coumadin in prosthetic valves

8/7/2019 coumadin in prosthetic valves

1/13

DOI 10.1378/chest.102.4_Supplement.445S1992;102;445S-455SChest

Goldman and A. G. G. TurpiePaul D. Stein, Joseph S. Alpert, Jack Copeland, James E. Dalen, Steven

ValvesMechanical and Biological Prosthetic HeartAntithrombotic Therapy in Patients With

http://chestjournal.chestpubs.org/content/102/4_Supplement/445S

can be found online on the World Wide Web at:The online version of this article, along with updated information and services

) ISSN:0012-3692http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(

without the prior written permission of the copyright holder.reserved. No part of this article or PDF may be reproduced or distributedChest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights

ofbeen published monthly since 1935. Copyright1992by the American Collegeis the official journal of the American College of Chest Physicians. It hasChest

1992, by the American College of Chest Physicians.by guest on December 13, 2010chestjournal.chestpubs.orgDownloaded from
http://chestjournal.chestpubs.org/content/102/4_Supplement/445Shttp://chestjournal.chestpubs.org/content/102/4_Supplement/445Shttp://chestjournal.chestpubs.org/site/misc/reprints.xhtmlhttp://chestjournal.chestpubs.org/site/misc/reprints.xhtmlhttp://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/site/misc/reprints.xhtmlhttp://chestjournal.chestpubs.org/content/102/4_Supplement/445S


2/13

Antithrombotic Therapy in Patients WithMechanical and Biological Prosthetic HeartValvesh u l D. Ste in, M. . , E C .C. R, Chai tmunJoseph S . Alpert, M. . , E C .C .RJack Copeland , M.D.James E . Dalen, M .D . , EC .C.PSteven Goldman, M. D .A. G . G . Turpie, M.D.

ecommendations of the 1986' and 198g2consensusR committee were that patients with mechanicalprosthetic heart valves be treated with long-termwarfarin, at a dose sufficient to prolong the prothrom-bin time (PT) ratio to 1.5 to 2.0 times control usingNorth American thromboplastin. It was suggestedthat administration of dipyridamole is optional, unlessthe patient suffered a systemic embolism despiteadequate therapy with warfarin. The level of the PTratio that was recommended was based on retrospec-tive data and nonrandomized trials. The present re-port, based on newer data, will try to assess the risksand benefits of various levels of the PT ratio accordingto the type of prosthetic valve and its site of insertion.

Only a few investigations have addressed the risksand benefits of more than one level of the PT ratio.Saour and associate^,^ in a level I1 study that includedpatients with Beall, StarrEdwards, Cutter-Smeloff,Bjork-Shiley, and St. Jude valves, compared the oc-currence of thromboemboli in patients with a NorthAmerican (NA) PT ratio of 1. 3 o 1.7 (moderate levelPT atio) with those with a PT atio of 2.3 to 2.7 (highlevel PT ratio). Moderate vs high levels of anticoagu-lation resulted in thromboembolic events in 4.01100patient-years vs 3.71100patient-years (NS). Somewhatmore than half of the thromboembolic events, 18of 33(55percent) occurred in patients whose PT ratios (NA)were 51.3 . A trend suggested that major bleedingwas less frequent in patients who received moderatelevels of anticoagulant, 0.91100 patient-years vs 2.U100 patient-years (NS). Minor bleeding was less fre-quent among those with moderate levels of PT ratio,5.21100 patient-years vs 10.11100 patient-years(pc0.001).Most bleeding occurred in patients with aPT ratio 23.0 . These data suggested that a PT ratio51 .3 , using NA thromboplastin, allowed an unsatis-factory number of thromboembolic events, a PT ratioReprint requests: Dr. Stein, Henry Ford Hospital, 2799 Wst GrandBlod, EbR 4016, Detroit 48202

of 1.4 to 1.7 was as preventive of thromboemboli ashigher levels, and a PT ratio of 2.3 to 2.7 wasunnecessary and led to bleeding. However, boththromboemboli and bleeding were most frequentwhen the PT ratios were outside the target level.

Altman and associates4 level 11) evaluated the effectsof anticoagulation in combination with dipyridamole,150 mg/d, and aspirin, 660 mg/d. Two levels of PTratio were evaluated, 1.3 to 1.6 and 1.6 to 2.0, basedon NA thromboplastin, assuming an InternationalSensitivity Index (ISI) of 2.2 and using the conversiontables published by Hirsh e t al.5 All but one of thepatients had Bicer (tilting pyrolitic carbo disk) valves.Thromboemboli were not significantly more frequentwith the lower range of FT ratio plus antiplateletagents, 1.91100patient-years vs 4.91100patient-years(NS). All patients with thromboembolic events hadpreoperative atrial fibrillation. Bleeding was less fre-quent with the lower PT plus antiplatelet agents, 3.81100 patient-years vs 24.71100 patient-years (pC0.02).Among the patients with bleeding episodes, 5 of 15(33percent) occurred at NA PT ratios >1.8.

Wilson and associates6 (level V) evaluated the rec-ords of 103patients, among whom 97 (94percent) hadBjork-Shiley or St. Jude valves, and 6 (6 percent) hadStarrEdwards valves, some with a bioprosthetic valvein addition as a second or third valve. With PT ratios(NA thromboplastin ) 2.0 had nothromboemboli, but this group was followed up foronly 20 patient-years. Hemorrhagic events with PTratios C1.3, 1.3 o 1.5, 1.6 to 2.0, and 2.1 to 2.5 were2.8 ,3 .8 ,5 .5 , nd 12.2/100patient-years, respectivelyOnly a few had PT ratios >2.5, and hemorrhagicevents in these patients were frequent.

Among patients with Starr-Edwards valves andBjork-Shiley standard disk valves (level I), patientstreated with warfarin, PT ratio 1.8 to 2.5 (NA throm-boplastin) were compared with patients treated with

CHEST 1 102 1 4 1 OCTOBER, 1992 1 Supplement 445s

http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/http://chestjournal.chestpubs.org/


3/13

dipyridamole, 150 to 225 mg/d plus aspirin, 650 to ratio of 2.3 to 2.7 had Starr-Edwards valves. The990 mg/d.' Fewer patients treated with warfarin had authors did not comment on any differences in thethromboemboli, 2.2400 patient-years vs 9.8/100 pa- incidence of thromboemboli related to the type oftient-years (p=0.004). The difference was primarily valve. Reports of thromboemboli in patients withamong patients with valves in the mitral position, 1.91 StarrEdwards valves, which lend themselves to an100 patient-years vs 12.41100 patient-years (p=0.005). estimation of the prothrombin time ratio, are shownPatients with valves in the aortic position had a similar in Table 1. Thromboemboli in patients receivingfrequency of thromboemboli, 3.6/100 patient-years vs anticoagulants, with valves in the aortic or mitral3.81100 patient-years. position, occurred at a rate of 1 .5 to 9.3/100 patient-Data are starting to accumulate that now give a years.%14 atients treated with antiplatelet agents alonebetter impression of the risks and merits of various had thromboemboli at a rate of 2.3 to 14.5'100 patient-levels of anticoagulation and the rates of occurrence years.lSl7 Thromboemboli in patients treated withof thromboemboli with different types of valves and warfarin plus antiplatelet agents occurred at a rate ofdifferent sites of insertion. Certain constraints, how- 1.8 to 2 .4100 patient-years.1J3~'"ever, should be kept in mind. Most studies are Regarding the standard Bjork-Shiley valve in theretrospective, definitions of thromboembolic events aortic position (Table 2), Bjork and Henzelg showeddiffer, the control of the PT ratio with various NA that it was unsafe to omit antithrombotic therapy, andthromboplastins varies, and conversion to standard antiplatelet agents alone were unsatisfactory. Levelsreference levels may be only an ap pr ox im at i~ n. ~~ ~ of PT ratio (NA thromboplastin) that varied between

There is only sparse new7 information regarding 1.5 and 3.0 did not show any marked difference in theSta rrEdwards ball valves. In the investigation of Saour rate of thromboemboli, which ranged from 0 o 1.91and associates3 (level 11), 39 patients with a PT ratio 100 patient-years.rn23 Valves in the mitral position,(NA thromboplastin) of 1. 3 to 1.7 and 29 with a PT among patients whose PT atio ranged from 1.5 o 3.0

Table 1- Thromboembdi With Starr-Edwards &rU Valves*- - -Valve No. of Valve NA IT TW100 EvMed Type Patients Position Ratio pt-yr Lev Source

None C 58 Ao, M 4 IV Moggio et al,I61978M 37 Ao 215 IV Duvoisin et al,la 1967M ? M 75 IV Yeh et al,ll 1967M 52 Ao 675 IV Akbarian e t al,= 196810 M 365P 29 Ao 6% V Stein et al ,= 1976Warfarin or dicumarol M, C 216 Ao 2.4-3.M 7.0 IV Da le e t al,O 1976

M , C 73 Ao 2.71 9.3 I Dale et al , l" 1977M ? M 2.5-3.M 1.8 1V Yeh e t al,I1 1967M 177 Ao 21.5 2.0$ IV Duvoisin et al,lg 1967? 50 Ao, M 1.8-2.37 15.55 I Sullivan et d ,13 1969

M , C , P 132 M 21.5 6.4 IV Fuster e t al ," 1982170 An 6.5ASA 1,000 M C 77 Ao 14.5 I Dale and Myhre, lS 1981ASA 1,300 M ,C 70 Ao, M 2.6 IV Moggio et d , la 1978D IP 400 M C 7 Ao, M 10.0 IV Moggio et al,161978ASA 20kg + D l P f i g ? t 150 Ao, M 2.3 V El Makh loufet al,171987Warfarin + ASA 500 ?$ 57 Ao, M 1.3-1.ql 2.41 I Altman et al,'"976Warfarin + ASA 1,000 M , C 75 Ao 2.71 1.8 1 Dale et al ,lU1977Warfarin + D I P 400 T 42 Ao, M 1.9-2.38 2.21 I Sullivan et d ,13 1969Inadequate warfarin M 140 Ao


4/13

Table 2- Thromboemboli W ith Bjork-Shilg( StandardDisk V' e s *No. of Valve NA PT TEf100 Ev

Med Patients Position Ratio Pt-yr Lev Sor~rceNone 27 Ao 23 IV Bjork and Henze,lS 1975ASA 1000+DIP 100 64 Ao 23 IV Bjork and Henze,lB1975Coumarin derivatives 73 Ao 2.5-3.0t 0.7 1V Bjork and Henze," 1979184 Ao 1.6-1.9$ 0.4 V Sethia et al,P1 98648 Ao 1.6-1.9$ 0.0 I1 Vogt et d," 1990

424 Ao 2.0-2.5t 1.9 1V Horstkotte et al." 1983193 M 2.5-3.Ot 4.2 IV Bjork and Henze," 1979323 M 1.6-1.9$ 1.5 V Sethia et al,21198625 M 1.6-1.9$ 4.6 11 Vogt eta]," 1990475 M 2.0-2.5t 2.8 IV Horstkotte et al," 1983452 M 2.0-2.5t 2.4 V Eberlein et al," 1990109 >1V 2.5-3.0t 2.2 1V Bjork and H e n ~ e , ~ '979222 >1V 1.6-1.9$ 1.0 V Sethia et al,%I 98611 >1V 1.61.9$ 1.9 I1 Vogt et al,= 1990119 >1V 2.0-2.5t 3.2 IV Horstkotte et al," 1983

*See Table 1 for explanation of abbrevations.?North American prothrombin ratio was calibrated from prothrombin activity (8)sing Figure 1 in Hirsh et al.r$North American prothrombin ratio was estimated from INR assuming an IS1 of 2.2."(NA thromboplastin) had a higher rate of thrombo-em bo li than valves in th e aortic position, ranging from1.5 to 4.640 0 p a t i e n t - y e a r ~ ~ ~ ~Table 2). The mosteffective PT ratio is unclear. Thromboemboli amongpatients with two or three Bjork-Shiley valves werenot mo re frequ ent than w ith single valves in the mitralposition (Table 2).The rate of occurrence of thromboemboli amongpatients w ith t he Bjork-Shiley convexoconcave valveseems to parallel the ex perience with th e Bjork-Shileystandard disk valve being 0.5/100 patient-years in theaortic position2' and 1.1 o 3.0/100 patient-years in th emitral p o s i t i ~ n ~ ' , ~ , ~Table 3). The PT ratio (NAthromboplastin) ranged from 1. 5 to 2.5.Regarding the S t. Ju de valve, the rate of occurren ceof thromboemboli was high in the absence of anti-throm botic therapym (Tables 4 through 6). In p atientswith S t. Jude valves in th e aortic position who receivedanticoagulants, PT ratio of 1 .5 to 2.5 (NA thrombo-plastin), thromboemboli occurred at a rate of 0.7 to3.0/100 patient-years.PP,e3,n spirin plus d ipyridarno leseemed to offer protection comparable to coumarinderivatives, 2. 1 to 3 .2/100 patient-ye arsn.% (Table 4).Throm boem boli with valves in the mitral position, 0 .9

to 3.0/100 patient-years, among patients with a PTratio of 1.5 o 2. 5 (NA thromboplastin) did not app earto be more frequent than with valves in the aorticp o s i t i ~ n ~ - ~ , ~ ~Table 5). In small numbers of patients,with more than one St. Jude valve, coumarin deriva-tives seem ed to offer protection that was comparab leto single valvesa.= (Table 6). An tiplatelet agen ts alon e,however, evaluated in only a few patients, seemedunsa t i s fac tory when pa t ients had more than onevalve mRegarding the Medt ronic -Hal l va lve , PT ra t ios>2.0, using NA thromboplastin, did not appear moreprotective than lower FT ratios and the risks ofthromboemboli with valves in the aortic position,mitral position, or more than one valve seemedcomparable, 0.7 to 2 . 9 / 1 0 0 p a t i e n t - y e a r ~ ~ , ~ , ~ 'Table7> .When antiplatelet agents were administered withanticoagulants, advantageous effects were usual lyshown. Dipyridamole, 400 m d d , in combination withwarfarin, was shown in a prospective randomized trial(level I) to reduce significantly the incidence ofthromboembolism compared with prophylactic treat-me nt w ith warfarin alone. '= Also, a prospective ran-

Table 3- Thromboemboli W ith Bjork-Shifty ConoexoconcaveValoe*No. of Valve NA PT lW100 EvMed Patients Position Ratio Pt-yr Lev Source

Coumarin derivatives 125 Ao 1.6-1.w 0.5 V Sethia et al,= '198651 M 1.9-2.2$ 1.1 V Cortina et al,= 1986228 M 1.6-1.9t 2.1 V Sethia et al,=' 1986118 M 2.0-2.5s 3.0 V Eberlein et al," 199089 >1V 1.6-1.w 2.3 V Sethia et al," 1986

*See Table 1 for explanation of abbreviations.tNorth American prothrombin ratio was estimated from INR assuming an IS1 of 2.2.=$North American prothrombin ratio was calibrated from prothrombin activity (%) using Figure 1 in Hirsh et al."CHEST 1 102 1 4 1 OCTOBER, 1992 1 Supplement 4478



5/13

Table 4- Th do em bo li With St. Jude Aortic Vibes*

Med No. of Valve NA PT TW100 EvPatients Position Ratio Pt-Yr Lev SourceNone 65ASA 325? DIP 225 42ASA 300+ DIP 75-225 52Coumarin derivatives 22147

152290

Baudet et al,= 1985Hartz et al,PR986Ribeiro al," 1986DiSesa et al," 1989Vogt et al,= 1990Horstkotte et al,= 1983Czer et al,'u 1990Kopf et a l,= 1987

*See Table 1 for explanation of abbreviations.?Estimated from author's data.$North American prothrombin ratio was estimated from INR assuming an IS1 of 2.2.5$North American prothrombin ratio was calibrated from prothrombin activity (%) using Figure 1 in Hirsh et al.R71831 pt-yrs before 1987.l(200 pt-yrs after 1987.Table 5- Thnmrboemboli Wi th St. Jude Mitrd vdOe8*

No. of Valve NA PT TE1100 EvMed Patients Position Ratio Pt-Yr Lev SourceNone 10 M 22.2 V Baudet et al,= 1985Coumarin derivatives 159 M 1.5 2.2t V DiSesa et al,n 198932 M 1.6-1.9$ 2.2 I1 Vogt et a , = 1990173 M 2.0-2.59 0.9 IV Horstkotte et al,= 1983217 M 2.0-2.59 3.0 V Eberlein et al," 1990252 M 1.5-2.57 1.9 V Czer et al,@19901.5-2.q1*See Table 1 for explanation of abbreviations.?Estimated from author's data.$North American prothrombin ratio was estimated from INR assuming an IS1 of 2.2.5$North American prothrombin ratio was calibrated from prothrombin activity (9%) using Figure 1 in Hirsh et al.n81831 pt-yrs before 1987.11200 pt-yrs after 1987.

Table 6- Thrvmboemboli With Two or Three St. Jude Vdw8No. of Valve NA PT TEf100 Ev

Med Patients Position Ratio pt-yr Lev SourceNone 3 >1V 91.0 V Baudet et al,= 1985ASA 300+DIP 75-225 15 >1V 10.0 V Ribeiro et d,' 1986Coumarin derivatives 15 >1V 1.6-1.9t 0.0 I1 Vogt et al,= 1990

63 >1V 1.6-2.17 0.9 IV Horstkotte et al,= 198374 >1V 1.5-2.5$ 2.3 V Czer et al,* 19901.5-2.09*See Table 1 for explanation of abbreviations.?North American prothrombin ratio was estimated from INR assuming an IS1 of 2.2.5$1831 pt-yrs before 1987.9200 pt-yrs after 1987.llNorth American prothrombin ratio was calibrated from prothrombin activity (%) using Figure 1 in Hirsh et al.Rdomized trial (level 11) in patients with various types one level I1 study showed no benefit.35of mechanical prosthetic valves indicated a trend Turpie and associate^^^ (level I study), among pa-toward reduction of thromboembolism with warfarin tients with mechanical prosthetic valves or tissueplus dipyridamole compared with warfarin alone or valves at high risk, evaluated the risks and benefits ofwarfarin plus aspirin.= Other prospective randomized warfarin, PT ratio of 1.6 to 2.0 (NA thromboplastin)trials (level 11) also showed advantageous effects of (INR 3.0 to 4 9 , in combination with aspirin, 100mg/warfarin in combination with dipyridamole,33J4 but d , vs anticoagulants alone at the same PT atio. Patients4485 A n t i t h W iTherw, Mechanicaland BiokgicalRw,theb Hsart Vahms (Steineta/)



6/13

Table 7- T h d o e m b o l i W ithMedtronicH d t d *No. of Valve NA PT TE/100 EvPatients Position Ratio Pt-Yr Lev Sou rce

Coum arin derivatives 11716 415 214 316 38352

- Ao 1.5-2.0 0.7 V Vallejo et a l,m 1990Ao 2.0-2.5 2.1 V Beaude t e t al,J1 1986M 1.42 .2t 2 .6 V Cortina e t d ,= 1986M 1.5-2.0 1.5 V Vallejo et al," 1990M 2.0-2.5 2.3 V Beaudet et al,J11986Ao+ M 1.5-2.0 2.9 V Vdlejo et al," 19902V 2.0-2.5 1.4 V Beaudet e t al,311986*See Table 1 for explanation of abbreviations.?North American prothrom bin ratio was calibrated from prothrombin activity (76) sing Figure 1 in H irsh e t al.n

who received warfarin plus aspirin had fewer major in patients in sinus rhythm, the frequencyemboli, 5 of 186 (2.7 percent) VS 13 of 184 (7.1 percent) boemboli among patients who did not receive anti-(P=0.04) (Table 8). More total hemorrhages, however, thrombotic therapy, except for the first six to eightoccurred among Patients with warfarin Plus aspirin, weeks, was 0.2 to 2.9/100 patient-years37- (Table 10).72 of 186 (32.7 Percent) vs 48 of 184 (26.1 Percent) This was comparable to the frequency of thrombo-(p= 0.006); but major hemorrhages were similar in emboli in patients with mechanical prosthetic valvesboth groups, 24 of 186 (12.9 percent) vs 19 of 184 (10.3 who received anticoagulants. The risk of thromboem-Percent) (NS) (Table 9).On the other hand, Chesebro boli with bioprosthetic valves, therefore, is not nil.and associate^,^^ (level 11) among patients with ball ~ ~ ~ i r i ~mong 260 patients and among 185valves treated with warfarin, P'' atio of 1.5 to 2.5 patients reduced the occurrence of thromboemboli to(NA thromboplastin), observed no reduction of throm- ,t 23 and 32 months, respectivelyw,4~ h~ inti-boemboli with the addition of aspirin, 500 mg/d, and dence of thromboemboli in patients in sinus rhythmthere was a significant increase of bleeding (Tables 8 with bioprosthetic valves in the mitral position whoand 9). were treated with warfarin for only eight weeks wasBIOPROSTHETICALVES 1.91100 patient-years.42 Among a few patients withRegarding bioprosthetic valves in the aortic position bioprosthetic valves in the mitral position who re-

Table 8- hnnnboemboli n Patients Treated W ith W a ~ a r i nnd AntiplateletAgents- - - - -Prothrombin Time Ratio*Antiplatelet Agent ThromboemboliNo. of Patients (No./100 pt-yr)

Valve Control Treat Con trol Treat Lev P SourceBall PT 1.7$ PT 1.7 55 3 I1 NS PACTE,= 1978Disk DIP 375Other (n= 154) (n = 136)Ball PT 1.9-2.3 PT 1.9-2.3 15.55 2.2 I


7/13

Table 9-B leedi ng in Patients Treated Wi th Warfarin and Antiplatelet AgentsProthrombin Time Ratio*Antipl;~teletAgerrt Bletdirrg

No , of Patients (h'o./lOO pt-yr)V;tlve Control Trc~at Col~t rol Treat Lev 1) Sor~rce

R;111 IT 1.7$ PT 1.7 - - I I NS PACTE, 1978Disk DIP 375Other (11= 154) ( n = 136)Ball PT 1.9-2.3 PT 1.9-2.3 - - I KS S~rlli\~anbtal," 1969DIP 400

(n = 50) (11 = 12)Ball PT 1.5-2.5 PT 1.5-2.5 1.8 1.6 II N S (:hcsel)ro rt nl." 1983Disk DIP 100(11 = lK3) (11 = 181)

? PT 1.3-1.6t PT 1.3-1.6 - - 1 NS R;~jalr t ; I I , 1980DIP 225-100 -(11 = 87) (11 = 78)

Ball PT 1.3-1.6f PT 1.3-1.6 - - 11 N K~S;I~;II . ;I .1977Disk DIP 1O O(11 = 39) (11= 39)Mech;u~ic;~l I T 1.6-2.0t PT 1.6-2.0 6.9s 7.9 I NS T~rl.l)it>t ill. Y' 1992Bio1~rostt)rt~tic ASA 100( e = 184) (11 = 186)

Bell PT 1.5-2.5 YC 1.5-2 .5 1.8 6.6 I I


8/13

Table 11- hromboemboli and Bleeding in Children and A dolescents W ith Prosthetic Valves*N o . of Valve Vdve TE/lW IlEM/lW

Metl Age Patients Type Position pt-yr pt-yr Lev Sor~rceN o n eNone

AS A 6/kg+D IP 25kgAS A 900+DIP 150AS A 20kg+D IP 5/kgAS A 10kg+D IP 2-5/kgWarfarinPT= 1.5-2.5WarfarinPT= pLVarLirinPT= 1.8-2.7$Warfarinp T = ?LVarfarir~PT= 1.8-2.0

+AS A 150-500

St. Ju d ev;1rious

S t . JudeSt . JudeSt. Jude

Various

\ \ ~ r i o ~ ~ s

V i ~ r i o ~ ~ s\T,iriousS t . JutleVarious

Varior~s

Cirior~s

A o, MA o + MA 0M2 2A 0h.1A o, M2 2Ao . M22A oM22A o , MA o , h.42 2Ao , h.122Ao, hle 2A 0M2 2A o , hf2 2

--Sdde et 1988Rao et a1.I' 1989

Serra et al," 1987

S~)cavc~kt al," 1986El hlakhlor~f t :1I,l7 1987Il;lr;id;~ t dl," 19%)S tewar t et nl,H' 987Rice cBt II.\ ' 1989

*hledic;ition levtbl=rng/d/dayo r ~rlfig/da): See Ti11)le1 li)r explanation of'al,i)reviatioris.tEstimated fron l ; ~ r ~ t h o r \icta.$Nor th America11prothroml)irr ratio \\,;IS ca1il)ratt.d fro111protl~ro~nt,inct ivi ty (% ) 11si11gFigure 1 r l I l i rsh et al."North American prothro111l)inratio w:rs et i rn i~ted ro m I N R ;~\srilning n IS1 of 2.2.5of noncompliance and trauma, there has been a specialeffort to evaluate alter~ latives o warfarin therapy inchildren and adolescents with mechanical prostheticvalves. With no antithrombotic therapy, thro~nboem-boli in children and adolescents with St. Ju de valvesoccurred at a rate of 5.7/100 patient-years""1evel V)(Table 11). Thromboemboli in patients with othertypes of valves, except perhaps when i l l the aorticposition, occurred at a considerably higher rate.sl,F*'-qIn some studies of children and adolescents withvarious types of valves, aspirin plus dipyridamole wasprotective; thromboemboli occurred at a rate of 2.3 to3. 41 00 patient-years.ii."' O ther investigators, employ-ing aspirin plus dipyridamole in youngsters with St.Jude valves or with various other valves, reportedextremely high rates of thro mb oe mb ol is n~ ~~ .' .~ ~Table11).Only coumarin derivatives consistently protectedagainst thromboemboli; the frequency in all studieswas 15.1/100 patient-years~7,x.rd,s:-5~Table 11).Cou-marin derivatives plus aspirin resulted in few throm-boemboli (1.8/1OO patient-years), but only a few pa-

tients were studied.'

Major bleeding with coumarin derivatives in pa-tients with prosthetic hear t valves ranged between 0.7and 6 .3 episodes per 100 patient-years (Table 12). Theinvestigation of Wilson and associatesh seems to showa clear trend toward more bleeding with higher levelsof the PT ratio using NA thromboplastin. At all levelsof the PT ratio, their data showed higher rates ofbleeding than was shown by other inves t iga-t o r ~ . ~ . ~ ~ . ~ . ~ ~ . ~ ~ - ( * T h e i rata, therefore, ar e not includedin Table 12, but they are described separately (Table13). Bleeding was generally not more frequent inchildren and adolescents, 0.8 to 4.01100 patient-years(Table 10).53.5i.5Y mong pat ients older than 70 years,anticoagulant-related hemorrhage was high (9.2/100patient-years) although the PT ratio was not r e p ~ r t e d . ~

Some circumstances, such as noncardinc surgery,CHEST / 102 / 4 / OCTOBER. 1992 / Supplement 451s



9/13

Table 12-Major Anticoagulant-Related HemorrhageNorth American HemorrhageProthrombin Events/ EvidenceRatio 100 pt-yr Level Source1.2-1.6 0 .7 V Butchart et al,"' 19881.3-1.5 1.3 V Kopf et al," 19871.6-1.9' 1.7-2.2 I1 Vogt et al,= 19901.5-2.0 1.5 V Czer et al,= 19901.5-2.0 0.4 V Vallejo et al," 19901.8-2.0 2.7$ IV Rao et al,= 1989(children)1.5-2.5 2.7 V Czer et al," 19901.5-2.5 0. 8 V Spevak et al,571986(children)2.0-2.5t 1.6 V Eberlein et al," 19902.0-2.5 1.2 V Beaudet et al,3119862.0-2.5 1.1 V Callaghan et al," 19862.2-2.7t 2.4 V Lund et al," 19902.5-3.0t 6.3 IV Bjork and Henze," 19792.5-3.0t 1.7 V Gossinger et al,m19%*North American Rothrombin Ratio was estimated from Interna-tional Ratio (INR) assumingan International Sensitivity Index (ISI)of 2.2.'+North American Prothrombin Ratiowas calibrated from Rothrom-bin Activity (46) sing Figure 1 in Hirsh and asso~iates.~$Estimated from author's data.may necessitate the interruption of anticoagulant ther-apy. The discontinuation of treatment with oral anti-coagulant agents one to five days before surgery, withreinstitution as soon as possible in the postoperativepe r i od , has been r e~omrnended . ~~~ome recom-mend t he use of antiplatelet agents during the preop-erative period of increased risk.= Others suggestintravenous infusions of heparin both before and aftersurgery.73

Hospitalizations for patients with prosthetic heartvalves undergoing noncardiac surgery are frequentlyprolonged for intravenous heparin therapy to decreasethe incidence of thromboembolism while patients arenot taking oral anticoagulant agents.74Because the rateof thromboembolic events is quite low and the periodof increased risk is very short, the cost of preventingthese rare events can be great.

Rustad and Myhren (level 111) showed no majordifference in blood loss during cholecystectomy orgastric resection in individuals without prostheticvalves who were ei ther anticoagulated or nonanticoag-u l a t e d . M ~ I n t y r e ~ ~level 111) showed that dentalextractions can be performed safely in individualsTable 13- Major Anticoagulant-Related Hemorrhage*

North American HemorrhageProthmmbin Ratio Events/100 pt-yr

*Evidence Level= IV. Source, Wilson et al,"lQJl.452s A

with a therapeutic level of anticoagulation. Tinker andTarhad9 (level V), in a small retrospective study,showed no difference in thromboembolism betweenpatients who discontinued anticoagulation therapy oneto three days before surgery vs those who did not witheither aortic or mitral prostheses. Katholi andassociates73 level V), however, retrospectively showeda higher rate of postoperative thromboembolism insubjects with a prosthesis in the mitral position vsaortic position when anticoagulant therapy was discon-tinued perioperatively.

It is well known that individuals with a prostheticvalve in the mitral position are more prone to developthromboembolism. Katholi and associates77(level V)found no difference in postoperative thromboembo-lism when anticoagulant therapy was discontinued forthose with aortic prostheses compared with the use ofpreoperative and postoperative heparin in those withmitral prostheses.

After a riskhnefit assessment is made, one canelect to do the following: (1) discontinue warfarintherapy several days before the procedure to allow theIT to return to normal and reinstitute therapy shortlyafter surgery; (2) reduce the warfarin dose so as tomaintain the patient in a lower or subtherapeuticrange during the procedure; or (3)discontinue warfa-rin therapy and institute heparin therapy. Discontinueheparin 2 to 4 h before surgery and reinstitute whenconsidered safe after surgery and follow with oralanticoagulation therapy. The last of these three optionsprovides the shortest interval totally free of anticoag-ulation, but usually requires hospitalization for heparintherapy before surgery. The cost-effectiveness of thispractice, as applied to all patients, has been questionedby Eckman and associate^.^^ They recommend thatonly those patients with the most thrombogenic pros-theses be treated with perioperative heparin, unlesssuch therapy can be given within the confines of thehospitalization required for the procedure.

If reversal of oral anticoagulation needs to beachieved in a more timely manner, small parenteraldoses of vitamin K, are recommended (0.5 to 1 mgIV).78With normal liver function, such therapy shouldsignificantly reduce the PT atio in 12 to 24 h withoutcreating a state of relative warfarin resistance whenanticoagulation is resumed, as might occur with largerdoses of vitamin K,.

For patients who require minimal invasive proce-dures (dental work, superficial biopsies), we recom-mend reducing the level of anticoagulation to the lowor subtherapeutic range briefly, resuming the normaldose of warfarin immediately following the procedure.Perioperative heparin therapy is recommended onlyfor those situations in which the risk of bleeding onanticoagulation and the risk of thromboembolism offanticoagulation is high (major surgery in the set ting of

ntilhrombdlcTherapy Mechenical andBbbgkalRosmetic Heart Valves (Steinel a/ )



10/13

a mitral valve prosthesis). For situations between thesetwo extremes, physicians must assess the risklbenefitof reduced anticoagulation vs perioperative heparintherapy.

SUMMARYMechanical A-osthetic Heart Valves

1. Long-term (permanent) warfarin therapy offersthe most consistent protection.

2. Doses of warfarin that increase the PT ratio toan INR greater than 4.5 are associated with excessivebleeding.

3. Levels of warfarin that prolong the PT ratio toan INR of 1.8 or less appear to lead to a high risk ofthromboembolic events3 (level 11).

4. Levels of warfarin that prolong the PT ratio toan INR of 2.5 to 3 .5 are as satisfactory for tilting diskvalves as higher levels (level I1 and V s t ~ d i e s ) . ~ ' . ~ ~ . ~ ~ . ~ ~

5. Experience in patients with ball valves with aPT ratio below an INR of 4.5 is sparse3 (level 11).Levels of warfarin that prolong the PT ratio to an INRof 2.2 to 3 .3 are probably adequate for ball valves aswell as tilting disk valves3 (level 11).

6. Dipyridamole (375 to 400 mud) in addition towarfarin may have an additive benefit (level I, 11), 3 3 3although beneficial effects sometimes were nots h o ~ n ~ * . ~ ~level 11). Bleeding was not increased withdipyridamole

7. Aspirin (100 mg/d) in addition to warfarin PTratio (INR) 3.0 to 4.5 may have an additive effectwithout greatly increasing the risk of bleeding36 (levelI). However, no benefit, as well as increased bleeding,was shown with aspirin 500 mg/d plus warfarin PTratio (INR) 2.5 to 7.832 level 11).8. Antiplatelet agents alone may offer satisfactoryprotection in patients in sinus rhythm with St. Judevalves in the aortic p o ~ i t i o n ~ , ~ ~level 111, V), but goodresults were inconsistent. Antiplatelet agents alonewith the standard Bjork-Shiley valve showed unsatis-factory resultslg (level IV).

9. Among patients with bioprosthetic valves in themitral position less intense warfarin therapy (PT ratiowith an INR of 2.0 to 2.25) was as effective as a moreintense regimen (INR 2.5 to 4.5) but was associatedwith fewer bleeding complication^^^ (level I).

RECOMMENDATTONSMechanical hsthetic Heart Values1. It is strongly recommended that all patients withmechanical prosthetic heart valves receive warfarin

therapy (grade C recommendation based on level Vevidence).2. Levels of warfarin that prolong the INR to 2.5 to3.5are recommended3.e'~"-m*8elevel 11,V).3. Aspirin, 160mdd, in addition to warfarin (INR

3.0 to 4.5) may offer additional protection withoutincreased risk. This is extrapolated from Turpie andassociates38 (level I). However, aspirin, 500 mdd, inaddition to warfarin, PT ratio (INR) of 2.5 to 7.8,caused increased bleeding, and efficacy was nots h o e level 11).4. Dipyridarnole (400mdd) in addition towarfarinmay be considered for additional protection, becausesome studies have shown an additive benefit*.= (levelI), although one level I1 study showed no benefit? andone level I1 study showed only a trend."5. Patients with mechanical prosthetic heart valveswho suffer systemic embolism despite adequate ther-apy with warfarin may benefit from aspirin, 160 mg/d, in addition to warfarins (level I). Dipyridamole,400 mdd, in addition to warfarin, is an alternativeo p t i ~ n ' ~ . ~level I). These recommendationsare basedon extrapolations of results in patients who did nothave emboli.

6. When full-dose warfarin therapy is contraindi-cated, long-term therapy with warEarin sdc ien t toincrease the INR 2.0 to 3.0 in combination withdipyridamole, 150mdd, and aspirin, 660 mgld, maybe used4 (level 11). Whether aspirin, 160 m#d, incombination with warfarin at an INR of 2.0 to 3.0 iseffective, is undetermined, and its use would be anextrapolationof results obtained with an INR of3.0 to4.5 and aspirin, 100 mdd, among patients with me-chanical and bioprosthetic valves who were at a highrisk of embolisms (level I).BiupmstheticHeart Mws1. It is recommended that all patients with bio-prosthetic valves in the mitral position be treated for

the first three months after valve insertion with lessintense warfarin therapy (INR 2.0 to 3.0). This gradeA recommendation is based on one level I study."Anticoagulant therapy of patients with bioprostheticvalves in the aortic position who are in sinus rhythmis optional during the &st three months.2. It is recommended that patients with biopros-thetic valves who have atrial fibrillation be treatedwith long-term warfarin therapy with a dose sutficientto prolong the INR to 2.0 to 3.0. This grade Crecommendation is based on level n7 evidence.3. It is recommended that patients with biopms-thetic valves who have evidence of a left atrial throm-

bus at surgery be treated with long-term warfarintherapy with a dose sufficient to prolong the INR to2.0 to 3.0. The duration is uncertain. This grade Crecommendation is based on level N evidence.4. It is recommended that patients with biopms-thetic valves who had a history of systemic embolismbe treated with long-term warfarin therapy. The PTratio and duration are uncertain. The consensus is totreat with warfarin for 3 to 12 months with doses

CHEST 1 102 1 4 I OCTOBER. 1992 1 Sumemen1 453s



11/13

sllflclent to prolong the INR to 2.0 to 3.0,This gradeC mmmenda t ion is based on level 1V widenee.

5. Among patients with bioprosthetic valves whoare in sinus rhythm, long-term therapy with aspirin,3 E m$d, may offer protectior~against thromboem-h l i s m and may he cansidered uptional un the hasisofone level IV shldYa

1 Stein PD, Collins JJ, Kantrnwik A. Antithrombotic therapy inmechanical and biological prosthetic heart valves and saphenousvein bypass grafts. Chest 1986; 89(suppl):46S-53s2 Stein PD, Kantrowik A. Antithrombotic therapy in mechanicaland biological prosthetic hear t valves and saphenous vein bypassgrafts. Chest 1989; 95(suppl):lMS-117s3 Saour JN, Sieck JO, Rahim Mamo LA, et al. Trial of differentintensities of anticoagulation in patients with prosthetic heartvalves. N E n d J Med 1990; 322:42&324 Alhnan R, Rouvier J, Gurfinkel E, et al. Comparison d wolevels of anticoagulant therapy in patients with substitute heartvalves. J Thorac Cardiovasc Surg 1991; 101:427-315 Hinh J, Poller L, Deykin D, et al. Optimal therapelltic rangefor oral anticoagulants. Chest 1989; 95(suppl):5S-11s

6 Wilson DB, Dunn MI, Hassanein K. Low intensity anticoagu-lation in mechanical cardiac prosthetic valves. Chest 1991;100:1553-577 Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention of prostheticheart valve thrnmboembolism: a prospective randomized clinicaltrial. Circulation 1985; 72:1059& -8 Hinh J, Deykin D, Poller L. Therapeutic range for oralanticoagulant therapy. Chest 1986; 89(suppl):llS-15s

9 Dale J. Arterial thromboembnlic complications in patients withStamEdwards aortic ball valve prostheses. Am Heart J 1976;9165.3-5910 Dale J, Myhre E, Storstein 0 , e t al. Prevention of arterialthromboembolism with acetylsalicylic acid: a controlled clinicalstudy in patients with aortic ball valves. Am Heart J 1977;94:lOl-11

11 Yeh TJ. nabtawi IN, Cornett VE, et al. Influence of rhythmand anticoagulation upon the incidence of embolization associ-ated with Starr-Edwards prostheses. Circulation 1967; 35-36(suppl 1):I-77-8112 Duvnisin GE, Brandenburg RO, McCnnn DC. Factors affectingthn)mboembolism associated with prosthetic heart valves. Cir-culation 1967; 3536(suppl 1):I-70-7613 Sullivan JM, Harken DE, Gnrlin R. Effect of dipyridamole onthe incidence of arterial emboli after cardiac valve replacement.Circulation 1969; 39-40(suppl 1):I-1441-15314 Fuster C: Pumphrey CW, McGoon MD, et al. Systemic throm-boembolism in mitral and aortic StamEdwards pmstheses: a10-19 year follow-up. Circulation 1982; 66(suppl 1):I-157-16115 Dale J, Myhre E . Can acetylsalicylic acid alone prevent arterialthromboembolism: a pilot study in patients with aortic ball valveprostheses. Acta Med Scand 1981; 645:73-716 Moggio RA.Hammond GL, Stansel HC Jr, et al. Incidence ofemboli with cloth-covered Starr-Edwards valve without antico-agulation and with varying forms of anticoagulation: analysis of183 patients followed for 3% years. J Thorac Cardiovasc Surg1978; 75:296-9917 El Makhlouf A, Friedli B, Oherhansli I , et al. Prosthetic heartvalve replacement in children. J Thorac Cardiovasc Surg 1987;93:80-518 Altman R, Bo~~llon,Rouvier J, et al. Aspirin and pmphylaxisof thrnmboemholic complications in patients with substitute

heart valves. J Thorac Cardiovasc Sure; 1976; 72:127-2919 Bjork VO, Henze A. Management of thmmb n-embl ism afteraortic valve replacement with the Bjork-Shiley tilting disc valve.Scand J Thorac Cardiovasc Surg 1975; 9:183-9120 Bjork VO, Henze A. Ten years' experience with the Bjork-Shileytilting disc valve. J Thorac Cardiovasc Surg 1979; 78:331-4221 Sethia B, Turner MA, Lewis S, et al. For~rteen ears' experiencewith the Bjork-Shiley tilting disc prosthesis. J Thorac CardiovascSurg 1986; 91:350-6122 Vogt S, Hoffmann A, Roth J, et al. Heart valve replacement withthe Bjork-Shiley and St. Jude Medical prostheses: a randomizedcomparison in 178 patients. Erlr Heart J 1990; 11:583-9123 Horstkotte D, Korfer R, Seipel L, et al. Late complications inpatients with Bjork-Shiley and St. Jude Medical heart valve

replacement. Circulation 1983;68(suppI 2):II-7524 Eberlein U, von der Emde J, Rein J, et al. Thrnmbc~mbnlicand bleeding complications after mitral valve replacvment. E I I ~

J Cardiothor Surg 1990; 4:605-1225 Cortina JM, Martinell J, Artiz C: et al. Comparative clinicalresults with Omniscience (STMl), Medtmnic-Hall, and Bjork-Shiley convexo-concave (70 degrees) prostheses in mitral valvereplacement. J Thorac Cardiovasc Surg 1986; 91:174-8326 Baudet EM, Oca CC, Rcqoes XF, t al. A 5% year experiencvwith the St. Jude medical cardiac valve prosthesis. J ThoracCardiovasc Surg 1985; 90:137-4427 DiSesaVJ, Collins JJ Jr. Cohn LH. 1Iemato;c)gical cnmplications

with the St. Ju de valve and redr~cwl-dose numadin. Ann ThoracSurg 1989; 48:280-8328 Hartz RS, LoCicero J 111, Kucich C: et al. Comparative study ofwarfarin versus antiplatelet therapy in patients with a St. Judemedical valve in the aortic position. J Thorac Cardinvasc Surg1986; 92:684-9029 Riheiro PA, Al Zaibag MA, ldri s M, e t al. Antiplatelet drugsand the incidence of thromboembolic complications of the St.Jude medical aortic prosthesis in patients with rhenmatic heartdisease. J Thorac Cardiovasc Surg 1986; 91:92-830 Vallejo JL, Gonzalez-Santos JM, Alhertos J, et al. Eight years'experience with the Medtronic-IIall valve prosthesis. AnnThorac Surg 1990; 50:429-3631 Beaudet RL, Poirier NL, Doyle D, et al. The Medtrnnic-Hallcardiac valve: 7% years' clinical experience. Ann Thorac Surg

1986; 42:644-5032 Chesebro JH, Fuster \! Elveback LR, et al. Trial of combinedwarfarin plus dipyridamole or aspirin therapy in prosthetic heartvalve replacvment: danger of aspirin compared with dipyrida-mole. Am J Cardiol 1983; 51:1537-4133 Kasahara T. Clinical effect of dipyridamole ingestion aRerprosthetic heart valve replacement-especially on the blnodcnag~lation ystem. Nippon Kyobr~Geka Gakkai Zasshi 1977;

25:1007-2134 Rajah SM, Sreeharan N. Joseph A, et al. Prospective trial ofdipyridamole and warfarin in heart valve patients [abstract].Acta Thera (Brussels) 1980: 65435 Groupe de recherche P.A.C.T.E. Prevention des accidentsthrombo-emlmliques systemiques chez les pnrteun de pmthesesvalvulaires artificielles. Coeur 1978; 9:915-6936 Turpie AGG, Gent M, Laupacis A, et al. Reduction in mortalityby adding aspirin (100 mg) to oral antict~agulants n patientswith heart valve replacement. [abstract]. J Am Call Cardiol1992; 19(soppl A):103A37 Cohn LH, Allred EN, DiSesa VJ, et al. Early and late risk of

aortic valve replacement: a 12-year cwnmmitant cumparison t~ fthe porcine biopn~sthetic nd tilting disc prosthetic aortic valves.J Thorac Cardiovasc Surg 1984; 88:695-70538 Bolooki H. Kaiser CA , Mallon SM, et al. Comparison of long-term results of CarpentierEdwards and Elancock I~ioprostheticvalves. Ann Thorac Surg 1986; 42:4M-99

4545 AntithromboticTherw. Mechanical and Biokg i i l -tic Heart Valves (Steinet el)



12/13

39 H 1c~)mfield I! Kitchin AH , Whe atley DJ. et al. A pros1wctivc~e v a l ~ ~ a t i o nf the Rjork-Shile); Han ctck . and (:;trl)t.l~tic~r-Etl-war ds hear t v:llve prosthe ses. (;irculation 19%: 73:12 13-2240 Nt111e.t L. Ag~~iadoM , C e le m i n D , e t al . A sp ir in o r c u a ~ n ~ ; ~ t l i ~ ~as the t lr t lg of clloice for valve replacer~~el~tvith porcir~e1)ioprosthesis. Ann Th orac Su rg 1982: 33354-5 841 Nunez L, A g ~ l a d oG M , L a rr e a JI,, e t a l. P r e v e ~ ~ t i o ~ ~f th ro rn -tmmhnlism using aspirin after mitral valve replacement withporcine 1)ioprosthesis. Ann Th orac S urg 1984; 37:84-742 Cohn LI1, Allred EN. Cohn LA , et al . Early a t~t l ate r isk of

mitral valve replacement. J Thorac Cardiovasc Surg 198.5;W:872-8 143 Gonm lex-Lavin I,. Ch i S. Blair TC. t a l . T h r o m l n ~ e m l n ~ l i s n ~and bleeding after mitral valve replacement with pwcine viilves:influence of thrornt w~ mbo lic isk factors. J Surg Res 1984;3 6 : W - 1 544 Williams JR, Karp RB, Kirklin J\v e t a l . Cor~s ide ra t ions llselection and management of patients undergoing valve replace-ment with glntaraldehyde-fixed porcine bioprostl~es rs. An11Thorac Surg 1980: 30:247-58

45 Gon7.lez-Lavin L, Tandon AE! Chi S , e t :11. The risk oftl~r oml wm nhol isln nd hemo rrhag e following mitral v;llvc. re-p l a c e m e ~ ~ t .Thorac Carditwasc Srlrg 1W;87:340-5146 I ie tze r R . Tn~a l id isT. Bors t I IG. Th rom ln~ ml w) l i s l ~~nd.anticoagr~la tion after isolated mitral valve re placem ent with

porcine he temgrafts. In: Cohn L II , Ga1luru.i V, e ds . P n ~ e e d i n g s ,Second International Symposinm on Cardiac Biop rostl ~t~s t~s.New, %)rk: Ynrke M edical Books, 1982; 170-7247 Oyer PE . Stinson EB , Grie pp RB, et at . Valve replacerncr~tvitllthe S ta r rEdw~ ards nd I ianm ck p ros theses : com1~wet iveanal! -sis t)f late morhidity and mortality. Ann Surg 1977: 186:301-09

48 1onesc11h l l , Smi th DR, Hasan SS , e t a l . C l in ica l d~~ rah i l i t yfthe pericardial xenograft valve: ten years experienc e with ~n itra lreplacem ent. Ann Thora c Sorg 1982; 34:265-7749 Magilligan DJ Jr, Lewis JW Jr, 'Iilley B, et al. Th e p)r ci ne1)ioprosthetic valve-helve yean later. J Thorac Cardiovilsc Surg1985; 89:499-50750 Turpie A CG, Gu nstensen J , H irsh J, e t HI. Rando~n ised ornpar-ison of two intensities of oral anticoagulant therapy after tissue

heart valve replacem ent. Lancet 1988: 1:1242-4551 Hobbins RC , Bowman FO Jr, Malm JR . Car diac valve rc~p1ar.t.-me nt in ch ildren: a 20-year s eries. Ann Thofile Surg 1988; 45:,56-6 152 Sade RM , Crawford FA Jr, Fyfe DA, e t al. Xtlve prostheses inchild ren: a rea ssessmen t of anticwagulation. J Thorac CardioviiscSrlrg 1988: 95:.553-61

53 R;lo PS, Solyn~arL, hlardini M K, et al . Anticoagi~lant l~c.r :~~)yin children with prosthetic valves. Ann Thorac Sr~rg 1989;47:589-92

54 Stein D\V, Rahimttw)la SIT, Kloster FE, et al. Throln1n)ticl ~ h e n o n i e n a with nnnanticoagulated, compc)site-strut icorticprostl~eses. Thorac Cardiovasc Sr ~r g 976: 71:680-8455 Serfii AJS, MeNicholas KW, Olivier H F Jr, et al. The choice. ofantic~)agulatiol~n pediatric patients with the St. Jr~ tl r ledic;~lvalve prostheses. J Cardiovasc Surg 1007: 28 :M -9 156 McGrath L B , G o n 7 ~ l r z - L a v i nL , E ld redge WJ, e t a l. Thro l~ r -

tn)e~nln)lic nd othe r even ts following valve replacement il l ;Ipediatric population treated with antiplatelet agents. AIIII horacStlrg 1987; 43:U15-8757 Spevak PJ, Freed M D , Castaneda AR. et al . Valve repl;ice ~~le ntin cltildrrri less than 5 yew s of age. J Ani C:ardiol 1986; 8:N )I-

08FiX 1Ia rada Y, lmai K P ~ ~ r o s a u . a1, et a l. Te n-ye ar fi )llow-ill) ;tI'tc.r

\;11vc> r t~ l ) l ; ~cc ~~n tv~ tit11 the. St. J i~ (le l t~(lic;11 )r ~~ \t l~ t> si %11c l ~ i l ( l r c ~ ~ ~ .Tl~ oriic :;~rcIiov;~sc11rg l$NO; lo() :175-80*59 S t e w i ~ r t , C i i i ~ ~ c i o t t ; ~1.A I ~ \ X S O I I:. et i l l . ' l ' l~t ,O I I ~ - I ( - ~ I I I isk a p t '

. ,in c11iIdre11il'ter pro sth t~t ic ;tr(Ii;ic, i ; iI \( . r t ~ l ) l ; ~ c c ~ ~ ~ ~ ~ ~ ~ ~ t .' l ' l ~ o r i ~ c(:iirdiovas Srtrp 1987; 93:551-51HI \\Vcnnls A. C!.irg:ls J, Brrri (;, t*t ;tl. ,2l1titl1ror11lw)tiClt('rill)y inc l ~ i l d r e l ~nd ;tdolrscents. Tllrornl) Rrs 1986; 42:289-3016 1 H ~ ~ t c l ~ a r tG . Lewis PA. r io ~~ sltllw~licC C ( * I I ~ \ t*s l) ite, Iow i~~ t ta~ ~s i t !

; t ~ ~ t i ( ~ o ~ i g t ~ I a t i o ~ ~ .i r c l ~ l ; ~ t i o r ~988: 78(\11ppl1):I-M-1-7762 li11pf ( ;S . I l an ~n ~o nd;I,. Cieh;~AS. (4 i l l . 1,ong-tt.r111 t,rli)r~l~-; I I I ~ ( .of the St. 111dch.lt.tlica1 \;lI\(.: Io\v i ~ ~ c i t l r r ~ c vf t111o111lw)-e1111w)lis11incl h t ~ n ~ o r r l ~ ; ~ g i cu ) ~ t ~ p I i c ~ ~ t i o ~ ~ \it11 I I I ~ K I ( ~ \ ~lo\t-s fwi~rf;tr i~l. i r c i ~ l i ~ t i o ~ ~987; 76(s11ppl 3):llI-132

K3 ( ; ~ r SC , (:II;IIIX A, hlatloff' Jh l, rt ;)I. 'li.~~-!ct;~r%\l)c-ri t-~~ct.\vith t he St. Jrldc*hlcdical v;~lve )r prlnl;ir! \ .11\e r ~ ~ ~ ) l . ~ c . t ~ l ~ ~ t -J Thorac (;ardiovasc S l~ rg 990: 100:44-5564 Chllaghan JC , Tt,i jeira FJ. Ro n ne a ~~1. cat al. A f i v r !~.;II stud!

of the incidenrv of valve-related colnplications with t11(%O I I I I I ~ -scie nce c:irtli;tc prosthr sis. J (:ardio\itsc Sul-g 1986; 27.X)O-0265 L,l~ncl0 , Pileg;t;lrtl IiK . Magnr~ss'n P , cbt ll . L A ) I I ~ - ~ ~ ~ I - I I Iro\-thesis-related ;tntl sll dde ~l ardiac-re1:ittvl comp lic;tt it~t~ \tftervalve repl;~ce.lncr~tor aortic strn~)sis .Ann 7'11oriic 51 1r g I%fiM):50:3%-406

66 Borkon MA. So~lleLM . H ang hn ~an k1,. (4 ;it. At)rtic \alvcas r lec t io r~n th e eldrrly paticbnt. AIIII ho ri~ c l ~r g 988. 1A:270---I67


13/13

DOI 10.1378/chest.102.4_Supplement.445S1992;102; 445S-455SChest

and A. G. G. TurpiePaul D. Stein, Joseph S. Alpert, Jack Copeland, James E. Dalen, Steven Goldman

Prosthetic Heart ValvesAntithrombotic Therapy in Patients With Mechanical and Biological

December 13, 2010This information is current as of

http://chestjournal.chestpubs.org/content/102/4_Supplement/445SUpdated Information and services can be found at:

Updated Information & Services

http://www.chestpubs.org/site/misc/reprints.xhtmlonline at:Information about reproducing this article in parts (figures, tables) or in its entirety can be foundPermissions & Licensing

http://www.chestpubs.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

Reprints

the right of the online article.Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to

Citation Alerts

slide format. See any online figure for directions.articles can be downloaded for teaching purposes in PowerPointCHESTFigures that appear in

Images in PowerPoint format
http://chestjournal.chestpubs.org/content/102/4_Supplement/445Shttp://chestjournal.chestpubs.org/content/102/4_Supplement/445Shttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://chestjournal.chestpubs.org/content/102/4_Supplement/445S

Documents

coumadin in prosthetic valves