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Gastrointestinal Complications of Dual Antiplatelet Therapy1. Neelima G. Vallurupalli, MD;2. Samuel Z. Goldhaber, MD

+Author Afliations

1. From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard

Medical chool, Boston, Mass.

1. Correspondence to amuel !. "oldha#er, MD, Cardiovascular Division, Brigham and

Women’s Hospital, $% Francis t, Boston, MA &'11%. ()mailsgoldha#er*partners.orgCase presentation: A %+)ear)old man -ith a histor o hpertension, dslipidemia, and smo/ing-as hospitali0ed -ith acute coronar sndrome reuiring emergenc percutaneous coronarintervention -ith 2 drug)eluting stents. His discharge medications included dual antiplatelettherap -ith aspirin 3'% mg4d and clopidogrel $% mg4d. 5hree -ee/s ater discharge, he returnedto the (mergenc Department -ith #lood stools and a hematocrit o '36 7previousl 3869 andreuired 3 : o pac/ed red #lood cells. (ndoscop sho-ed a #leeding duodenal ulcer -ithadherent clot 7Figure9.

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(ndoscopic image o #leeding duodenal ulcer -ith clot on top. 5his image -as ta/en in a patient-ith a histor similar to that o our patient. Arro- points to the #ase o duodenal ulcer -ith active#leeding. >icture contri#uted # arathchandra ?edd, MD, and (d-in Chun @uang, MD, >hD,Division o "astroenterolog, Brigham and Women’s Hospital, Boston, Mass.

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Background

We prescri#e dual antiplatelet therap -ith aspirin and clopidogrel to prevent and treatcardiovascular, cere#rovascular, and peripheral arterial disease. According to American HeartAssociation statistics, $&& &&& patients had stro/e, 13 million had coronar arter disease, and to 1' million suered rom peripheral arterial disease in '&&'. (ach ear, 1.' million patients inthe :nited tates receive dual antiplatelet therap -ith aspirin and clopidogrel ater

percutaneous coronar intervention -ith drug)eluting stents. 5he num#er o patients in the:nited tates -ho receive dual antiplatelet therap or various vascular conditions such ascoronar arter disease, transient ischemic attac/, throm#otic stro/e, and peripheral vasculardisease pro#a#l eceeds several million.

 5he use o aspirin compared -ith place#o reduces the ris/ o mocardial inarction, stro/e, ordeath rom vascular causes # E'%6.1 =n the Clopidogrel ;ersus Aspirin in >atients at ?is/ o =schemic (vents 7CA>?=(9 trial, administration o clopidogrel decreased the relative ris/ o vascular events # .$6 compared -ith aspirin.'  5he addition o clopidogrel to aspirin in patients

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-ith acute coronar sndrome reduces the ris/ o reinarction, stro/e, and death # '&6compared -ith aspirin alone.3

 5he net #enet rom using dual antiplatelet therap in high)ris/ vascular disease patients comesat the cost o increased gastrointestinal 7"=9 complications. MaGor complications includegastroduodenal ulcerations that can lead to "= hemorrhage, peroration, and death. Minorcomplications include dspepsia, pill esophagitis, su#epithelial hemorrhages, erosions, andulcerations in the stomach and duodenum. >atients at especiall high ris/ or "= complications

-hile on antiplatelet therap are the elderl those -ith a histor o gastroduodenal ulcers,gastroesophageal reIu disease, esophagitis, untreated Helicobacter pyloriinection, intestinalpolps, or cancer and those using concomitant anticoagulants, steroids, or nonsteroidal anti)inIammator drugs.

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Risk of GI Complications With Aspirin

 5he suppression o gastroduodenal mucosal prostaglandin snthesis is one o the importantmechanisms o mucosal damage # aspirin.2 erious "= ulcer complications are ') to 2)old morecommon in patients -ho ta/e $% to 3&& mg4d o aspirin compared -ith controls. %,8 Aspirin dosesas lo- as 1& mg4d can signicantl decrease the gastric mucosal prostaglandin level and causegastric erosions.$ During a 2)ear period in the :nited Jingdom 5ransient =schemic Attac/ stud,"= complications in patients ta/ing aspirin ranged rom mild dspepsia 73169 to lie)threatening

#leeding and peroration 7369.

While eamining the relationship #et-een aspirin inta/e and hospitali0ation -ith peptic ulcer#leeding, Weil et al% ound that all doses o aspirin are associated -ith an increased ris/ o "=#leeding. 5he ris/ o "= #leeding -as dose related< odds ratio '.3 or $% mg4d, 3.' or 1%& mg4d,and 3.+ or 3&& mg4d. 5he ris/ o upper "= #leeding or plain, enteric)coated, or #uered aspirindid not dier.+ Kong)term aspirin therap, even at a lo- dose 7%& to 18'.% mg4d9, ma cause overt"= #leeding.1&

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Risk of GI Complications With Clopidogrel

=t is unclear ho- clopidogrel causes "= erosions or ulcerations. Clopidogrel has no eect on theccloogenase path-a and thereore acts independentl o aspirin. =n a retrospective analsis,the reuenc o "= #leeding in a high)ris/ population -ith prior peptic ulcer disease -as 1'6. 11

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Risk of GI Complications With Dual Antiplatelet Therapy 

 5he ris/ o overt "= #leeding -ith dual antiplatelet therap can #e as high as 1.36 -ithin the rst3& das o therap.3 =n the Clopidogrel or :nsta#le Angina to >revent ?ecurrent (vents 7C:?(9stud, >eters et al1' sho-ed that the ris/ o #leeding increases -ith increasing dose o aspirin -ithor -ithout clopidogrel. 5he dose o clopidogrel remained ed at $% mg4d. At the highest dose o aspirin 7L'&& mg9 given -ith place#o, #leeding -as higher 73.$69 than the ris/ o "= #leeding-ith the com#ination o clopidogrel and aspirin in the lo-est)dose 71&& mg9 group 73.&69.

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Efficacy of Dual Antiplatelet Therapy 

Drug)eluting stents have #ecome the standard o care or percutaneous coronar intervention toreduce the ris/ o in)stent restenosis. Ho-ever, in)stent throm#osis, a catastrophic andpotentiall atal complication, ma occur more oten -ith drug)eluting than #are metal stents.

 5he strongest predictor o stent throm#osis is discontinuation o antiplatelet therap, eceedingother independent predictors such as renal ailure, #iurcation lesions, dia#etes, and lo- eGectionraction.13 Hence, ater percutaneous coronar intervention -ith drug)eluting stents, aspirin isprescri#ed lielong and clopidogrel is prescri#ed or at least 3 months. 12 Ho-ever, McFadden etal1% reported 2 cases o late stent throm#osis occurring as late as 22' das ater implantation o drug)eluting stents and resulting in mocardial inarction -hen antiplatelet therap -asdiscontinued. Kate throm#osis seen -ith drug)eluting stents is attri#uted to delaed vascular

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healing and delaed re)endotheliali0ation, rendering the stent prothrom#otic. ome cardiologistscontinue patients on antiplatelet therap indenitel i no adverse #leeding events areencountered.

Aspirin and clopidogrel NresistanceO has #een increasingl identied -ith the availa#ilit o point)o)care platelet aggregation tests. Man patients on aspirin and clopidogrel therap do notachieve the desired level o platelet inhi#ition. @ne -a to overcome aspirin and clopidogrel

resistance is to use higher loading and maintenance doses.

 5he inhi#ition o platelet aggregation # clopidogrel is dose dependent. A higher loading dose o clopidogrel is no- #eing used more oten than the conventional 3&&)mg dose #ecause o morerapid and higher levels o platelet inhi#ition. >atti et al18 reported that a 8&&)mg loading dose -assae and more eective in reducing periprocedural inarction than a 3&&)mg loading dose.

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Monitoring and Diagnosis of GI Complications

everal methods can #e used to monitor and diagnose occult and overt "= complications o dualantiplatelet therap. 5he tests range rom least specic 7ecal occult #lood test9 to the goldstandard o traditional endoscop. >atients can also #e monitored or clinical smptoms such asdspepsia or #loating # using a smptom diar or a validated scoring sstem similar to the

"astrointestinal mptoms ?ating cale uestionnaire 7 5a#le9.;ie- this ta#le<

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Gastrointestinal Symptom Ratin S!ale" # Validated Ratin S!ale o$ G% Symptoms in&atients 'ith &epti! (l!er Disease

A noninvasive imaging test that does not reuire sedation to diagnose occult "= complications isthe >illCam (@ capsule endoscop 7"iven =maging, =nc, orcross, "a9. 5he disposa#le, ingesti#le>illCam (@ endoscope is an 11P'8)mm capsule. =t acuires video images rom #oth ends o thedevice during passage through the esophagus. 5he capsule transmits the acuired images via adigital radioreuenc communication channel to an eternal data recorder unit. @n completion o the eamination, the accumulated data are processed -ith image reconstruction and are

interpreted # a "= specialist. 5he >illCam is ecreted in the eces and does not need to #eretrieved.

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Is GI rophyla!is "eeded for Dual Antiplatelet Therapy#

>atients on dual antiplatelet therap can develop #oth upper and lo-er "= #leeding. "=hemorrhage is associated -ith an increased mortalit rate, a greater need or surger, #loodtransusions, a prolonged length o hospital sta, and increased overall healthcare costs.Although upper "= #leeding can #e prevented -ith appropriate prophlais, there is no eectiveprophlais or lo-er "= #leeding.

>rophlactic acid)suppressive therap is #enecial in the prevention o upper "= complications. 5-o maGor classes o protective agents are 719 H' antagonists and 7'9 proton pump inhi#itors7>>=s9.H' antagonists reversi#l #loc/ H' receptors on the #asolateral mem#rane o gastric parietalcells.1$ :ntil the earl 1++&s, H' antagonists -ere the mainsta o pharmacotherap or theprevention and management o upper "= #leeding. Bet-een 1+2 and '&&&, 3' randomi0edcontrolled trials compared H' antagonists -ith place#o.1 Agents evaluated in these studiesincluded cimetidine, ranitidine, and amotidine. Man -ere limited # a small sample si0e andunsatisactor stud design.

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Factors limiting the utilit o H' antagonists include the development o tachphlais, the needor dosage adGustment in renal insufcienc, and side eects such as throm#octopenia andmental status a#normalities.

 5he introduction o >>=s has led to a saer and more eective strateg in the prevention andmanagement o "= ulceration.1$ >>=s irreversi#l inhi#it hdrogen ion pumps in gastric parietalcells. >>=s #loc/ the nal step o acid production, negate stimulation o gastric secretion, and leadto prolonged acid suppression.

 Qeomans et al1+ sho-ed that omepra0ole, a >>=, is more eective than H' receptor antagonists insuppressing gastric acid, preventing ulcers, and healing ulcers that are related to chronic use o nonsteroidal anti)inIammator drugs such as aspirin.Chan et al'& randomi0ed 3'& patients -ith vascular disease -ho had previous "= #leeding -hileta/ing aspirin to clopidogrel alone versus aspirin plus esomepra0ole. 5he cumulative incidence o recurrent ulcer #leeding over a 1')month period in this stud -as .86 in patients -ho receivedclopidogrel and &.$6 in patients -ho received aspirin and esomepra0ole.

=s it Gustia#le to start all patients reuiring dual antiplatelet therap on prophlactic acid)suppressive therapR 5he ris/ o an adverse "= event in antiplatelet users depends on thepatient’s #aseline ris/, added ris/ associated -ith the dose and duration o aspirin andclopidogrel therap, and protection conerred # cotherap -ith acid)suppressive agents.>hsicians -ho prescri#e antiplatelet therap should #e a-are o an individual patient’s ris/ o "=complications. During ever ofce visit, phsicians should as/ a#out ne- or -orsening "=smptoms. =nitiating prophlactic acid)suppressive therap ma #e reasona#le in high)ris/patients or the duration o antiplatelet therap ho-ever, clinical trials are urgentl needed toconrm or reute this hpothesis.

>atients -ho undergo >C= or acute coronar sndrome are usuall discharged on % classes o medications< aspirin, clopidogrel, a S)#loc/er, an angiotensin)converting en0me inhi#itor, and astatin. 5hese medications reduced the mor#idit and mortalit rates in large)scale randomi0edcontrolled trials. Beore su#Gecting >C= patients to a routine prophlactic acid)suppressive therapas the sith standard medication, -e need large)scale trials to assess cost)eectiveness and todetermine -hether the #enet out-eighs the ris/s o polpharmac.

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Case@ur patient represents a reuent clinical scenario that phsicians oten encounter in theirpractice. "iven his multiple ris/ actors and the recent implantation o 2 drug)eluting stents, heshould receive indenite antiplatelet therap. Although antiplatelet agents -ere stopped or 1da during the upper "= #leeding, the -ere resumed immediatel -hen active #leeding stopped.He -as discharged home on a >>= along -ith antiplatelet therap.

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References

1. ) 

Antiplatelet 5rialists’ Colla#oration. Colla#orative overvie- o randomi0ed trials oantiplatelet therap, =< prevention o death, mocardial inarction, and stro/e # prolonged

antiplatelet therap in various categories o patients. BMJ.1++2 3&< 1T1&8.

 

#bstra!t*R ull -et

'. ) 

CA>?=( teering Committee. A randomi0ed, #linded, trial o Clopidogrel ;ersus Aspirin in

>atients at ?is/ o =schaemic (vents 7CA>?=(9. Lancet. 1++832< 13'+T133+.

 

7/21/2019 Gastrointestinal Complications of Dual Antiplatelet Therapy

http://slidepdf.com/reader/full/gastrointestinal-complications-of-dual-antiplatelet-therapy 5/7

/rossRe$Medline

3. ) 

 Qusu , !hao F, Mehta ?, Chrolavicius , 5ognoni ", Fo JJ. (ects o clopidogrel in

addition to aspirin in patients -ith acute coronar sndromes -ithout 5)segment

elevation. N Engl J Med. '&&1 32%< 2+2T%&'.

 

/rossRe$Medline2. ) 

Cohen MM, MacDonald WC. Mechanism o aspirin inGur to human gastroduodenal

mucosa. Prostaglandins Leukot Med. 1+' +< '21T'%%.

/rossRe$Medline

%. ) 

Weil U, Colin)Uones D, Kangman M, Ka-son D, Kogan ?, Murph M, ?a-lins M, ;esse M,

Wain-right >. >rophlactic aspirin and ris/ o peptic ulcer #leeding. BMJ. 1++% 31&< '$T

3&.

 

#bstra!t*R ull -et

8. ) 

orensen H5, Mellem/Gaer K, Blot WU, ielsen "K, teensen FH, McKaughlin UJ, @lsen UH.?is/ o upper gastrointestinal #leeding associated -ith use o lo-)dose aspirin. Am J

astroenterol. '&&& +%< ''1T'''2.

 

Medline

$. ) 

Crer B, Feldman M. (ects o ver lo- dose dail, long)term aspirin therap on gastric,

duodenal, and rectal prostaglandin levels and on mucosal inGur in health

humans. astroenterology. 1+++ 11$< 1$T'%.

 

/rossRe$Medline

. ) 

Farrell B, "od-in U, ?ichards , Warlo- C. 5he :nited Jingdom 5ransient =schaemic Attac/7:J)5=A9 aspirin trial< nal results. J Neurol Neurosurg Psyc!iatry. 1++1 %2< 1&22T1&%2.

 

#bstra!t*R ull -et

+. ) 

Jell U>, Jauman DW, Uurgelon UM, heehan U, Jo ?, hapiro . ?is/ o aspirin)associated

maGor upper)gastrointestinal #leeding -ith enteric)coated or #uered

product. Lancet. 1++8 32< 1213T1218.

 

/rossRe$Medline

1&. ) 

Derr , Ko/e QJ. ?is/ o gastrointestinal haemorrhage -ith long term use o aspirin< meta)

analsis. BMJ. '&&& 3'1< 113T11$.

#bstra!t*R ull -et

11. ) 

g FH, Wong Q, Chang CM, Chen WH, Jng C, Kanas A=, Wong BC. High incidence o

clopidogrel)associated gastrointestinal #leeding in patients -ith previous peptic ulcer

disease. Aliment P!armacol "!er. '&&3 1< 223T22+.

/rossRe$Medline

1'. ) 

7/21/2019 Gastrointestinal Complications of Dual Antiplatelet Therapy

http://slidepdf.com/reader/full/gastrointestinal-complications-of-dual-antiplatelet-therapy 6/7

>eters ?U, Mehta ?, Fo JA, !hao F, Ke-is B, Jopec/ K, Dia0 ?, Commerord >U, ;alentin

;, Qusu . (ects o aspirin dose -hen used alone or in com#ination -ith clopidogrel in

patients -ith acute coronar sndromes< o#servations rom the Clopidogrel in :nsta#le

Angina to >revent ?ecurrent (vents 7C:?(9 stud. Circulation. '&&3 1&< 18'T18$.

#bstra!t*R ull -et

13. ) 

=a/ovou =, chmidt 5, Boni00oni (, "e K, angiorgi "M, tan/ovic ", Airoldi F, Chieo A,Montorano M, Carlino M, Michev =, CorvaGa , Briguori C, "erc/ens :, "ru#e (, Colom#o A.

=ncidence, predictors, and outcome o throm#osis ater successul implantation o drug)

eluting stents. JAMA. '&&%'+3< '1'8T'13&.

 

/rossRe$Medline

12. ) 

Antman (M, An#e D5, Armstrong >W, Bates (?, "reen KA, Hand M, Hochman U, Jrumhol0

HM, Jushner F", Kamas "A, Mullan CU, @rnato U>, >earle DK, loan MA, mith C Ur, Alpert

 U, Anderson UK, Faon D>, Fuster ;, "i##ons ?U, "regoratos ", Halperin UK, Hirat0/a KF, Hunt

A, Uaco#s AJ. ACC4AHA guidelines or the management o patients -ith 5)elevation

mocardial inarction< a report o the American College o Cardiolog4American Heart

Association 5as/ Force on >ractice "uidelines 7Committee to ?evise the 1+++ "uidelines orthe Management o >atients -ith Acute Mocardial =narction9. Circulation. '&&2 11&< e'T

e'+'.

R ull -et

1%. ) 

McFadden (>, ta#ile (, ?egar (, Cheneau (, @ng A5, Jinnaird 5, uddath W@, Weissman

U, 5orguson ?, Jent JM, >ichard AD, atler KF, Wa/sman ?, errus >W. Kate throm#osis in

drug)eluting coronar stents ater discontinuation o antiplatelet

therap. Lancet. '&&2 382< 1%1+T1%'1.

/rossRe$Medline

18. ) 

>atti ", Colonna ", >asceri ;, >epe KK, Montinaro A, Di ciascio ". ?andomi0ed trial o high

loading dose o clopidogrel or reduction o periprocedural mocardial inarction in patientsundergoing coronar intervention< results rom the A?MQDA)' 7Antiplatelet therap or

?eduction o MQocardial Damage during Angioplast9 stud. Circulation. '&&% 111<'&++T

'1&8.

 

#bstra!t*R ull -et

1$. ) 

?iv/in J, Ka/hovets/i A. 5reatment o nonvariceal upper gastrointestinal #leeding. Am J

Healt! #yst P!arm. '&&% 8'< 11%+T11$&.

#bstra!t*R ull -et

1. ) 

Kevine U(, Keontiadis "=, harma ;J, Ho-den CW. Meta)analsis< the efcac o intravenous

H')receptor antagonists in #leeding peptic ulcer. Aliment P!armacol "!er. '&&' 18< 113$T

112'.

 

/rossRe$Medline

1+. ) 

 Qeomans D, 5ulassa !, Uuhas0 K, ?ac0 =, Ho-ard UM, van ?ens#urg CU, -annell AU,

Ha-/e CU. A comparison o omepra0ole -ith ranitidine or ulcers associated -ith

nonsteroidal antiinIammator drugs< Acid uppression 5rial< ?anitidine versus @mepra0ole

7/21/2019 Gastrointestinal Complications of Dual Antiplatelet Therapy

http://slidepdf.com/reader/full/gastrointestinal-complications-of-dual-antiplatelet-therapy 7/7

or A=D)Associated :lcer 5reatment 7A5?@A:59 tud "roup. N Engl J

Med. 1++ 33< $1+T$'8.

 

/rossRe$Medline

'&. ) 

Chan FJ, Ching UQ, Hung KC, Wong ;W, Keung ;J, Jung , Hui AU, Wu UC, Keung WJ, Kee

;W, Kee JJ, Kee Q5, Kau UQ, 5o JF, Chan HK, Chung C, ung UU. Clopidogrel versus aspirinand esomepra0ole to prevent recurrent ulcer #leeding. N Engl J Med. '&&% 3%'< '3T'22.

 

/rossRe$Medline