Oral anticoagulation in peripheral vascular surgery: how intense, for how long, or at all?

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1 Journl of Internl Medicine 1999; 245: 389]397 MINISYMPOSIUM Orl nticogultion in peripherl vsculr surgery: how intense, for how long, or t ll? G. KRETSCHMER & T. J. HOÈ LZENBEIN From the Deprtment of Vsculr Surgery, University of Vienn, Medicl School, Vienn, Austri nd the L. Boltzmnn Institute of Interdisciplinry Reserch in Vsculr Medicine Abstrct. Kretschmer G, HoÈlzenbein TH (Medicl School, University of Vienn, Austri). Orl nticogultion in peripherl vsculr surgery: how intense, for how long, or t ll? (Minisymposium: orl nticogulnts). J Intern Med 1999; 245: 389]397. To evlute the influence of postopertive phrmcotherpy (ntipltelet therpy with cetylslicylic cid (ASA) or orl nticogultion) following vrious peripherl vsculr surgicl interventions (femoro-poplitel reconstruction, femoro-popliteotibil venous bypss;) two clinicl series of ptients were nlysed (A1]2) nd we mde the hypothesis tht djuvnt therpy my be beneficil. Therefter two clinicl trils were crried out (B1]2), to ssess the vlue of postopertive ntiggregnt nd nticogulnt tretment. It ws not possible to demonstrte ny influence of ASA on improving ptency t the ilico-poplitel level or on ptient survivl. It ws concluded tht the ASA dosge of 1500 mg dily ws too high, nd produced severe side-effects, probbly leding to insufficient ptient complince to therpy. In the B2 tril 130 ptients received femoro-poplitel bove- or below-knee vein bypss, nd were ssigned to the therpy group (n = 66) nd treted with nticogulnts or to the control group (n = 64) which received no therpy. During the follow-up, for mximum of 10 yers, the probbility of bypss function, limb slvge nd ptient survivl were significntly in fvour of the tretment. The described single centre clinicl tril B-2 produced in ccordnce with other trils level II evidence in fvour of postopertive phrmcotherpy. Level 1 trils ssessing the direct comprison of ntiggregnt versus nticogulnt therpy re underwy, but results re unvilble yet, similrly the results of the Antithrombotic Trilist's Collbortion (ATT) re currently unknown. Keywords: ntipltelet tretment, clinicl trils, orl nticogultion, peripherl rteril disese, postopertive phrmcotherpy. Introduction Atherosclerosis is the most common cuse of chronic peripherl occlusive rteril disese. The im of the therpy is to prevent or eliminte ischemic symptoms nd tissue loss, counterct progression to rteril occlusion nd nticipte thrombotic]reocclusive complictions following vsculr reconstructions nd other interventions [1]3]. Below the inguinl ligment bypss grfting, employing utologous vein, hs evolved to the stndrd of cre. Long-term observtions covering time periods of 5 nd 10 yers re t hnd. # 1999 Blckwell Science Ltd 389

2 390 G. KRETSCHMER & T. J. HOÈ LZENBEIN: IN PERIPHERAL VASCULAR SURGERY Nevertheless, such utologous vsculr conduits either in femoro- distl or orto-coronry position show substntil rtes of reoblitertion [4]. Due to the limited vilbility of high qulity utologous conduits, it is resonble policy to try to mintin ptency, employing ny form of postopertive phrmcotherpy s soon s primry function is chieved. In ddition, it my be prticulrly importnt to tret ll `difficult' grfts (e.g. very distl crurl or pedl grfts or composite conduits constructed with veins hrvested from so clled lterntive sources) ccordingly. The need for peripherl bypss surgery is n ominous sign of the underlying therosclerotic process nd such ptients re t substntil risk of experiencing vrious forms of vsculr events, especilly in the myocrdil nd cerebrl vsculture. Compring the probbility of grft function to postopertive ptient survivl, it is obvious tht beyond the third postopertive yer more ptients lose their lives thn grfts tend to reocclude. Both spects, grft ptency s well s ptient survivl, hve to be considered when selecting the most pproprite type nd durtion of phrmcotherpy in these vsculr ptients [5]. The problem Vrious investigtors hve discussed the problem of postinterventionl djunctive phrmcotherpy in peripherl vsculr surgery [3, 5]8]. In order to develop widely ccepted recommendtions for clinicl mngement `rules of evidence' hve to be generted. So clled level 1 evidence (most scientificlly sound) must be bsed on preferbly more thn one rndomized clinicl tril hving enrolled lrge numbers of ptients nd hving delivered results independently, which re usully definite [9]. Such trils nswering in direct comprison the specific question posed in the hed line re currently, to our knowledge, not vilble. Ptients, methods nd results In 1965 the Deprtment of Vsculr Surgery in Vienn initited computer-ssisted Documenttion System designed by Piz nd continued by Wgner, devoted especilly to vsculr surgicl opertions nd it is still in use [10]. Bsed upon tht system vrious nlyses of the clinicl series s well s clinicl trils hve subsequently been crried out, which re briefly summrized herein. Anlyses of the clinicl series (A-1 ] A-2) Clinicl series A-1. During the period 1970] bove-knee reconstructions were crried out, using either the reversed utologous sphenous vein (n = 379), lloplstic grfts (n = 178) or long distnce thrombendrterectomies in the semiclosed technique (n = 49). Immedite occlusions were excluded from nlysis, becuse we intended to test the vlue of long-term phrmcotherpy nd wnted to omit ny opertive technicl influence of the vrious procedures [11]. The results re summrized in Tbles 1 nd 2 in terms of ptency nd survivl, respectively. Clinicl series A-2. During the 20 yers 1970]90 the results of femoro]popliteo (bove- nd belowknee) ]tibil reversed utologous vein grfts (n = 712) were ssessed with prticulr emphsis on postopertive phrmcotherpy [12]14]. A brief summry of the results is shown in Tbles 1 nd 2. Both nlyses demonstrted the positive influence of postopertive phrmcotherpy (nticogulnts or ntiggregnts) in regrd to ptency nd ptient survivl. Clinicl trils (B-1 ] B-2) Clinicl tril B-1. To determine the vlue of ASA following vsculr reconstructive surgery in the ilico-femoro]poplitel level 298 ptients were recruited during the yers 1971]74 nd llocted t rndom to the therpy group (n = 148) receiving ASA, mg per dy, or the control group (n = 150), which ws left without ntithrombotic mediction. The finl ssessment of the tril ws done by October Primry ptency s well s ptient survivl were used s finl end-points for evlution but, disppointingly, it ws impossible to demonstrte ny prophylctic influence [15]18] (Tble 3). Clinicl tril B-2. Following implnttion of reversed utologous vein grft below- or bove-knee position for femoro]poplitel therosclerosis 130 ptients were postopertively ssigned to either the therpy group (n = 66) or the untreted control

3 MINISYMPOSIUM: ORAL ANTICOAGULANTS 391 Tble 1 Femoro-distl (bove- nd below-knee) reconstructions (SVBG, ABG, TEA); proportionl hzrds regression model; probbility of function (primry ptency without immedite occlusions) Vribles No. of observtions P-vlue Reltive risk Above-knee reconstructions SVBG n 379 (n 606) A 1 [11] ABG n 178 TEA n 49 SVBG ABG TEA Clinicl sttus prior to reconstruction F II/II III n 315 F III/IV n 291 F III/IV F II/III Postopertive phrmcotherpy (ASA, AC) no n 269 yes n 337 no yes Femoro-distl reconstructions bove-knee n 272 (n 712) A 2 [12 14] below-knee n 261 (SVBG, bove-knee, below-knee, tibil) tibil n 179 Clinicl sttus prior to reconstruction F II/II III n 315 F III/IV n 397 F III/IV F II/III Postopertive AC therpy no n 327 yes n 385 no yes The worst group in ech vrible is listed furthest to the left. b SVBG, sphenous vein bypss grft; ABG, lloplstic bypss grft; TEA, long-distnce thrombendrterectomy; F II, intermittent cludiction; F II/III, very limited wlking distnce, disbling cludiction; F III, rest pin; F IV, gngrene; F, Fontine s clssifiction [42], ASA, cetylslicylic cid, AC, nticogulnt tretment; A-1, A-2, see text. group (n = 64). In the therpy group ptients were treted with orl nticogulnts (phenprocoumon tblets contining 3 mg), trgeted t 5]12% for the Thrombotest vlues. Finl evlution ws performed in Primry ptency, limb loss nd ptient survivl were the end-points of the study. The positive effects of nticogulnt tretment on ptient survivl, irrespective of grft performnce, were originlly published in 1988 [19]. The long-term results regrding primry ptency, limb slvge nd survivl were lso significntly better in the treted group [20] (Tble 4). Sttisticl methods Informtion concerning course of the disese nd detils of the therpeutic interventions ws obtined using the documenttion system [10] of the Austrin Society of Vsculr Surgery in modified form (180 vribles per surgicl procedure, more thn procedures hve been stored since 1965). Sttisticl procedures were crried out with n IBM 4381 min frme computer t the Medicl Fculty of the University of Vienn. For dt storge nd retrievl SAS Softwre ws used. The BMDP ] 1L progrmme (the Biomedicl Dixon Progrmme 1L, where L stnds for life) llowed to ssess probbilities of function nd survivl. Tretment ssignment ws performed by mens of dptive rndomiztion in ll trils [21] except in B- 1, in which contingency tbles ccording to Ku & KullbÈck were used [22, 23]. Survivl rtes were estimted using the Kpln]Meier method [24], possible sttisticl differences were clculted with the tests of Breslow [25] nd Mntel [26] in two-tiled mnner. In ll nlyses the intention to tret principle ws employed [27]. The Cox proportionl hzrds regression model [28], s implemented in the BMDP ] 2L progrmme, ws used to select those fctors independently ffecting vrious hzrds (ptency nd, most importntly, survivl). The most recent informtion regrding the survivl sttus of the ptients ws obtined from the Austrin Centrl Bureu of Sttistics, Vienn, t lest once yer. In Austri under the `Act on Reporting Residency' residents re obliged to report

4 392 G. KRETSCHMER & T. J. HOÈ LZENBEIN: IN PERIPHERAL VASCULAR SURGERY Tble 2 Femoro-distl (bove- nd below-knee) reconstructions (SVBG, ABG, TEA) proportionl hzrds regression model; probbility ptient survivl (without immedite occlusions) Vribles No. of observtions P-vlue Reltive risk Above-knee reconstructions SVBG n 379 (n 606) A 1 [11] ABG n 178 TEA n 49 SVBG ABG TEA Age groups (yers) 65 n n n 82 65, 55 65, Clinicl sttus prior to reconstruction F II/III n 315 F III/IV n 291 F III/IV F II/III Postopertive AC therpy no n 269 yes n 337 no yes Femoro-distl reconstructions bove-knee n 272 (n 712) A 2 [12 14] below-knee n 261 (SVBG, bove-knee, below-knee, tibil) tibil n 179 Clinicl sttus prior to reconstruction F III/IV F II/III Age groups 65 n n n , 55 65, Postopertive AC therpy no n 327 yes n 385 no yes The worst group in ech vrible is listed furthest to the left. b SVBG, sphenous vein bypss grft; ABG, lloplstic bypss grft; TEA, long-distnce thrombendrterectomy; F II, III, IV, Fontine s clssifiction [42]; ASA, cetylslicylic cid; AC, nticogulnt tretment; A 1, A 2, see text; sttistics, see [23 27]. their plce of residence nd ll chnges thereof to the locl uthorities or to the police. In ddition, if ptient dies in public hospitl, the director of the clinic or the physicin who performed the coroner's inquest, hs to report the cuse of deth to the locl uthorities, who will pss this informtion on to the Austrin Centrl Bureu of Sttistics. This leds to n estimted post-mortem exmintion rte of 70]75%, thereby rendering vilble ccurte informtion bout ptient survivl nd cuses of deth. Discussion In oblitertive rteril lesions thrombosis is the finl event in the progression of the disese. The most obvious drugs for prevention re gents which either inhibit pltelet ggregtion, dhesion or both or, on the other hnd, demonstrte n nticogulnt ction like heprin nd coumrin derivtives. It hs been conclusively demonstrted tht ntiggregnts re beneficil in the secondry prevention of vsculr disese [29]. The peripherl vsculr bypss seemed to be n excellent model to evlute ntithrombotic therpy, becuse primry end-points like grft ptency nd limb loss re esy to define even without ngiogrphy. Furthermore, there is usully only one grft per ptient (in contrst to coronry revsculriztions), which simplifies sttisticl nlysis. Nevertheless, mny more trils hve been conducted in ptients receiving ortocoronry grfts. The question remins whether it is cceptble to extrpolte results from coronry to peripherl vsculr surgery [30]. An often debted difference might be t wht point it is best to commence phrmcotherpy: prior to

5 MINISYMPOSIUM: ORAL ANTICOAGULANTS 393 Tble 3 Clinicl tril, B 1; rndomized, but not plcebo-controlled; intention to tret principle, Breslow s nd Mntel s tests (two- tiled) Recruited Finlly evluted Vribles Prophylxis ( ) (Oct 1989) % ptency % survivl ASA Ilico-fem-pop reconstructions B 1 [16, 17] C P NS P NS ASA, spirin dosge: 1500 mg per dy; C, untreted controls; B 1, see text. surgery, s soon s possible fter the procedure or lter during the postopertive period. The debte seems to continue, becuse other fctors thn djuvnt therpy might be of decisive influence in the development of grft reocclusion; technicl fctors, like qulity of the vsculr substitute (utologous vein, lloplstic grfts), techniques of vein preprtion, length of the conduit to bridge the lesion, veins hrvested from lternte sources [31] nd sttus of the run-off hve to be considered. But even if it still remined impossible to demonstrte conclusively which grfts gin the most from the phrmcotherpy [32], the vsculr ptients will benefit from reduction of vsculr events in generl, becuse the mjority of ptients (round 2/3) re t risk of dying from crdic or cerebrovsculr complictions [33]. Vrious Europen trils re summrized in Tble 5. There hs obviously so fr been no convincing evidence tht ny one of the ntiggregnt substnces in ny dosge currently in clinicl use produces superior results to the other [4]. However, recently the beneficil effect of ticlopidine on the long-term vein grft performnce in peripherl vsculr surgery ws evluted in multicentre plcebo-controlled, double-blind tril [34], resulting in strong recommendtion to use ticloplidine in such ptients. In our hnds the hypothesis tht postopertive ntithrombotic therpy might be of fvourble influence ws deduced from n explortory nlysis of the clinicl series. The results hve been reproduced in one [19, 20] out of two clinicl trils presented here, which were continued with persistence over long periods of time. The reson for the negtive results of our first tril (B-1) [17, 18] might hve been tht the dosge of mg ASA ws too high. Gstrointestinl side-effects were likely to occur nd might hve precluded stisfctory complince. The unstisfctory ASA results prompted us to embrk on long-term clinicl tril, B2, testing the vlue of nticogulnt tretment with respect to grft nd ptient survivl s well [20]. Ptient survivl ws incresed irrespective of grft performnce [19]. Study limittions Both trils presented were rndomized, but not plcebo-controlled, single-centre trils, deling with Tble 4 Clinicl tril, B 2; rndomized, but not plcebo-controlled; intention to tret principle, Breslow s nd Mntel s tests (two-tiled) Recruited Reocclusion Loss of limb Deths Vribles Prophylxis ( ) n (%) n (%) n (%) ptent grfts only Fem pop RSVG AC (22) [19] C (58) P 0.009* P 0.013** Fem pop RSVG AC (20) 04 (6) 27 (41) [20] C (36) 13 (20) 37 (58) P 0.006* P 0.012* P 0.055* P 0.013** P 0.009** P 0.037** AC, nticogulnt tretment; C, untreted controls; RSVG, reversed sphenous vein grft. b P*, Breslow s test; P**, Mntel s test; B 2: see text.

6 394 G. KRETSCHMER & T. J. HOÈ LZENBEIN: IN PERIPHERAL VASCULAR SURGERY Tble 5 Min dt of Europen trils, evluting postopertive phrmcotherpy Study [ref] Ptients enrolled Complictions Follow-up (n) Prophylxis Setting Ptency Survivl of therpy Complince Swiss tril RSVBG: 91 AC 70 rndomized in fvour not not not [35] TEA: 122 ASA 143 single of AC mentioned mentioned mentioned 2 yers centre in SVBG Swedish tril ABG: 33 AC 61 rndomized equl equl 10% not [38] SVBG: 49 C 55 single bleeding mentioned 5 yers TEA: 34 centre episodes, no deths Dutch tril conservtive nd AC 155 plcebo- in fvour equl 2 deths Thrombosis [36] opertive tretment C 145 controlled ptency nd SAB services 5 yers single progression [37] centre of disese Austrin tril RSVBG AC 66 rndomized in fvour in fvour 1 deth: 80% of tests [20] C 64 single of AC of AC gstric within 10 yers centre hemorrhge therpeutic limits French tril SVBG AGG 122 rndomized in fvour equl 1 deth pill count [34] C 121 plcebo- of AGG between SDB 2 yers controlled groups multicentre APTC SVBG? AGG 1613 met-nlysis in fvour not non-ftl pill count [4] ABG:? C 1613 of 14 trils of AGG mentioned bleeding 2.2% 19 months (men) AC, nticogulnt tretment; AGG, ntiggregnt tretment; C, untreted controls; RSVBG, reversed sphenous vein bypss grft; SVBP, sphenous vein bypss grft; ABG, lloplstic bypss grft; TEA, long-distnce thrombendrterectomy; SAB, subrchnoidl bleeding; SDB, subdurl bleeding; APTC, Antipltelets Trilist s Collbortion. limited numbers of ptients. Side-effects relted to the therpy were suspected in the ASA tril, but it ws not possible to prove ptient complince. On the other hnd it hs been possible to mintin ctive nticogultion with cceptble sfety in high percentge of ptients. To know ptient's dherence to the prescribed nticogulnt therpy (round 80% of the prothrombin time estimtions were found within therpeutic limits), seemed to be dvntgeous in the postopertive follow-up s compred to ptients receiving ASA. There were, however, not enough ptients in the treted group to show ny reltion between the qulity of nticogulnt tretment nd the primry grft ptency. Only one deth ws cused by the nticogulnt tretment, due to gstrointestinl hemorrhge, but with the significnt overll reduction of mortlity in the mteril with twothirds of the ptients 65 yers or older, we concluded tht the benefit of nticogulnts outweighed the risk even in subgroup of ptients t n dvnced ge. In western, northern nd centrl Europe (Netherlnds, Germny, Switzerlnd, Austri nd Scndinvi) so clled `rt' of nticogulnt tretment hs developed over the yers. As erly s 1979 single-centre tril ws conducted in Switzerlnd demonstrting beneficil effect of nticogulnts following vein bypss surgery, compred to tht of ntiggregnts following long-distnce thrombendrterectomy in the femorl rtery [35]. Orl nticogultion resulted in improved ptency in ptients with sphenous vein bypss grfts (87 vs. 65%; P = 0.05). Conversely, ASA improved ptency following thrombendrterectomy (80 vs. 55%; P = 0.002). Consequently the uthors recommended differentited tretment policy [36]. The `Dutch Tril' enrolled ptients treted surgiclly or conservtively nd showed peripherl vsculr, crdiovsculr nd cerebrovsculr beneficil effect in terms of disese. The tril tested phenprocoumon versus plcebo in double-blind setting [36]. In tht context, it might be importnt to note tht in the Netherlnds nticogulnt

7 MINISYMPOSIUM: ORAL ANTICOAGULANTS 395 tretment is orgnized centrlly in the so clled Thrombosis Services [37], non-profit orgniztion. The results of `Swedish Tril' [38] were in discordnce with the other previously mentioned investigtions [19, 20, 35, 36], showing no influence of dicumrol regrding ptency of vein grfts, lloplstic grfts or thrombendrterectomies, but the series ws smll nd inhomogeneous. Clinicl implictions Our results confirmed the efficcy of orl nticogultion in the prevention of vein grft reocclusion nd improving the limb slvge rte. In ddition, the probbility of ptient survivl ws higher, probbly irrespective of grft performnce. Tking into considertion ptency, limb slvge nd survivl, long-term nticogulnt tretment seemed justifible. Along with other, we hve produced level 2 evidence ccording to Clgett [1, 9] for nd ginst orl nticogulnt tretment, wheres the Antipltelet Trilist's collbortive efforts hve demonstrted level 1 (the most scientificlly sound nd vlid) evidence [4, 29]. The level of dequte nticogultion hs to be monitored whenever it is felt this is indicted, nd it seemed possible to chieve this gol over long observtion periods (up to 10 yers), being wre of ptient's complince. ASA lone (75]325 mg) seemed s effective s ny other pltelet regimen, but the optimum durtion of tretment is not exctly known nd further studies re needed to define when to strt nd when to stop mediction [4]. Future outlook To nswer conclusively the obvious question: `which ntithrombotic therpy is best following peripherl vsculr procedures', direct comprison is necessry. A proposl for such rndomized controlled tril does exist, nd should enrol round 1000 ptients [39] nd is expected to deliver level 1 evidence. Another such tril might be underwy in the Netherlnds [43]. Recently the Antithrombotic Trilist's Collbortion (ATT) hs been founded, bsed t the Clinicl Tril Service Unit in Oxford, to further investigte the problem of ntithrombotic therpy. A combintion of nticogulnts nd ntiggregnts might become n ttrctive therpeutic regimen, lthough substntil risk of bleeding with high-dose nticogulnts might be expected. Nevertheless, combintion of low-dose nticogulnts combined with medium-dose ASA might be promising therpeutic lterntive. A tril like this hs been presented, but exists only in bstrct form, nd it ws criticised t the time of its presenttion [40], minly due to the high incidence of prothrombin times outside the therpeutic rnge. Recently, single-centre tril ws conducted, showing the beneficil effect of the combintion of ntiggregnts plus orl nticogulnts in ptients with difficult grfts [44], lthough dverse events hve to be considered. Another question remining to be nswered is whether it is wise to switch from nticogulnts to ntiggregnts s soon s stble period of grft performnce hs been chieved, thereby omitting the necessry but cumbersome nd costly monitoring of the nticogultion level. The mere withdrwl of nticogulnts might be dngerous, especilly in ptients t high risk of vsculr events [41]. Conclusions Ptients needing revsculriztion procedures (opertions or trnsluminl interventions) will benefit from the so clled medium dose of ASA, becuse the risk of reocclusion is gretly reduced, but the best moment to begin is unknown. The durtion of tretment is still uncertin, but for ptients with obvious oblitertive rteril disese it might be prudent to consider life-long mediction, s long s the risk of vsculr events remins high nd no contrindictions hve become obvious. This might lso be possible public helth strtegy. Anticogulnt tretment over 10 yers nd more is possible, with continuous monitoring. The ptient's complince to therpy is esy to evlute s routine, nd this might be n dvntge. As long s the trils compring nticogultion with ntipltelet therpy, or the two combined, re underwy nd the results from the ATT Collbortion re not vilble, it is tempting to speculte tht nticogulnts might ply role in combintion with ASA in the sitution of difficult grfts t risk, which re observed with incresing incidence. In such situtions the possible benefit will outweigh the risk of hemorrhgic complictions.

8 396 G. KRETSCHMER & T. J. HOÈ LZENBEIN: IN PERIPHERAL VASCULAR SURGERY Acknowledgement We re indebted to the Austrin Centrl Bureu of Sttistics for mking vilble to us the most recent survivl dt on our ptients. References 1 Clgett PG, Gror RA, Slzmn EW. Antithrombotic therpy in peripherl rteril occlusive disese. Chest 1992; 102 (Suppl.): 516]28. 2 Berkoff HA, Levine RL. Mngement of vsculr ptients with multisystem therosclerosis. Prog in Crdiovsc Res 1987; 29: 347]68. 3 Dormndy J. Surgicl phrmcotherpy. Eur J Vsc Surg 1989; 3: 379]80. 4 Antipltelet Trilist's Collbortion. Collbortive overview of rndomised trils of ntipltelet therpy ] II. Mintennce of vsculr grft or rteril ptency by ntipltelet therpy. Br Med J 1994; 308: 159]68. 5 Kretschmer G. SekundÈrbehndlung der peripheren rteriellen Verschluûkrnkheit. Antiggregieren ] Antikogulieren (Editoril). Act Chir Austr 1992; 24: 2]4 6 Vn Urk H, Kretschmer G. Wht is the role of orl nticogulnts nd pltelet inhibitors in peripherl vsculr surgery? 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