Y D LODEO HRQOLQ H at httpccf orumc omc ontent 1063 17 YLGHQFH OXE EBM Journal Club Sectio n Editor Eric B Milbrandt MD MPH Journal clu ID: 339298
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$ Y D L O D E O H R Q O L Q H at http://ccf orum.c om/c ontent/ 10/6/3 17 ( Y L G H Q F H % D V H G 0 H G L F L Q H - R X U Q D O & O X E EBM Journal Club Sectio n Editor: Eric B. Milbrandt, MD, MPH Journal club critique $ G L V K H D U W H Q L Q J V W R U \ $ S U R W L Q L Q L Q F D U G L D F V X U J H U \ Marcus Lien 1 and Eric B. Milbrandt 2 1 Clini c al Fell ow , Departmen t o f Criti c a l Care Med i cin e , Univ er sity of Pi ttsbu r gh S c hool of Medi ci ne, Pittsburgh , Pen n sy l v ania, USA 2 A ssi stan t Pr ofe ssor, Dep a rtmen t of Critic a l Care Medi ci ne, Univ ty of Pi ttsbu r gh Sch ool o f Medicine , P i ttsburg h , P enn sy l v an ia, USA Publishe d on line: 8 Nov e mber T h is ar ti cle is onlin e at h ttp : / / c c forum . com / con t en t/10 / 6 / 3 17 © 2006 BioMed Ce ntral Ltd Critica l Care 2006 , 10: 317 (DOI 1011 86/cc50 72) ( [ S D Q G H G $ E V W U D F W & L W D W L R Q Mangano DT , Tudor IC, Dietzel C: T he risk ass o ciated w i th aprotinin in car d iac s rgery . N Eng l J Med 20 06, 354:353- 365 [1]. % D F N J U R X Q G The major i ty of patients under going surg ica l treatment for S T -e levation m y ocardial infarc tion rec e ive a n tifibrin oly t ic therap y to limit blo od los s . T h is appro a ch app ears counterintu itive to the accept ed medica l treatment of the same co ndit i on --namely , fibri noly s is to limit thrombosis. Desp ite this co ncern, no inde pendent, large- scale safety assessme n t has been undertak en. 0 H W K R G V ' H V L J Q D Q G V H W W L Q J Pro s p e ctive observa tional coh o rt stud in 69 ins t itutions in Nort h and So uth A m erica, the Middle East, Eu rope, and Asia. 6 X E M H F W V 43 74 patients undergo ing c o ronary - artery revascu larizat i o n . All p a tients w e �re 18 years old a n d completed a pr e-surgery interv iew . Patients were clas sified as undergo ing primary surgery (no previo us h eart surgery and no other surgery beside s a coro nary artery b y pass graft), or complex surgery (all other surgery ) . , Q W H U Y H Q W L R Q None. 0 H D V X U H P H Q W V T h e authors p r ospective ly as sessed three agents (aprotin in [1295 patients ], aminocapro i c acid [88 3 ], and tranex amic acid s compare d w i th no ag ent (1374 patients) w i th regard to s e rious card iova scular, renal, and cerebrov ascular outcomes b y pro pensity and multivar iab l e methods. 5 H V X O W V In propens ity - adjusted, mu ltivar iable log i stic regressio n (C- i n dex , 0.72), use of aprotinin w a s assoc i ated w i th a doubling in the risk of r enal failure req u irin g dia l y s is among patient s undergoing complex coronary - artery surgery (odds ratio, 2.59; 95 percent confid e n ce interva l , 1.36 to 4.95) or primary sur gery (odds ratio, 2.34; 95 percent confid e n ce interva l , 1.27 to 4.31). Similar l y , use of aprotinin in th e latter grou p a s associat ed w i th a 55 percent increas e in the risk of my ocardial infar c tion or heart failure (P 0 .001 ) and a 181 pe rcent increase in the risk of stroke or en cep halop athy (P=0.001). Ne ither a m inoca p roic acid nor tranex amic ac id w a s associated w i th an increas ed risk of re nal, cardiac, or ce rebral event s. Ad justment according to pr opens ity score for the use of a n y one of the three agents a s compare d w i th no ag ent y i elded near ly identical find ing s . All the agents reduced blo od loss. & R Q F O X V L R Q The asso ciat ion betw een aprotinin and seriou s end-organ damage ind i cat e s that co ntinu ed use is not prudent. In contrast, the less ex pensive g eneric medicat i ons aminoc aproic acid and tra nex amic acid are safe alternative s . & R P P H Q W D U \ The med i ca l an d surgica l appr o a ches to acute S T -e levation my ocardial infa rction pre s ent an interesting paradox . T h e medica l approa ch focus e s o n fibrin oly t ic therap y . Due to concerns over ble eding, the surgical appr oach a v oids fibrino l y t ic agents and instea d uses age nts that mitigate bleed ing, s o c a lle d antif ibrin o l y t ic agents, which inc l ude aprotinin, amin ocaproic acid, and tranex amic acid. hes e agents w e re generally considered safe based on a number of secondary analy s es of studies that w e re not primarily intended to as sess safety . T hese relatively small stud ies w e re underpowered to detect adverse ev ents and d i d not invo lve h ead-to -head comp aris ons of the co mmonly used antifibrinoly t ic agents. An imal studies sugge s t that these agents ha ve th e potentia l to cause isch emic damage to multip le orga n s y stems and sm all, large l y sing le-center studies have s uggested incr e a sed gr aft thrombosis and Page 1 o f 2 S D J H Q X P E H U Q R W I R U F L W D W L R Q S X U S R V H V \f Critica l Care 2006 , 10: 317 Lien and M i l b randt renal dy sfunction [2-6]. Ideally , the safety of these ag ents w ould be com pared in a lar ge, multi-ce nter, randomize d controlled trial. How e ver, because their use is embedded in practice an d be cause regu lator y approval of these age nts differs b y country , conducting such a trial w ill be difficult if not imposs i ble. To addres s the safety of these agents for cardiopu lmon ary b y pass surgery , Mangan o an d colleagu es [1] conducted a large, pro s pective, observ a tion al c ohort as ses s ing aprotin in, aminoc aproic acid, and tranex amic ac id as co mpared to no agent in 4 3 7 4 patients un dergoin g rev a scular i zatio n . Becaus e this w a s a prospec tive study , the authors w e re able to co llect a w ealth of c lin ica l information, inc l ud ing approx imately 7500 data fie l d s per patient. This perm i tted consideration of varia b les that might influe nce both ch oic e of antifibrinoly t ic agent a nd c l inica l outcom e . The a u thors used a propen sity score based on 4 5 treatment-selectio n covariates and multivar iab l e m odeling to contr o l for b a se line differences b e tw een groups. In doing so, th e y found that aprotinin, but not aminocapro i c acid or tranex amic acid, w a s associated w i th serious c a rdiova scular, renal, an d cerebrovasc u lar adverse e v e n ts. Furthermore, a dose- response re latio n ship w a s dem onstrated, strengthening the inference of cau s ality . The m a in w eakness of this stu d y is that the au thors failed to report details o f the surgery itself, such as w hether the surgery w a s on vs. off-pump, time on pump, and number of vessels by passed. T hese variables are like ly to influe nce not only choice of antifibrinol y t ic age nt but also outcome, and are, theref ore, a source of indication bias that cou l d reflect unfavora b ly on aprotinin. Based on the results of this stud y and thos e of another observatio nal study suggesting renal tox i c i ty [7], the Un ited States Foo d and Dru g A d ministration (F DA) h e ld an advis ory committee meetin g Septemb e r 21, 2006 to consider the ca rdiovas c ular s a fety of aprotinin. Becaus e of concerns a bout the methodolo g y of the stud y b y Mangano and colleag ues and because it w a s the o n ly s t ud y to suggest card io vascular adver se events [8], the advis ory committee conc luded that there w a s insufficient evide n ce to support chan ging the card iova scular s a fety labeling of the drug. How e ver, just six da y s after the committee met, it w a s reveale d that the drug s manufacturer , Bay e r, had prelim inary results from an o b servation a l st udy of 67,000 cardiac by pass patients that suggested a p rotinin w a s associated w i th increas ed risk of death, renal d y sfunction, congestive he art failure, a nd stroke [9]. T h e F D A subsequ ently issued a stateme n t indicating it w a s unaw are of this study w h en the adv isor y committee met and that it is evalu a ting the results of this stud y and the potentia l implications for the use of apro t i n i n [10]. In the mean ti me, the FDA sugge sts that ph y s ici ans w ho use aprotinin sh ould carefully monitor patients for the occurrenc e of tox i city , particularly to the kidney s, hear t, or brain, a nd promptly report observed adverse events . T hey go on to recommend that phy sicians should cons id er limiting apro t inin use to those situatio ns w here the clin ical ben efit of reduced b l ood loss is essential to medical ma nagement of th e patie nt and outw e ighs the potential ris ks. 5 H F R P P H Q G D W L R Q The w e ight of evide n ce s ugge sts that aprotin in incre a ses the risk for a poor outcome among p a tients undergo ing cardiac operations. Not o n ly is this dru g very ex pensive, it seems to be tox i c. Althou gh the risk of ex cessiv e bleed ing is certainly a ca use for conce r n in certain patients, and treatment w i th a p rotinin ca n dec rease bloo d los s in sele cted patients, data are lackin g to show that adminis tration of this agent actually improves surviv al. & R P S H W L Q J L Q W H U H V W V The authors de clare no compet ing interests. 5 H I H U H Q F H V 1. Mangano D T , Tu dor IC, Dietzel C : 7 K H U L V N D V V R F L D W H G Z L W K D S U R W L Q L Q L Q F D U G L D F V X U J H U \ . 1 ( Q J O - 0 H G 2006, :353-3 65. 2. Cosgrove DM, III , Heric B, L y tle BW, Ta y l o r PC, Novoa R, Golding LA, Stewart RW, Mc Carth y PM, Loo p FD: $ S U R W L Q L Q W K H U D S \ I R U U H R S H U D W L Y H P \ R F D U G L D O U H Y D V F X O D U L ] D W L R Q D S O D F H E R F R Q W U R O O H G V W X G \ . $ Q Q 7 K R U D F 6 X U J 199 2, :1031 -1036. 3. D'Ambra MN, A k ins CW, Blackstone EH, Bonney SL , Cohn LH, Cosg r o ve DM, Lev y JH, L y nch KE, M addi R: $ S U R W L Q L Q L Q S U L P D U \ Y D O Y H U H S O D F H P H Q W D Q G U H F R Q V W U X F W L R Q D P X O W L F H Q W H U G R X E O H E O L Q G S O D F H E R F R Q W U R O O H G W U L D O . - 7 K R U D F & D U G L R Y D V F 6 X U J 1996, :10 81- 1089. 4. Feindt PR, Walcher S, Volkmer I , Keller HE, Stra ub U , Hu w e r H, Se yfe r t UT, P e tzold T , Gams E: ( I I H F W V R I K L J K G R V H D S U R W L Q L Q R Q U H Q D O I X Q F W L R Q L Q D R U W R F R U R Q D U \ E \ S D V V J U D I W L Q J . $ Q Q 7 K R U D F 6 X U J 1995, :107 6-1 080. 5. Sundt TM, III, K ouchoukos NT, Saffitz JE, Murph y SF, Wareing TH, Stahl DJ: 5 H Q D O G \ V I X Q F W L R Q D Q G L Q W U D Y D V F X O D U F R D J X O D W L R Q Z L W K D S U R W L Q L Q D Q G K \ S R W K H U P L F F L U F X O D W R U \ D U U H V W . $ Q Q 7 K R U D F 6 X U J 1993, :141 8-1 424. 6. 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Harri s G: ) ' $ V D \ V % D \ H U I D L O H G W R U H Y H D O G U X J U L V N V W X G \ . 1 H Z 7 L P H V Septemb e r 30, 2006. Available a t : h t t p : / / w w w . n y times.com/2006/0 9 /30/health/30fd a .html 10. US Food and D r ug Administration. FDA Public Health Advisory : Ap roti nin Injection (marketed as Tra s y l ol). September 29, 2006. Available at: http:// www .f da.g o v/cder/drug/advi s or y / ap rotinin200 6092 9.htm Page 2 o f 2 S D J H Q X P E H U Q R W I R U F L W D W L R Q S X U S R V H V \f