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C H A P T E R 1 8
PharmacotherapyinPeripheralArteryDisease
FaisalHasanMD,KhwajaYousufHasanMBBS
WilliamL.BennettMD,PhD,andSamehMohareb,MD
I.Introduction
II.AntithromboticTherapy
A.AntiplateletAgents
B.BenefitsofAntiplateletTherapy
C.Vorapaxar
D.Heparin
E.OralAnticoagulationAgents
III.Statins
A.Hyperlipidemia
B.Trials
IV.AntihypertensiveTherapy
A.Trials
V.SymptomaticTherapyforClaudication
B.Cilostazol
KeyPoints
■TreatmentofhypertensionwithACEIhasbeenshowntohaveantiatherogenicpropertiesas
wellasreducedclinicaleventsinpatientwithperipheralarterialdisease(PAD).
■Aspirinmonotherapyhasbeenshowntobeofbenefitintreatmentofsecondaryprevention
patientwithperipheralarterialdisease.
■Statin therapy is known to improve morbidity and mortality in patients with peripheral
arterialdisease.
■Smoking cessationand supervised walkingprogramshaveshown benefitinpatients with
PAD.
I.Introduction
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Peripheral arterydisease (PAD) is amanifestationofsystemic atherosclerosis. It is associatedwith a
reductioninfunctionalcapacityandqualityoflife,butmoreimportantly,presenceofPADisassociated
withanincreasedriskofcardiovascularandcerebrovascularmorbidityandmortalitycomparedwiththe
general population.1 Treatment of PAD is based on lifestyle modification, relief of symptoms, and
aggressive treatment of risk factors of atherosclerosis. This includes aggressive management of
hypertension, dyslipidemia, diabetes mellitus, antiplatelet therapy, cessation of smoking, and graded
exercise prescription. Guideline-directed medical therapy (GDMT) has been shown to reduce
cardiovasculareventsandimprovefunctionalstatus ofpatients withPAD.However,these patientsare
lesslikelytoreceiveGDMTthanpatientswithotherformsofcardiovasculardiseasesuchascoronary
arterydisease.
2
Medical management ofPAD has a proven role in improving cardiovascular outcomes andfunctional
capacity.Therapywithantiplateletagentshasbeenshowntoimprovecardiovascularandlowerextremity
atheroscleroticdiseaseoutcomesamongpatientswithsymptomaticorasymptomaticPADirrespectiveof
revascularization. Treatment of hypertensionwith ACEinhibitors has been shown todecrease clinical
eventsinpatientswithPAD.ACEinhibitorshavealsobeenshowntohaveantiatherogenicpropertiesthat
would have favorable effects in PAD. Statins have been shown to lower the risk of adverse limb
outcomesofrevascularizationandamputationaswellasreducesymptomsinPAD.
II.AntithromboticTherapy
A.AntiplateletAgents
Antiplatelet agents have been studied extensively in cardiovascular diseases. The Antithrombotic
Trialists’Collaborationstudieshaveshownthatantiplatelettherapyisassociatedwithamortalitybenefit
thatis driven primarily bya significantreduction inmyocardial infarction, stroke, andvascular death
among patients with PAD.3 The recently published AmericanHeart Association/AmericanCollege of
CardiologyandEuropeanSocietyofCardiologyguidelinesonPADendorsethelong-termuseofsingle
antiplatelet agents (aspirin or clopidogrel) in patients with symptomatic PADfor prevention of major
adverse cardiac events.
4,5
Their role in asymptomatic patients with PAD (that is ABI <0.9) or with
atypicalsymptomsisuncertain;however,itisstillrecommended,asaspirinhasbeenshowntoreducethe
riskofvasculareventsinthispopulationaswell.
6
1. Aspirinactsbyirreversibly inhibitingcyclooxygenase-2andpreventsformationofthromboxaneA2
fromarachidonicacid.7Ithasbeenshowntoreducetheriskofmyocardialinfarction,stroke,anddeath
fromcardiovasculareventsinpatientswithsymptomaticandasymptomaticPAD.Theuseofaspirinfor
secondarypreventionhasbeenwellestablishedbytheAntithromboticTrialists’Collaborationstudies.A
meta-analysis of 287 studies involving more than 200,000 patients compared different antiplatelet
regimensorantiplateletagentswithcontrols.Antiplatelettherapyresultedinareductioninoutcomesof
myocardial infarction by 33%, reduction in stroke by 25% and reduction in vascular death by 17%
withoutanyapparentsideeffects.3Similarlyinameta-analysisof60studies(mostlyaspirinaloneorin
combination with dipyridamole) antiplatelet therapy was associated with a significant reduction in
arterialorvenousgraftocclusionamongpatientsundergoinganyformofavascularprocedure.8Therole
of aspirin in primary prevention has been less well established. The Aspirin for Asymptomatic
Atherosclerosis(AAA)trialexaminedtheroleofaspirininpatientswithsubclinicalPAD(ABI[anklebrachial index] <0.95). The primary endpoint ofthe study was aninitial fatal or nonfatal myocardial
infarction,stroke,orneedforrevascularization.Therewasnodifferenceintheprimaryendpointamong
patients whoreceived aspirinor placebo over afollow-upof8.2 years.9 The POPAD trial similarly
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compareduseofaspirinandantioxidantsversusplaceboamongdiabeticpatientswithsubclinicalPAD.
Again,nodifferencewasfoundintheprimaryendpointsofnonfatalorfatalcardiovasculareventsdespite
thehigh-riskprofileofthepatients.
10
2. The adenosine diphosphate (ADP) P2Y12 receptor antagonists include the thienopyridines
(ticlopidine, clopidogrel, prasugrel) and ticagrelor. Thienopyridines are irreversible antagonists,
whereasticagrelorisareversibleantagonistoftheADPreceptor.
11,12
Ticlopidinewasfoundtobevery
effective in prevention of vascular events; however, its use has beendiscontinued because significant
hematologicsideeffects. Only clopidogrel and ticagrelorhavebeen studied in patientswith PAD.The
CAPRIE(Clopidogrel versusAspirinin Patientsat Risk ofIschemic Events) was a largemulticenter
double-blinded randomized controlled trial that compared aspirin with clopidogrel for secondary
preventioninpatientswhohadevidenceofatheroscleroticdisease.13ThePADcohortincludedpatients
whohadintermittentclaudicationwithanABIof<0.85or thosewho hadintermittentclaudicationand
had undergone a peripheral vascular intervention in the form of surgical or percutaneous
revascularization. Generally, the results of the trial favored the use of clopidogrel over aspirin
monotherapy for PAD; however, the absolute benefit was small, albeit statistically significant. The
PLATO (ticagrelor versus clopidogrel in patients with acute coronarysyndrome) trial established the
superiorityofticagreloroverclopidogrelinacutecoronarysyndrome.14Inlightofthesefindings,itwas
hypothesized that similar findings could be extrapolated among patients with PAD. The EUCLID
(ExaminingUseofTicagrelorinPeripheralArteryDisease)trialwascarriedouttotestthishypothesis;
however,itfailed toestablishthe superiority of ticagrelor overclopidogrelinPAD.15There were no
significantdifferences intheprimaryandsecondaryendpointsamongbothdrugs;however,therewasa
higherrateofdiscontinuationofticagrelorduetosideeffects(mainlydyspneaandminorbleeding).Both
theACCandESCguidelinestodaterecommendtheuseofclopidogreloraspirinassingleantiplatelet
therapyforpreventionofmajoradversecardiaceventsinpatientswithPAD.
4,5
B.BenefitsofAntiplateletTherapy
TheoverallbenefitofdualantiplatelettherapyforsymptomaticPADisuncertain.Aposthocanalysisof
theClopidogrelforHighAtherothromboticRiskandIschemicStabilization,ManagementandAvoidance
(CHARISMA) trial failed to demonstrate a significant benefit of dual antiplatelet therapy with
clopidogrelandaspirinoveraspirinaloneinpreventionofmajoradversecardiaceventswithanincrease
intheriskofminorbleeding.
16,17
However,asmallrandomizedcontrolledtrialdemonstratedadecrease
inthe riskofrevascularization amongpatientswhohadundergoneendovascularrevascularizationwith
useofdualantiplatelettherapy.
18,19
Similarly,adecreaseinlimb-relatedeventswasnotedamongpatients
whohadundergonebelow-kneeprostheticbypassgrafts.20Thereforedualantiplatelettherapymayonly
be reasonable in a small subset of patients with PAD who have had surgical or endovascular
revascularization.
C.Vorapaxar
VorapaxarisanovelPAR-1receptorantagonist,whichistheprinciplethrombinreceptoronplateletsand
is also present on vascular endothelium. The TRA2°P-TIMI 50 was a double-blind randomized
controlledtrialthattestedtheefficacyofvorapaxarontopofstandardantiplatelettherapyforsecondary
prevention amongpatients withstable atherosclerotic diseaseandevidenceoflower extremityarterial
disease.21 Vorapaxar did not reduce the risk of myocardial infarction, death, or stroke; however, it
significantly reduced the incidence of acute limb ischemia and peripheral revascularization. The trial
demonstratedareductioninriskofbothnativearteryandbypassgraftthrombosis.Thisbenefitwasoffset
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byanincreaseintheriskofmoderateandseverebleedingincludingintracranialhemorrhage.Vorapaxar
mayprovidesomeclinicalbenefitamongpatientswithacutelimbischemia;however,itsoverallefficacy
on top ofexisting antiplatelet therapy among patients with symptomatic PAD is unclear and warrants
furtherresearch.
D.Heparin
Systemicanticoagulationwithheparinoradirectthrombininhibitorisindicatedinpatientswhopresent
with acute limb ischemia. Anticoagulation with heparin prevents thrombus propagation and reduces
inflammation.
22,23
Anticoagulation with warfarin for PAD is not recommended. Warfarin has been
demonstratedtoincreaseriskofbleedingandsubsequentlyincreasemortalityamongpatientswithPAD
when added to aspirin. The guidelines do not recommend the routine use of warfarin or vitamin K
antagonistsinadditiontoaspirininPAD.
E.OralAnticoagulationAgents
Recently, therehasbeena lotofinterestin therole ofnovel oral anticoagulation agents insecondary
cardiovascular prevention.Theseagentshave been extensivelystudiedand approved forpreventionof
thromboembolismassociated withnonvalvular atrial fibrillation.They includerivaroxaban, edoxaban,
dabigatran,andapixaban.Rivaroxabanisa powerfulfactorXainhibitor;itbindstofreefactorXaand
factor Xa associated with prothrombinase complex. The recently published COMPASS trial is an
international, double-blind randomized controlled trial that compared low-dose rivaroxaban in
combinationwithaspirin(rivaroxaban2.5mgtwiceadayplusaspirin100mg),rivaroxaban(5mgtwice
aday)alone,andaspirin(100mg)aloneforsecondarycardiovascularprevention.Thetrialwasstopped
prematurelyat23 monthsbecauseofsuperiorityofthelow-dose rivaroxabanandaspiringroup.24The
trial enrolled7470patients withlowerextremity PADandcarotidarterydisease.Amongpatientswith
PAD,additionoflow-doserivaroxabantoaspirinwhencomparedwithaspirinaloneresultedina28%
reduction in major adverse cardiovascular events and a 46% reduction in limb-threatening ischemia
including amputation. However, there was an increase in the risk of major nonfatal bleeding in the
rivaroxabanandaspirincombination group. Therefore, therole of novel oral anticoagulationagents in
PADisnotyetcompletelyestablished.Furthertrialsareneededtoclarifytheroleoftheseagentsinthe
preventionandtreatmentofPAD.
III.Statins
A.Hyperlipidemia
Hyperlipidemia is closely associated with the atherosclerosis. Statins are HMG-CoA reductase
inhibitors,theprincipalenzymeinvolvedinendogenouscholesterolsynthesis.Statinsinhibitcholesterol
biosynthesis, increase uptake and degradation of low-density lipoproteins, decrease the secretion of
lipoproteins, and inhibit LDL oxidation. Statins also modulate intracellular processes that reduce
accumulation of esterified cholesterol in macrophages, increase activity of nitric oxide synthetase,
decreasethe inflammatoryprocess,andincrease stability of atherosclerotic plaques.25 Lipid-lowering
therapywithstatinsisassociatedwithareductioninsymptoms,morbidity,andmortalityassociatedwith
cardiovasculardisease.
B.Trials
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Trials with simvastatin and atorvastatin have demonstrated an improvement in walking distance in
patientswithPAD.
1.IntheHeartProtectionStudy(HPSStudy),simvastatintherapywasassociatedwitha17%reduction
invascular mortality, 24% reductionin coronary arteryevents,anda 27% reduction in stroke among
patients with PADat 5 years, regardless of their presentingcholesterol levels.26 Conversely, similar
trials with bezafibrate and high-dose niacin failed to demonstrate a reduction in fatal and nonfatal
cardiovascular events. This proves that it is not just the lipid-lowering effects of statins but also the
pleiotropiceffectsthatmayberesponsibleforthemortalitybenefitthatstatinsprovideforcardiovascular
diseases.Treatmentwithstatintherapyisalsoassociatedwithimprovementinsymptomsofclaudication.
2. ACochrane systematic review of 18 trials involving more than 10,000 patients demonstrated that
lipid-loweringwithstatinsisassociatedwithareductionincardiovascularmorbidityandmortalityand
animprovementinlocalsymptoms.
27
3.ResultsfromtheREACHregistryalsodemonstratethatstatintherapyisassociatedwithareductionin
adverse limboutcomes, includingworseningsymptoms,needforrevascularization,andamputation-free
survival.Inanotherstudy,useofstatinswasassociatedwithareductioninmajoradversecardiacevents
andall-causemortalityamongpatients with asymptomatic patientswith PAD.28Therefore, all patients
withPADshouldbetreatedwithstatins.
IV.AntihypertensiveTherapy
A.Trials
The angiotensin-converting enzyme inhibitors have vasculo-protective, antiproliferative, and
antiatherogenicproperties.Theypromotethedegradationofbradykinin,whichincreasestheendothelial
releaseofnitrousoxideanddecreasesendothelialoxidativestress.
1.TheHOPE(HeartOutcomesPreventionEvaluation)trialwasalargemulticenterrandomizedcontrol
trial of more than 9000 patients.29 It demonstrated that use of ramipril in high-risk cardiovascular
patients, whodidnot have a low ejectionfractionorevidenceofheartfailure,wasassociatedwith a
25%reductioninriskofmyocardialinfarction,death,andstroke.TheHOPEstudypromptedaninterest
in the use of ACE inhibitors for patients with symptomatic PAD. A small study of 212 patients
demonstrated that after 6 months of treatment with ramipril, patients with PAD and intermittent
claudicationwere able towalksignificantlylongerdistances painfreeas comparedwith patientswho
receivedplacebo.
30
2.TheONTARGETtrialcompareduseoftelmisartan,ramipril,andcombinationtherapyinpatientswith
PAD.31ThetrialestablishedtheefficacyoftelmisartaninPADanddemonstratedittobeanacceptable
alternativetoramipril.Patientswhoreceivedacombinationoframiprilandtelmisartanhadahigherrate
ofside effects, which included hypotension,renalfailure, and syncope;thus combineduseofanACE
inhibitorandanangiotensinreceptorblockerisnotrecommended.
V.SymptomaticTherapyforClaudication
B.Cilostazol
1. Cilostazol is a selective phosphodiesterase-3 inhibitor. It is very effective in improving walking
distanceand symptomsofclaudication. Itincreases the amountofcyclic AMP (cAMP) resultinginan
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increaseinproteinkinaseA,whichinhibitsactivationofmyosinlight-chainkinase.Thispreventssmooth
muscle contraction in the arterial vascular bed, causing vasodilation. Cilostazol has been studied
extensivelyinPADanditsuseisassociatedwithadecreaseinthesymptomsofclaudicationwithoutan
improvementincardiovascularoutcomesoranimprovementinqualityoflife.32Itsimportantsideeffects
include abdominal diarrhea, headache, and dizziness. Cilostazol is contraindicated in patients with
congestiveheartfailure.
2.TherapiessuchaspentoxifyllineandchelationtherapyhaveproventobeineffectiveinPADandare
not recommended.
33,34
Management of PAD would be incomplete without having a comprehensive
approachtoward maintaininga healthylifestyle that wouldincludegoodglycemiccontrol, maintaining
optimal blood pressure, quitting smoking, and following a supervised home-based or hospital-based
exerciseregimen.
References
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10.BelchJ,MacCuishA,CampbellI,etal.Thepreventionofprogressionofarterialdiseaseanddiabetes(POPADAD)trial:factorial
randomisedplacebocontrolledtrialofaspirinandantioxidantsinpatientswithdiabetesandasymptomaticperipheralarterialdisease.BMJ.
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11.CapodannoD,DharmashankarK,AngiolilloDJ.Mechanismofactionandclinicaldevelopmentofticagrelor,anovelplateletADP
P2Y12receptorantagonist.Expertreviewofcardiovasculartherapy.2010;8(2):151-158.
12.SaviP,NurdenP,NurdenAT,Levy-ToledanoS,HerbertJM.Clopidogrel:areviewofitsmechanismofaction.Platelets.1998;9(3-
4):251-255.
13.CommitteeCS.Arandomised,blinded,trialofclopidogrelversusaspirininpatientsatriskofischaemicevents(CAPRIE).CAPRIE
SteeringCommittee.Lancet.1996;348(9038):1329-1339.
14.WallentinL,BeckerRC,BudajA,etal.Ticagrelorversusclopidogrelinpatientswithacutecoronarysyndromes.NEnglJMed.
2009;361(11):1045-1057.
15.HiattWR,FowkesFG,HeizerG,etal.TicagrelorversusClopidogrelinsymptomaticperipheralarterydisease.NEnglJMed.
2017;376(1):32-40.
16.CacoubPP,BhattDL,StegPG,TopolEJ,CreagerMA,InvestigatorsC.PatientswithperipheralarterialdiseaseintheCHARISMA
trial.EurHeartJ.2009;30(2):192-201.
17.BhattDL,FoxKA,HackeW,etal.Clopidogrelandaspirinversusaspirinaloneforthepreventionofatherothromboticevents.NEnglJ
Med.2006;354(16):1706-1717.
18.TepeG,BantleonR,BrechtelK,etal.Managementofperipheralarterialinterventionswithmonoordualantiplatelettherapy–the
MIRRORstudy:arandomisedanddouble-blindedclinicaltrial.EurRadiol.2012;22(9):1998-2006.
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19.StroblFF,BrechtelK,SchmehlJ,etal.Twelve-monthresultsofarandomizedtrialcomparingmonowithdualantiplatelettherapyin
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20.BelchJJ,DormandyJ,BiasiGM,etal.Resultsoftherandomized,placebo-controlledclopidogrelandacetylsalicylicacidinbypass
surgeryforperipheralarterialdisease(CASPAR)trial.JVascSurg.2010;52(4):825-833,33.e1-2.
21.BonacaMP,SciricaBM,CreagerMA,etal.Vorapaxarinpatientswithperipheralarterydisease:resultsfromTRA2°P-TIMI50.
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C H A P T E R 1 9
VascularAccessComplications
SameerNagpalMD
YoungErbenMD
I.Introduction
II.AccessSiteComplication
A.Hematoma
B.ArteriovenousFistula
C.Pseudoaneurysm
D.ArterialOcclusion
III.Intervention-SpecificComplications
A.Infection
I.Introduction
Thedramaticincreaseinendovascularproceduresby317%from2000to2009hasledustoencounter
procedural complications ingreater frequency.1 Furthermore, thedevelopment of newer endovascular
technologieshaveuncovered anewer setofcomplications relatedtothese techniques.We canclassify
thesecomplicationsinto(1)accesssitecomplications,(2)complicationsrelatedtotheuseofwiresand
catheters,(3)interventionspecificcomplications,and(4)miscellaneous.
II.AccessSiteComplication
A.Hematoma
Accesssitebleedingisthemostcommoncomplicationofendovascularprocedures,withanincidenceof
groin hematoma reported as high as 23%, dependent on a variety of procedure- and patient-related
circumstances.
2,3
Modifiable risk factors include puncture technique,chosen access site, larger sheath
size and indwelling time, and the aggressive use of antiplatelet and anticoagulant medications.
Nonmodifiable risk factors include obesity, anatomic anomalies, hypertension, chronic renal
insufficiency, female gender, low body weight, obesity, coagulopathy, and inability to cooperate with
postproceduralrestrictions.
4
Bleedingis mostcommonlyanimmediatecomplication;however,itmayoccurupto48hoursafterthe
procedure in cases requiring ongoing use ofanticoagulants. Localized hematoma is the most common
presentation, resulting from extravasation of blood from the arteriotomysite into the surrounding soft
tissue. Ultrasound is occasionally used to confirm the diagnosis if physical examination findings are
equivocal(Fig.19.1),mostofteninobesepatients.Incasesofaccesssitehematomawithsignificantpain,
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ultrasoundmaybenecessarytoexcludeassociatedpseudoaneurysmorarteriovenousfistula.Inthevast
majority of cases, extended manual or device-assisted compression of the arteriotomy site and gentle
manual diffusion ofthehematoma is all that is needed. Transfusionis generallyreserved for cases of
significantbloodloss,evidenceofneworworseningmyocardialischemia,orhemodynamicinstability.
FIGURE19.1 Ultrasoundimageofasofttissuehematoma.
1.FemoralAccessSiteBleeding
Femoralaccesssitebleedingiscorrelatedwithalongerhospitalizationandhigherratesofmorbidityand
mortalityat30dayspostprocedure,especiallywhentransfusionisrequired.
2,5
ThemodifiedSeldingertechniqueisthemostcommonlyusedmethodofgainingfemoralarterialaccess.
Technicalandanatomicprecisionarecriticaltominimizingtheriskofbleeding.Arterialpunctureshould
occurwithinthe commonfemoral artery (CFA),belowthe inguinalligamentandabove itsbifurcation,
directly over the middle one-third of the femoral head. Puncture at this site allows for manual
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compressionagainstanoncompliantstructuretoachieveadequatehemostasis.Superficially,thislocation
isapproximately1-2cmbelowtheinguinal ligamenthalfwaybetweentheanteriorsuperioriliaccrest
andthepubicsymphysis.Theinguinalskincreaseshouldnotbeusedasalandmarkforarterialpuncture
asitislocatedbelowthefemoralarterybifurcationin70%ofpatients.Fluoroscopyisroutinelyusedto
locatethefemoral headandassistinguiding anatomicallyprecise CFAcannulation.Care mustalsobe
takento avoid puncture ofthe posterior wall of the femoral arteryfrom which bleeding may be less
readilyapparent.The useofa micropunctureneedleis generally preferredtoreducearterial trauma in
casemultipleattemptsataccessareneeded.
2.RetroperitonealHemorrhage
Retroperitoneal (RP) hemorrhage is arare butdreaded complication of highfemoral arterial puncture
abovetheinguinalligamentandoccursinapproximately0.3%-0.8%ofcasesinvolvingfemoralarterial
access.
2,6,7
Theetiologyisusuallyinjurytoasuprainguinalvesselorpunctureoftheposteriorwallofthe
femoral or external iliac artery. Other than this, traditional riskfactors include (1) female gender, (2)
peripheral vascular disease, and (3) low body surface area.
4,6
RP hemorrhage has two potential
manifestations.First,thehemorrhagemaybecontainedwithinthefasciaoftheiliopsoasmuscle,which
canbeassociatedwithcompressionneuropathyinvolvingthelumbarplexus.Second,theRPhemorrhage
may occur within the space between the peritoneum and RP structures, which is large enough to
accommodatelifethreateningamountsofbloodloss(Fig.19.2).Onereportclassifiedthemostcommon
presenting signs and symptoms of RP hemorrhage in 26 patients, which were hypotension (92%),
diaphoresis (58%), groin discomfort(46%), abdominal or flank pain(42%), bradycardia (31%), and
backpain(23%).6Bruisingoftheflanks,describedas “GreyTurner”sign,ortheumbilicus,knownas
“Cullen” sign is typically a late manifestation. Occasionally, RP bleeding can present as a “vagal”
reactionwith bradycardia and diaphoresis, typicallythought of asa benign responsetopainor sheath
removal,butonlytransientlyresponsivetointravenousfluidsand atropine. Noncontrastabdominal and
pelviccomputedtomographyscanishighlysensitiveandspecificforconfirmingthediagnosisandisalso
helpful in identifying possible hydronephrosis due to ipsilateral ureter or bladder compression.
Successful management depends on early recognition, supportive care with intravenous fluids, blood
products,andoptimizingthecoagulationandplateletprofileisallthatisusuallyrequireduntilhemostasis
isnaturallyachieved.Inuncommoncasesofextremehemodynamicconsequenceconsiderationshouldbe
giventourgentangiographywithprolongedpercutaneousballooninflationatthearteriotomysite,useofa
coveredstent,orsurgicalexplorationanddirectrepairofthearteriotomysite.
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