin; RR: 0.62 (95% CI: 0.42–1.92); venous 25.1% warfarin þaspirin vs. 24.7% aspirin; RR: 1.04(95% CI: 0.72–1.51)

Major bleeding: 8.4% warfarin þaspirin vs. 3.6% aspirin; p ¼ 0.02

Warfarin þ aspirin was notsuperior to aspirin alone inreducing peripheral graftocclusion and wasassociated with higher ratesof major bleeding

Jivegård et al.,2005 (74)

RCT 284 Surgical bypass forPAD

Dalteparin x3 months plusaspirin vs.aspirin

1 yr Primary graft patency: 59% vs.59% (p ¼ NS)

Postoperative dalteparin did notimprove peripheral bypassgraft patency

Monaco et al.,2012 (73)

RCT 341 Femoropoplitealbypass surgery forPAD

Warfarin plusclopidogrel vs.clopidogrelplus aspirin

6.4 yrs‡ 8-yr primary graft patency:44.4% warfarin þ clopidogrelvs. 30.4% clopidogrel þ aspirin;p ¼ 0.026;

8-yr freedom from amputation:77.6% warfarin þ clopidogrelvs. 63.9% clopidogrel þ aspirin;p ¼ 0.044

Bleeding (%/patient-year): 4.6%warfarin þ clopidogrel vs. 3.0%clopidogrel þ aspirin (p ¼ 0.06)

Warfarin þ clopidogrel wassuperior to clopidogrel þaspirin in maintainingfemoropopliteal graftpatency and reducing severelimb ischemia leading toamputations




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TABLE 2 Continued

Study/First Author,Year (Ref. #) Study Design

SampleSize


MaximumFollow-Up Main Results Interpretation

Endovascular revascularization

Single antiplatelet therapy

ATC, 2002(29)


946 Peripheral angioplastyfor PAD

Variousantiplateletsvs. placebo


Statistically nonsignificantdecrease in MACCE withantiplatelets in peripheralangioplasty for PAD

DAPT

Cochrane,2012 (75)


356 Endovascularrevascularizationfor PAD

High-dose aspirinplusdipyridamolevs. placebo

6 months Reocclusion: OR: 0.40 (95% CI:0.19–0.84)

Aspirin þ dipyridamole reducedreocclusion after peripheralendovascular treatment forPAD

MIRROR, 2013(76,77)

RCT 80 Peripheralangioplasty �stenting forRutherford 3–4PAD

Clopidogrel 75 mgplus aspirin x6 months vs.aspirin

1 yr 6-month TLR: 5% clopidogrel þaspirin vs. 8% aspirin; p ¼ 0.04

1-yr TLR: 25% clopidogrel þ aspirinvs. 32% aspirin; p ¼ 0.35

Clopidogrel þ aspirin reducedTLR after endovascularintervention for PAD at6 months, although benefitwas lost at 1 yr

Iida et al.,2008 (78)

RCT 127 Femoropoplitealangioplasty �stenting forsymptomatic PAD

Cilostazol 200 mgplus aspirin vs.ticlopidine200 mg plusaspirin

3 yrs 3-yr patency: 73% cilostazol þaspirin vs. 51% ticlopidine þaspirin; p ¼ 0.013

3-yr freedom from TLR: 82%cilostazol þ aspirin vs. 58%ticlopidine þ aspirin; p ¼ 0.036

Cilostazol þ aspirin reducedrestenosis afterendovascular treatment forsymptomatic PAD

Soga et al.,2009 (79)

RCT 78 Femoropoplitealangioplasty �stenting forintermittentclaudication

Cilostazol 200 mgplus aspirin vs.aspirin

2 yrs 2-yr freedom from TLR: 85%cilostazol þ aspirin vs. 62%aspirin; p ¼ 0.04

Restenosis: 44% cilostazol þaspirin vs. 70% aspirin;p ¼ 0.02

Cilostazol þ aspirin reducedrestenosis and repeatrevascularization afterendovascular treatment forfemoropopliteal PAD

STOP-IC, 2013(80)

RCT 200 Femoropoplitealangioplasty plusstenting forsymptomatic PAD

Cilostazol 200 mgplus aspirin vs.aspirin

1 yr Angiographic restenosis: 20%cilostazol þ aspirin vs. 49%aspirin; OR: 0.26 (95% CI: 0.13–0.53)

TLR: 17% cilostazol þ aspirin vs.40% aspirin; p ¼ 0.001

Cilostazol þ aspirin reducedangiographic restenosis afterangioplasty plus stenting forsymptomatic PAD

*Range of follow-up. †Median follow-up. ‡Mean follow-up.

BOA ¼ Bypass Oral anticoagulants or Aspirin; CASPAR ¼ Clopidogrel and Acetylsalicylic acid in bypass Surgery for Peripheral Arterial disease; CLI ¼ critical limb ischemia; MIRROR ¼ Management ofPeripheral Arterial Interventions with Mono or Dual Antiplatelet Therapy; OR ¼ odds ratio; RR ¼ risk ratio; STOP-IC ¼ Sufficient Treatment of Peripheral Intervention by Cilostazol; TLR ¼ target lesionrevascularization; other abbreviations as in Table 1.


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such as the PRECISE-DAPT (PREdicting bleedingComplications In patients undergoing Stent implan-tation and subsEquent Dual Anti Platelet Therapy),provide incremental ability to balance ischemic andbleeding risks in determining duration of dual anti-platelet therapy (84). Furthermore, increased costsand twice-daily dosing with ticagrelor are other fac-tors that should be considered when prescribing long-term dual antiplatelet therapy.

REVASCULARIZATION. Patients who undergorevascularization for PAD should be prescribed life-long antithrombotic therapy. With respect to surgicalrevascularization, aspirin, clopidogrel, and rivarox-aban plus aspirin are all reasonable strategies asdiscussed in the context of symptomatic PAD.Further intensification of antithrombotic therapyshould be considered in patients who are at high riskfor MALE events such as graft thrombosis or ampu-tation. As shown in the Central Illustration, factors

associated with increased limb risk include pros-thetic infrainguinal bypass, below-the-knee bypass,suboptimal conduit, poor arterial runoff, extensivelesions, or tissue loss (71,85,86). In these cases, sin-gle antiplatelet therapy can be intensified to aspirinplus rivaroxaban, dual antiplatelet therapy, or anti-coagulation with a vitamin K antagonist. However,current data are strongest for aspirin plus rivarox-aban with respect to lowering MALE events insymptomatic PAD patients. As usual, limb andischemic risks must be weighed against bleedingrisk. Generally, triple therapy with 2 antiplateletagents plus anticoagulation should we avoided dueits association with high bleeding rates(82,83,87,88).

With respect to endovascular revascularization(angioplasty with or without stenting), the standardof care in the absence of high-quality evidence is totreat patients with dual antiplatelet therapy for 1 to6 months after the procedure given data available

FIGURE 1 Overview of Major Clinical Trials of Antithrombotics in PAD

Single Antiplatelet

CAPRIE 1996 (Clopidogrel vs Placebo)CLIPS 2007 (ASA vs Placebo)EUCLID 2016 (Ticagrelor vs Clopidogrel)

Dual Antiplatelets

CHARISMA 2009 (Clopidogrel+ASA vs ASA)PLATO 2015 (Ticagrelor+ASA vs Clopidogrel+ASA)PEGASUS-TIMI 54 2016 (Ticagrelor+ASA vs ASA)PRODIGY 2016 (Clopidogrel+ASA for 24M vs 6M)DAPT 2017 (P2Y12 Inhibitor+ASA for 30M vs 12M)

Endovascular

MIRROR 2013 (Clopidogrel+ASA vs Placebo)

Anticoagulation

WAVE 2007 (Warfarin+antiplatelet vs antiplatelet)COMPASS 2017 (Rivaroxaban+ASA vs ASA)

PAR-1 Antagonist

TRA2°P-TIMI 50 2013 (Vorapaxar vs Placebo)TRACER 2014 (Vorapaxar vs Placebo)

Revascularizationfor PAD

Surgical

Dutch BOA 2000 (Anticoagulation vs ASA)CASPAR 2010 (Clopidogrel+ASA vs ASA)

SymptomaticPAD

AsymptomaticPAD

POPADAD 2008 (ASA vs Placebo)AAA 2010 (ASA vs Placebo)

Shown are the names of the trials and year of publication of the overall trial or peripheral artery disease (PAD) subgroup. AAA ¼ Aspirin for Asymptomatic

Atherosclerosis; ASA ¼ acetylsalicylic acid; BOA ¼ Bypass Oral anticoagulants or Aspirin; CAPRIE ¼ Clopidogrel versus Aspirin in Patients at Risk of

Ischaemic Events; CASPAR ¼ Clopidogrel and Acetylsalicylic acid in bypass Surgery for Peripheral Arterial disease; CHARISMA ¼ Clopidogrel for High

Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CLIPS ¼ Critical Leg Ischaemia Prevention Study; COMPASS ¼ Cardio-

vascular Outcomes for People Using Anticoagulation Strategies; DAPT ¼ dual antiplatelet therapy; EUCLID ¼ Examining Use of Ticagrelor in Peripheral

Artery Disease; M ¼ months; MIRROR ¼ Management of Peripheral Arterial Interventions with Mono or Dual Antiplatelet Therapy; PAR ¼ protease-

activated receptor; PEGASUS-TIMI 54 ¼ 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; PLATO ¼ Study of Platelet Inhibition and Patient Outcomes; POPADAD ¼ Prevention of

Progression of Arterial Disease and Diabetes; PRODIGY ¼ Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia

Study; TRA2�P-TIMI 50 ¼ Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis In Myocardial

Infarction 50; TRACER ¼ Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome; WAVE ¼ Warfarin Antiplatelet Vascular

Evaluation.



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from the MIRROR study (76,77). There is insufficientevidence to recommend tailored antithrombotic reg-imens in patients undergoing conventional balloonangioplasty versus drug-eluting balloon angioplastyor bare-metal versus drug-eluting stenting. The initialtreatment period should be followed by lifelong sin-gle antiplatelet therapy (aspirin or clopidogrel), orpotentially rivaroxaban plus aspirin, given data fromthe COMPASS trial. The results of the ongoing theVOYAGER PAD (Vascular Outcomes studY of ASA

alonG with rivaroxaban in Endovascular or surgicallimb Revascularization for Peripheral Artery Disease)trial should provide information regarding the mosteffective antithrombotic regimen in patients whohave undergone surgical or endovascular revascular-ization for PAD (89). Prolonged dual antiplatelettherapy should be considered in patients at high riskfor limb events. However, benefit of prolonged dualantiplatelet therapy should be weighed with a higherrisk for bleeding.

TABLE 3 Guidelines on Antithrombotic Therapy in PAD

SVS 2015 AHA/ACC 2016 ESC 2017

Asymptomatic PAD No recommendation Antiplatelet therapy is reasonable in ABI#0.90(IIa, C-EO)

Usefulness of antiplatelet therapy is uncertainin ABI 0.91–0.99 (IIb, B-R)

Antiplatelets not routinelyrecommended (III, A)

Symptomatic PAD Aspirin 75–325 mg (I, A)Clopidogrel 75 mg is an effective alternative to

aspirin (I, B)Warfarin should not be used to reduce

cardiovascular events (I, C)

Aspirin (75–325 mg) or clopidogrel (75 mg)SAPT (I, A)

Usefulness of aspirin þ clopidogrel DAPT is notwell established (IIb, B-R)

Anticoagulation should not be used to reduceischemic events (III, A)

Aspirin or clopidogrel SAPT (I, A)Clopidogrel may be preferred over

aspirin (IIb, B)

Surgicalrevascularization

Treatment with antiplatelet therapy (aspirin,clopidogrel, or aspirin þ clopidogrel DAPT)for venous and prosthetic bypass (II, B)

Aspirin þ clopidogrel DAPT may be reasonableto reduce limb events (IIb, C-LD)

Usefulness of anticoagulation to improvebypass patency is uncertain (IIb, B-R)

Aspirin or clopidogrel SAPT (I, A)VKA may be considered after vein bypass

(IIb, B)Aspirin þ clopidogrel DAPT may be

considered after below-kneeprosthetic bypass (IIb, B)

Endovascularrevascularization

Aspirin þ clopidogrel DAPT for $1 month (II, B) Aspirin þ clopidogrel DAPT may be reasonableto reduce limb events (IIb, C-LD)

Aspirin þ clopidogrel DAPT for $1 monthafter stent placement (IIb, B)followed by long-term aspirin orclopidogrel SAPT (I, A)

Specificantithrombotics

— Benefit of vorapaxar added to existingantiplatelet therapy is uncertain (IIb, B-R)

—

Values in parentheses are Class, Level of Evidence.

AHA/ACC ¼ American Heart Association/American College of Cardiology; B-R ¼ level B randomized; C-LD ¼ level C limited data; C-EO ¼ level C expert opinion; ESC ¼ European Society for Cardiology;SAPT ¼ single antiplatelet therapy; SVS ¼ Society for Vascular Surgery; VKA ¼ vitamin K antagonist; other abbreviations as in Table 1.


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GUIDELINE RECOMMENDATIONS

The American Heart Association/American College ofCardiology (AHA/ACC) (23), the European Society forCardiology (ESC) (24), and the Society for VascularSurgery (SVS) (25), have recently published detailedrecommendations on the use of antithrombotic ther-apies in patients with PAD, with some similarities andseveral discrepancies (Table 3).

All 3 guidelines give a class I recommendationbased on level A evidence for single antiplatelettherapy with either aspirin or clopidogrel for symp-tomatic PAD. However, robust data from adequatelypowered randomized controlled trials are lacking forthe efficacy of aspirin monotherapy in patients withsymptomatic PAD, and some authors have arguedthat recommendation for aspirin monotherapyshould be supported by a lower level of evidence (90).The recently updated ESC 2017 guidelines suggestclopidogrel may be preferred over aspirin based onLevel of Evidence: B.

The AHA/ACC 2016 PAD guidelines indicate thatthe usefulness of dual antiplatelet therapy withaspirin and clopidogrel is not well established insymptomatic PAD. It states, however, that dual anti-platelet therapy may be reasonable to reduce limbevents in patients undergoing peripheral revasculari-zation. The SVS and ESC guidelines both recommenddual antiplatelet therapy for $1 month after endovas-cular revascularization. Also, the SVS guidelines sug-gest single or dual antiplatelet therapy is reasonable in

patients undergoing surgical revascularization. Inaddition, the ESC guidelines recommend consideringdual antiplatelet therapy after below-the-knee pros-thetic bypass and anticoagulation with a vitamin Kantagonist after venous bypass—these are Class IIbrecommendations based on Level of Evidence: B.

These guidelines universally recommend againstfull-dose anticoagulation to reduce ischemic eventsin patients with stable PAD with no other indicationfor anticoagulation. Each of these guidelines waspublished before the COMPASS trial was published;therefore, the role of aspirin plus low-dose rivarox-aban in patients with symptomatic PAD was notconsidered in their development.

The guidelines vary in their treatment recommen-dations for patientswith asymptomatic PAD. AHA/ACCrecommends antiplatelet therapy is reasonable ifthe ABI is #0.90; the ESC recommends against routineantiplatelet therapy in asymptomatic patients; andthe SVS provides no specific recommendations in thisregard.

KNOWLEDGE GAPS AND

FUTURE DIRECTIONS

Although recent clinical trials have reported on theefficacy and safety of several different antithromboticregimens in PAD, significant knowledge gaps remain.In patients with stable symptomatic PAD, aspirin orclopidogrel are generally considered as first-linetherapy. However, as summarized in this review,



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data on aspirin and clopidogrel in the PAD populationare limited. Furthermore, low-dose rivaroxaban plusaspirin has not been directly compared with clopi-dogrel monotherapy. Therefore, additional well-powered controlled trials are needed to define theoptimal antithrombotic regimen in patients with sta-ble PAD (91). A review of ClinicalTrials.gov onlyrevealed 2 ongoing trials enrolling 200 patients eachexamining the effect of vorapaxar (NCT02660866)and cilostazol (NCT02770274) in stable PAD patients.Therefore, data in this area are expected to continueto be derived from subanalyses of larger cardiovas-cular trials. The THEMIS (Effect of Ticagrelor onHealth Outcomes in Diabetes Mellitus Patients Inter-vention Study) trial, which is enrolling w19,000 pa-tients with diabetes and stable coronary arterydisease and collecting data on PAD patients, mayprovide insight into the effect of ticagrelor plusaspirin versus aspirin alone in a subgroup of high-riskPAD patients (NCT01991795).

Few data exist on the optimal antithrombotictherapy regimen after different peripheral vascularprocedures, and this represents a major focus offuture research. The VOYAGER PAD trial is studyingthe effect of adding low-dose rivaroxaban to anti-platelet therapy in 6,500 PAD patients after lowerextremity peripheral artery revascularization(NCT02504216) (89). In addition, 2 smaller trials(ASPIRE [Antiplatelet Strategy For Peripheral ArterialInterventions for Revascularization of Lower Ex-tremities] and LONGDAPTPAD [Effects of ProlongedDAPT After Lower Extremity Percutaneous Trans-luminal Angioplasty In Patients with Lower ExtremityPAD]) are comparing short versus long duration ofdual antiplatelet therapy with aspirin plus clopidogrelin patients undergoing endovascular peripheralrevascularization (NCT02217501 and NCT02798913,respectively). Finally, our review revealed no ongoingstudies of antithrombotic therapies in patients withasymptomatic PAD or specifically in symptomaticpatients with critical limb ischemia.

Although the focus of this review was on antith-rombotic therapies, emerging lipid-lowering (92) andantidiabetic (10,93,94) therapies have also shown to beof benefit in PAD patients. Therefore, the decision-making process for optimal risk reduction will getmore complex in light of these new therapies; howev-er, cardiovascular and limb outcomes in patients withPAD will also improve. Furthermore, completed andongoing studies of inflammation reduction (95,96) andstem cell (97) therapies may help shed light on thepathophysiologically distinct mechanisms of MACCEand MALE benefit in this population. Finally, greaterefforts are required to increase the utilization ofestablished guideline-based risk reduction therapiessuch as statins, angiotensin-converting enzyme in-hibitors, adequate blood pressure control, lipid con-trol, diabetic glycemic control, smoking cessation, anddiet or exercise—PAD patients continue to be treatedsuboptimally with these therapies (18,20).

CONCLUSIONS

Patients with PAD are at high risk for vascular andlimb-related events, but as a group, they are under-treated with antithrombotic therapy. Controlled datafrom well-powered randomized trials of variousantithrombotic agents in PAD patients are limited,particularly so among those with asymptomatic PAD,critical limb ischemia, or undergoing peripheralvascular interventions. Recent advances haveincreased the number of antiplatelet and anticoagu-lant choices available for patients with stable symp-tomatic PAD. An evidence-based approach toantithrombotic therapy should be used in this popu-lation, weighing ischemic, limb, and bleeding risks.

ADDRESS FOR CORRESPONDENCE: Dr. Deepak L.Bhatt, Brigham and Women’s Hospital Heart & VascularCenter, Harvard Medical School, 75 Francis Street, Bos-ton, Massachusetts 02115. E-mail: [email protected]. Twitter: @DLBHATTMD

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KEY WORDS anticoagulation, antiplatelet,antithrombotic therapy, peripheral arterydisease, risk reduction












































antithrombotic therapy for peripheral artery disease · recent advances mohamad a. hussain, md,...

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