Aspirin Resistance in Patients with Saphenous Vein Coronary Bypass Graft Occlusion

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ORİJİNAL ARAŞTIRMA Aspirin Resistance in Patients with Saphenous Vein Coronary Bypass Graft Occlusion Göksel ÇAĞIRCI, MD, a Özcan ÖZDEMİR, MD, b Sevinç YILMAZ, MD, c Selime AYAZ, MD, d Dursun ARAS, MD,
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ORİJİNAL ARAŞTIRMA Aspirin Resistance in Patients with Saphenous Vein Coronary Bypass Graft Occlusion Göksel ÇAĞIRCI, MD, a Özcan ÖZDEMİR, MD, b Sevinç YILMAZ, MD, c Selime AYAZ, MD, d Dursun ARAS, MD, e Yücel BALBAY, MD, e Hatice ŞAŞMAZ, MD, e Şule KORKMAZ, MD e a Department of Cardiology, Ministry of Health Dışkapı Yıldırım Beyazıt Research and Educational Hospital, b Department of Cardiology, Akay Hospital, d Biochemistry Clinics, e Department of Cardiology, c Hematology Clinics, Turkiye Yuksek Ihtisas Hospital, Ankara Ge liş Ta ri hi/re ce i ved: Ka bul Ta ri hi/ac cep ted: Ya zış ma Ad re si/cor res pon den ce: Göksel ÇAĞIRCI, MD Ministry of Health Dışkapı Yıldırım Beyazıt, Research and Educational Hospital, Department of Cardiology, Ankara, TÜRKİYE/TURKEY ABS TRACT Ob jec ti ve: Au to lo go us sap he no us ve ins are wi dely used for co ro nary ar tery bypass surgery (CABG) des pi te a hig her in ci den ce of graft clo su re. Early ini ti a ti on of an tip la te let drugs re du - ces the in ci den ce of graft occ lu si ons. In this study, we as ses sed the as pi rin re sis tan ce by PFA-100 (Pla te let Func ti on Analy zer) system in the pa ti ents with sap he no us ve in graft (SVG) occ lu si on. Mate ri al and Met hods: Fo urty-fo ur pa ti ents who un der went car di ac cat he te ri za ti on we re eva lu a ted. Pa ti ents we re di vi ded in to two gro ups ac cor ding to SVG pa tency. Pa ti ents with occ lu ded SVG we - re com pa red with pa ti ents with pa tent SVG in terms of cli ni cal, an gi og rap hi cal and la bo ra tory para me ters. Re sults: Thir te en of 44 (29.5%) pa ti ents we re as pi rin non-res pon der. The num ber of non-res pon ders in pa ti ents with and wit ho ut occ lu si on in SVG we re si mi lar (35% vs 24%, p= 0.4). Ba sal cha rac te ris tics and me an aperture closure time/adp (CT/ADP), aperture closure time/epinephrine (CT/EPI) va lu es we re si mi lar in pa ti ents with occ lu ded and pa tent SVGs. Hyper li pi de mi a was only sig ni fi cantly in cre a sed the risk of SVG occ lu si on in mul ti va ri a te analy sis. The re was no sig ni fi cant dif fe ren ce bet we en as pi rin res pon ders and non res pon ders in terms of cli ni cal pa ra me - ters, ma jor car di o vas cu lar risk fac tors, occ lu si on in SVGs in any ti me pe ri od. Ho we ver, me an pla te - let vo lu me, CT/EPI and CT/ADP va lu es we re hig her in the non-res pon der gro up. CT/EPI was ne ga ti vely cor re la ted with me an pla te let vo lu me and he ma toc rit le vels. Conc lu si on: As pi rin re sis - tan ce do es not se em to play an im por tant ro le in SVG occ lu si on. Key Words: As pi rin; co ro nary ar tery di se a se; sap he no us ve in ÖZET Amaç: Oto log sa fen ven ler ko ro ner ar ter bay pas cer ra hi sin de, yük sek greft tı ka nık lı ğı in si - dan sı na rağ men sık ça kul la nıl mak ta dır. An tip la te let ilaç la rın bay pas son ra sı er ken dö nem de baş lan - ma sı greft tı ka nık lı ğı in si dan sı nı azalt mak ta dır. Biz bu ça lış ma da, sa fen ven greft (SVG) tı ka nık lı ğı olan has ta lar da PFA-100 (Pla te let Fonk si yon Ana li za tö rü) yön te mi ni kul la na rak as pi rin di ren ci - ni araş tır dık. Gereç ve Yöntemler: Ko ro ner an gi og ra fi ya pı lan 44 has ta in ce len di. Has ta lar SVG açık lı ğı na gö re 2 gru ba ay rıl dı. SVG tı ka nık lı ğı olan has ta lar, SVG'i açık olan has ta lar la kli nik, an - gi og ra fik ve la bo ra tu ar pa ra met re le ri açı sın dan kar şı laş tı rıl dı. Bulgular: Onüç (%29.5) has ta da as - pi rin di ren ci var dı. SVG tı ka nık lı ğı olan ve ol ma yan has ta lar da ki as pi rin di ren ci ben zer di (%35 ve %24, p= 0.4). İki grup ara sın da baş lan gıç öze lik le ri ve or ta la ma Kol la gen/adp, Kol la gen/epi nef rin de ğer le ri açı sın dan fark yok tu. Çok lu de ğiş ken ana liz le rin de, SVG tı ka nık lı ğı ris ki ni art tı ran tek de ğiş ken hi per li pi de mi idi. As pi rin di ren ci olan ve ol ma yan iki grup kli nik özel lik ler ve ma jör kar - di yo vas kü ler risk fak tör le ri açı sın dan kar şı laş tı rıl dı ğın da, iki grup ara sın da fark yok tu. Fa kat, or ta - la ma trom bo sit hac mi, Kol la gen/adp ve Kol la gen/epi nef rin de ğer le ri as pi rin di ren ci olan grup ta da ha yük sek idi. Kol la gen/epi nef rin ile or ta la ma trom bo sit hac mi ve he mo tok rit ara sın da ne ga tif ko - re las yon var dı. So nuç: As pi rin di ren ci SVG tı ka nık lı ğın da önem li bir rol oy na ma mak ta dır. Anah tar Ke li me ler: As pi rin; ko ro ner ar ter has ta lı ğı; sa fen ven Turkiye Klinikleri J Med Sci 2010;30(2):603-9 Cop yright 2010 by Tür ki ye Kli nik le ri oronary saphenous vein-graft disease is an important factor contributing to the morbidity after coronary bypass surgery (CABG). 1 Early and late occlusion of saphenous vein graft is a serious clini- Turkiye Klinikleri J Med Sci 2010;30(2) 603 Çağırcı ve ark. cal con di ti on that li mits the use of sap he no us ve in as a co ro nary bypass con du it. Sap he no us ve in grafts (SVGs) are clo sed with ra te of 15% in the first ye - ar. Bet we en one and six ye ars, an nu al graft at tri ti - on ra te is 1 to 25% and be co mes 4 to 6% per ye ar af ter that, so abo ut half of SVGs ha ve sig ni fi cant ste no sis or are occ lu ded af ter 10 ye ars. 2,3 As pi rin is the cor ners to ne of an tip la te let the rapy in car di o - vas cu lar me di ci ne to day. Early ini ti a ti on of an tip - la te let or an ti co a gu lant drugs re du ces the in ci den ce of graft occ lu si on af ter co ro nary ar tery bypass surgery. 4,5 Des pi te the de mons tra ted be ne fits of as pi rin in co ro nary he art di se a se, a lar ge seg ment of the po pu la ti on un der went CABG do es not be ne fit from as pi rin. 6 As pi rin re sis tan ce de fi ned by fa i lu re to effec ti vely in hi bit throm bo xa ne synthe sis is as so ci a - ted with a hig her risk of re cur rent myo car di al isc he mi a and car di o vas cu lar de ath. 7 In this study, we as ses sed the as pi rin re sis tan ce in pa ti ents with SVG occ lu si on af ter CABG. MA TE RI AL AND MET HODS STUDY PO PU LA TI ON Fo urty-fo ur pa ti ents who un der went car di ac cat - he te ri za ti on be ca u se of an gi na and/or dyspne a we - re eva lu a ted. All pa ti ents had a his tory of CABG with imp lan ta ti on of aor to co ro nary sap he no us ve - in grafts and had be en used as pi rin at do se of mg/da y. Pa ti ents with acu te or chro nic inf lam ma tory di se a se, mye lop ro li fe ra ti ve di sor ders, ma lig nancy, re nal, he pa tic or thyro id di se a se and pa ti ents tre a ted with im mun sup res si ve or cyto to - xic drugs, acu te co ro nary syndro mes, a he ma toc rit 0.30 or 0.52 and a pla te let co unt 100 G/L we - re exc lu ded. A writ ten con sent was ob ta i ned from all pa ti ents, and our lo cal et hi cal com mit te e ap pro - ved the study. CO RO NARY AN GI OG RAPHY All ci ne an go ig rams we re re vi e wed by two ex pe ri - en ced car di o lo gists, who we re blin ded to the pa ti - ents cli ni cal sta tus and la bo ra tory fin dings. The re vi e wers we re in for med about the num ber and localization of SVG s, and re wi e ved the ci ne an gi og - ram only the de ter mi ne the sta tus of grafts. The bypass grafts we re exa mi ned in mul tip le pro jec ti - Kalp ve Damar Cerrahisi ons and the deg re e of ste no sis was de ter mi ned in the pro jec ti on that sho wed the most se ve re nar ro - wing. Pa ti ents we re di vi ded in to two gro ups ac cor - ding to SVG pa tency. The occ lu ded SVG was de fi ned 100% ste no sis and pa tent SVG was de fi ned as 20% nar ro wing in the graft. In pa ti ents with occ lu ded grafts (100% ste no sis), stumps of grafts we re se lec ti vely in jec ted or vi su a li zed on aor tog - raphy in the ap prop ri a te pro jec ti on. Pa ti ents with occ lu ded SVGs we re com pa red with the pa ti ents with pa tent SVG. BLO OD SAMP LING AND LA BO RA TORY DE TER MI NA TI ONS Blo od samp les we re drawn from each sub ject, 2-4 h af ter as pi rin in ta ke in the mor ning bet we en 8 and 10 a.m. in the fas ting sta te. Blood was with drawn by an te cu bi tal ve ni punc tu re and the ini ti al first mi - li li ters of blo od we re dis car ded to avo id spon ta ne - o us pla te let ac ti va ti on. Cit ra ted blo od (0.129 M tri so di um cit ra te in di lu ti on 1:10) we re analy zed for as pi rin re sis tan ce by PFA-100 (Pla te let Functi on Analy zer, Da de Beh ring, Ger many) using collo gen and/or epi nep hri ne (CT/EPI) and col lo gen and/or ADP (CT/ADP) car trid ges to me a su re apertu re clo su re ti me (CT). As pi rin re sis tan ce was de fi - ned as CT/EPI 186 s. To tal cho les te rol, HDL cho les te rol and trig li se ri de le vels we re me a su red enz yma ti cally by the au to a naly zer (Hi tac hi 911, Ja - pon). LDL cho les te rol le vels de ter mi ned with Fri - e de wald for mu la. STA TIS TI CAL ANALY SES Re sults are re por ted as me an ± stan dard de vi a ti on (SD) and per cen ti les. Stu dent s t-test was used to com pa re nor mally dis tri bu ted con ti nu o us va ri ab - les and the Man n W hit ney U test for va ri ab les wit - ho ut nor mal dis tri bu ti on. Ca te go ri cal va ri ab les we re com pa red by using χ² test. In or der to de ter - mi ne in de pen dent pre dic tors of la te sap he no us ve - in graft occ lu si on, mul tip le lo gis tic reg res si on analy sis was per for med by inc lu ding ma jor risk factors at ri bu tab le to at he rosc le ro sis. Spe ar man cor re - la ti on analy sis was used to eva lu a te the re la ti ons hip bet we en dif fe rent va ri ab les. A va lu e of p 0.05 was con si de red as sta tis ti cally sig ni fi cant. SPSS-10.0 for Win dows sta tis ti cal soft wa re pac ka ge prog ram was used for sta tis ti cal analy ses. 604 Turkiye Klinikleri J Med Sci 2010;30(2) Cardiovascular Surgery RE SULTS This study inc lu ded 44 pa ti ents (34 ma les, 10 fema les, ages ran ged bet we en 41 and 77 ye ars). Of 44 pa ti ents, 13 (29.5%) we re as pi rin non-res pon - der. The ra te of non-res pon der pa ti ents in two gro - ups we re si mi lar (35% vs 24%, p= 0.465). The ti me bet we en sur gery and con trol co ro nary an gi og - raphy ran ged bet we en months. The re was no dif fe ren ce bet we en both gro ups con cer ning age, gen der, body masss in dex, ti me in ter val af ter sur gery, ma jor car di o vas cu lar risk fac tors such as hyper li pi de mi a (HL), hyper ten si on (HT), di a be tes mel li tus (DM), smo king, me di cal tre at ment inc lu - ding da ily as pi rin do sa ge, myo car di al in farc ti on (MI) his tory or left ven tric le ejec ti on frac ti on (Tab le 1). Furt her mo re, among la bo ra tory pa ra - me ters, whi te blo od cell and pla te let co unts, he - ma toc rit (Htc), me an pla te let vo lu me (MPV), fib ri no gen and cho les te rol le vels, graft num bers, me an CT/ADP, CT/EPI va lu es and ra te of res pon - se to as pi ri ne we re si mi lar in two gro ups (Tab le 2). Ho we ver, on mul ti va ri a te lo gis tic reg res si on analy sis, among ma jor risk fac tors at ri bu tab le to at he rosc le ro sis, only hyper li pi de mi a was fo und as an in de pen dent va ri ab le that sig ni fi cantly in cre a - Çağırcı et al sed the risk of aor to co ro nary sap he no us ve in graft occ lu si on. When as pi rin res pon ders were com pa red with non res pon ders (as pi rin re sis tant), the re was no sig ni - fi cant dif fe ren ce bet we en both gro ups in terms of cli - ni cal pa ra me ters, ma jor car di o vas cu lar risk fac tors, me di cal tre at ments, as pi rin do sa ges or occ lu si on ra te in sap he no us ve in co ro nary grafts in any ti me pe ri od. Ho we ver, me an pla te let vo lu me, CT/EPI and CT/ADP va lu es we re hig her in non-res pon der gro up when com pa red to res pon der gro up (Tab le 3). Me an CT/ADP and CT/EPI va lu es we re si mi - lar in pa ti ents with ste no sis in sap he no us ve in grafts 12 months af ter sur gery and tho se with pa - tent sap he no us grafts 12 months af ter sur gery. The re was no dif fe ren ce in me an CT/ADP and CT/EPI va lu es when the pa ti ents with ste no sis in sap he no us grafts 12 months and 36 months were compared with each other or with tho se wit - ho ut ste no sis in sap he no us ve in grafts (Tab le 4). On cor re la ti on analy sis, CT/ADP was fo und to be ne ga ti vely cor re la ted (r= -0.4, p= 0.003) with age. In ad di ti on, CT/EPI was ne ga ti vely cor re la ted (r= -0.5, p= 0.024) with me an pla te let vo lu me and with he ma toc rit le vels (r= -0.2, p= 0.042). TABLE 1: Baseline characteristics of patients with saphenous vein graft stenosis and non-stenosis. Non-stenosis group (n = 21) Stenosis group (n = 23) p value Age (years) 63.1 ± ± Male/female 16/5 18/ BMI (kg/m 2 ) 26.3 ± ± Time interval after surgery (months) 52.8 ± ± Hypertension 10 (48%) 12 (52%) Diabetes mellitus 7 (33%) 6 (26%) Smoking 5 (24%) 6 (26%) Hyperlipidemia 16 (76%) 14 (61%) History of myocardial infarction 7 (33%) 7 (31%) Ejection fraction (%) 51.1 ± ± Aspirin dose (mg/day) ± ± Beta-blockers 18 (86%) 17(74%) ACE inhibitors 13 (62%) 13 (57%) Statins 11 (52%) 10 (44%) Nitrates 10 (48%) 9 (39%) BMI: body mass index, ACE: angiotensin converting enzyme. Values are mean ± SD and percentiles. P values are based on the student t test and Mann-Whitney U test for continuous variables and on the χ² test for categorical variables. Turkiye Klinikleri J Med Sci 2010;30(2) 605 Çağırcı ve ark. Kalp ve Damar Cerrahisi TABLE 2: Compared laboratory findings of patients with saphenous vein graft stenosis and without stenosis. No-stenosis group (n = 21) Stenosis group (n = 23) p value Hematocrit (%) 43.1 ± ± White blood cells (nl -1 ) 8.1 ± ± Platelets ± ± Mean Platelet Volume (fl) 11.0 ± ± Fibrinogen (mg/dl) 3.5 ± ± Total cholesterol (mg/dl) ± ± LDL cholesterol (mg/dl) ± ± HDL cholesterol (mg/dl) 39.2 ± ± Trigliserid (mg/dl) ± ± Graft number 1.5 ± ± Patients with one or multipl saphenous vein grafts One 15 (47%) 17 (49%) Two 16 (50%) 16 (46%) Three or more 1 (3%) 2 (5%) Internal mammary artery graft 17 (%) 18 (%) CT/ADP 98.1 ± ± CT/EPI ± ± Aspirin non-responders 5 (%24) 8 (%35) LDL: low density lipoprotein, HDL: high density lipoprotein, CT/EPI: closure time for collagen/epinephrine, CT/ADP: closure time for collagen/adenosine diphosphate Values are mean ± SD and percentiles. P values are based on the student t test and Mann-Whitney U test for continuous variables and on the χ² test for categorical variables. DIS CUS SI ON Au to lo go us sap he no us ve ins are wi dely used for CABG des pi te a hig her in ci den ce of early and la te graft clo su re. 1 Fo ur con se cu ti ve pha ses of aor to co - ro nary bypass sap he no us ve in-graft di se a se we re de fi ned: 8 1) an early pos to pe ra ti ve pha se of pla te let throm bo tic occ lu si on which is sig ni fi cantly pre ven - ted by pla te let in hi bi tor the rapy when star ted in the pe ri o pe ra ti ve pe ri od and accompanied with a good sur gi cal and tech ni cal ex pe ri en ce; 2) an in ter me di a - te pha se of pla te let-re la ted in ti mal hyperp la si a wit - hin the first pos to pe ra ti ve ye ar which is not pre ven ted with an ti-pla te let the rapy; 3) a la te pha - se of occ lu si on to ward the end of the first ye ar in which in ti mal hyperp la si a and comp li ca ted pla te let throm bi su pe rim po sed and pla te let in hi bi tor the rapy is of sig ni fi cant be ne fit in pre ven ti on, 4) a pha se of at he rosc le ro tic di se a se af ter the first ye ar in which as pi rin tre at ment is be ne fi ci al alt ho ugh the re are co - me con tro ver si es abo ut the du ra ti on. 9 Se ve ral fac tors af fect the fa te of SVGs such as smo king, 10 hyper li pi de mi a, 11 re ci pi ent ar tery di a - me ter, 12,13 and hyper ten si on. 13 So me he mos ta tic fac tors such as fac tors VII and VI I I, fib ri no gen and tis su e plas mi no gen ac ti va tor are re la ted to graft occ lu si on and the as ses se ment of the se fac tors may con tri bu te to the iden ti fi ca ti on of in di vi du als at risk for an early ve in graft clo su re. 14 Re cently, Zimmer mann et al. 15 de mons tra ted that pla te let ac ti va - ti on by as pi rin is com pro mi sed wit hin se ve ral days af ter CABG pro bably du e to an im pa i red in te rac ti - on bet we en as pi rin and pla te let cyclo oxy ge na se. As pi rin exerts its an tit hrom bo tic ef fect pri ma - rily by in ter fe ring with the bi osyn the sis of throm bo - xa ne A 2 16,17 and se ve ral stu di es ha ve de mons tra ted be ne fi ci al ro le of as pi rin in pri mary or se con dary pre ven ti on he art di se a se. 18,19 Ho we ver, as pi rin s antip la te let ef fect is not uni form in all pa ti ents. 20 As pi rin re sis tan ce, as de fi ned by fa i lu re to effec ti vely in hi bit throm bo xa ne synthe sis, is as so ci - a ted with a hig her risk of re cur rent myo car di al isc he mi a and car di o vas cu lar de ath, 7 as well as recur rent ce reb ral isc he mic at tacks. 21 Gum et al. 22 repor ted that as pi rin re sis tan ce was as so ci a ted with 606 Turkiye Klinikleri J Med Sci 2010;30(2) Cardiovascular Surgery Çağırcı et al TABLE 3: Characteristics of the aspirin responder and non-responder groups. Non-responders (n= 13) Responders (n= 31) p value Age (years) 65.1 ± ± Male/female 9/4 25/ BMI (kg/m 2 ) 25.8 ± ± Time interval after surgery (months) 65.0 ± ± Hypertension 7 (54%) 14 (45%) Diabetes mellitus 5 (39%) 8 (26%) Smoking 4 (31%) 7 (23%) Hyperlipidemia 8 (62%) 22 (71%) History of myocardial infarction 4 (30%) 6 (19%) Ejection fraction (%) 47.3 ± ± Aspirin dose (mg/day) ± ± Beta-blockers 9 (69%) 26 (79%) ACE inhibitors 9 (69%) 17 (55%) Statins 6 (46%) 15 (48%) Nitrates 5 (39%) 14 (45%) Hematocrit (%) 44.1 ± ± White blood cells (nl-1) 8.0 ± ± Platelets ± ± Mean Platelet Volume (fl) 11.1 ± ± * Fibrinogen (mg/dl) 3.9 ± ± Total cholesterol (mg/dl) ± ± LDL cholesterol (mg/dl) ± ± HDL cholesterol (mg/dl) 37.4 ± ± Trigliseride (mg/dl) ± ± Graft number 1.8 ± ± Occlusion in saphenous grafts (%) 8 (62%) 15 (48%) Occlusion 12 months (%) 4 (31%) 6 (19%) Occlusion 36 months (%) 3 (23%) 7 (22.5%) CT/EPI ± ± * CT/ADP 76.5 ± ± * BMI: body mass index, ACE: angiotensin converting enzyme, LDL: low density lipoprotein, HDL: high density lipoprotein, CT/EPI: closure time for collagen/epinephrine, CT/ADP: closure time for collagen/adenosine diphosphate. Values are mean ± SD and percentiles. P values are based on the student t test and Mann Whitney-U test for continuous variables and on the χ² test for categorical variables. * statistically significant. 4.1-fold ex cess ad jus ted ha zard of se ri o us vas cu lar events, in de pen dent of age, gen der and con ven ti o - nal vas cu lar risk fac tors. Additionally, the in ci den - ce of as pi rin re sis tan ce ran ges bet we en 5-61% de pen ding on ti ming and tech ni qu e of exa mi na ti - on, ti me of the last as pi rin in ta ke, do se of as pi rin as well as he te ro ge ne city of pa ti ent po pu la ti on As pi rin re sis tan ce may be a con se qu en ce of fol lo wing mec ha nisms: ) no nad he ren ce to aspi rin; 2) re qu i re ment for hig her do ses of as pi rin; 3) al ter na ti ve ups tre am path ways of pla te let ac ti va ti - on that are not bloc ked by as pi rin; 4) as pi rin-in - sen si ti ve throm bo xa ne synthe sis; 5) drugs that in ter fe re with the an tit hrom bo tic ef fects of as pi rin; 6) pla te let glycop ro te in poly morp hism. Gro te me yer et al. 25 fo und that pa ti ents with ele va ted pla te let re ac ti vity des pi te as pi rin were mo - re li kely to ex pe ri en ce vas cu lar de ath, MI or ce reb ro vas cu lar ac ci dent. An der sen et al. 24 de mons tra ted that P-se lec tin but not β-throm bog lo bu lin Turkiye Klinikleri J Med Sci 2010;30(2) 607 Çağırcı ve ark. Kalp ve Damar Cerrahisi TABLE 4: Comparison of CT/ADP and CT/EPI values of the patients with occlusion in SVG 12 months after surgery with occlusion 12 months and
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