Antithromboticc Drugs in the Primary Medicall Management of Intermittent Claudication N

UvA-DARE (Digital Academic Repository)

Diagnostic and therapeutic management of venous and arterial disease

Bernardi, E.

Publication date 2003

Link to publication

Citation for published version (APA): Bernardi, E. (2003). Diagnostic and therapeutic management of venous and arterial disease.

General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:27 Sep 2021 CHAPTERR 10

ANTITHROMBOTICC DRUGS IN THE PRIMARY MEDICALL MANAGEMENT OF INTERMITTENT CLAUDICATION N

AA META-ANALYSIS

Girolamii B, Bernardi E, *Prins MH, tten Cate JW, Prandoni P, *Hettiarachchii R, Marras E, Stefani PM, Girolami A, fBüller HR

Thrombosiss Haemostasis 1999;81:715-722

Fromm the Institute of Medical Semiotics, University Hospital of Padua, Italy; thee *Department of Clinical Epidemiology, and the tCentre for Haemostasis, Thrombosis,, Atherosclerosis and Inflammation Research, Academic Medical Centre,, University of Amsterdam, the Netherlands

Thee 1st and 2nd authors equally contributed to thee work and writing of the paper

Summary y Backgroundd - There is no consensus on the efficacy of the antithrombotic drugss available for patients with intermittent claudication. Methodss - A Medline and manual search was used to identify relevant publications.. Uncontrolled or retrospective studies, double reports or trials without clinicall outcomes were excluded. Included studies were graded as level 1 (randomisedd and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomisedd comparative). Mortality, cerebro- or cardiovascular events, amputations,, arterial occlusions or number of revascularisation procedures performedd in the lower limbs, pain-free and total walking distance, ankle brachial indexx and calf blood flow, were the main outcomes considered. When feasible, endd of treatment results, either continuous or binary, were combined with appropriatee statistical methods. Resultss - Mortality was significantly decreased by ticlopidine compared to placeboo (common OR, 0.68; 95% CI, 0.49 to 0.95); clopidogrel decreased vascularr events in comparison to aspirin (OR, 0.76; 95% CI, 0.63 to 0.92) in level

155 5 11 studies. Arterial occlusions and the number of revascularisation procedures performedd were statistically significantly decreased by aspirin and ticlopidine, respectively.. A small but statistically significantly improvement in pain free walkingg distance was determined by picotamide, indobufen, low molecular weight heparins,, sulodexide and defibrotide, in small studies. Conclusionss - Clopidogrel and ticlopidine do reduce clinically important events inn patients with intermittent claudication and could be added to the primary medicall treatment of these patients. The use of aspirin in these patients cannot bee based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis,, where it has documented efficacy. Other antithrombotic drugs weree not properly evaluated in patients with intermittent claudication.

Introduction n Intermittentt claudication and the underlying peripheral arterial disease is a commonn invalidating disorder of the Western society. In males, the prevalence approximatess 5% in males over 50 years of age, while the incidence raises from 0.2%% per year at the age of 501-2 to 1 % per year among those older than 65.3 Moreover,, in patients with peripheral arterial disease, total mortality is increased inn comparison to the general population, mainly due to an augmented risk of vascularr death.24 Sincee platelets and thrombosis play a central role in the atherosclerotic process, itt is reasonable to evaluate the usefulness of antithrombotic, and in particular antiplatelett drugs, as a primary treatment in these patients. Even more so, since itt is well documented that patients with coronary atherosclerosis do benefit fromm antiplatelet therapy.5 Moreover, in patients with peripheral arterial disease whoo have undergone a revascularisation procedure, aspirin improves patency, whilee a beneficial effect on mortality is likely.6 Finally, the role of antithromboticc drugs in the primary medical treatment of peripheral arterial obstructive dis- easee is still debated.7 Therefore, we performed a meta-analysis to evaluate the evidencee on the effectiveness of antithrombotic drugs, whose action in pre- ventingg clot formation is primarily a consequence of antiplatelet or anticoagu- lantt effects, in patients with intermittent claudication with regard to walking distance,, vascular events and mortality.

Materialss and Methods WeWe performed a Medline search on English-language medical literature (1976 - Junee 1998), supplemented by manual searches on references of pertinent

156 6 reviewss and articles, to identify studies on intermittent claudication (key words: atherosclerosis,, intermittent claudication, peripheral vascular diseases). Studiess were eligible for inclusion if they evaluated primary treatment of intermittentt claudication in patients at stage II of disease according to Fontaine8 withh antithrombotic drugs, independently of their design. Studies regarding selectedd populations (hypertensive, dislipidaemic, diabetic patients), or evalu- atingg merely analgesic treatment, were not considered. The quality of this selec- tionn process was evaluated on a random sample of one hundred articles analysedd by three independent operators (BG, EB, MHP), achieving a Kappa rangingg from 0.90 to 0.95. Studies were excluded if uncontrolled, retrospective,, duplicating other published material or not adequately defining or assess- ingg at least one of the following outcomes: pain-free or total walking distance, anklee brachial index, calf blood flow, number of lower limb arterial occlusions, numberr of revascularisation procedures performed in the arteries of the lower limbss (angioplasty, bypass graft, endarterectomy, thromboendarterectomy), numberr of amputations in the lower limbs, cerebro- or cardiovascular events (stroke,, myocardial infarction) or mortality. Included trials were graded by two independentt observers (BC, EB) as level 1 (randomised, double-blind or with blindd assessment of the outcome), level 2 (other randomised trials) or level 3 (non-randomisedd comparative studies). Level 3 studies were considered only if levell 1 data were not available. Dataa from included studies were extracted by two independent observers (BG, EB)) using a standardised form and summarised in tabular format. Since our pur- posee was to give a quantitative summary estimate of treatment effect, the cri- teriaa used for inclusion in the final summary measure of effectiveness was that thee report enabled direct extraction or derivation of a difference in effect betweenn the treatment groups and its common standard deviation (continuous outcomee measures) or of the exact proportion of the outcome events in each groupp (binary outcome measures). Whenever possible, outcome data, expressedd as means and standard deviations or as proportions, were combined usingg appropriate meta-analytical statistical procedures.910 Only results obtainedd at the end of the treatment period were compared, provided that baselinee values for the (continuous) outcomes considered were comparable amongg studies. The statistical advisability of combining the results of different trialss was estimated by means of a statistical heterogeneity test, which apprais- ess whether differences in treatment effect over individual trials are consistent withh natural variation around a constant effect. Results were expressed as (common)) differences of the means or as (common) odds ratios, with 95% confi-

157 7 dencee interval (95% Cl). In case of disagreement at any step of the meta-ana- lyticall process, consensus was reached by adding a third observer (MHP).

Results s Outt of 60 potentially eligible studies, 3 were uncontrolled,1113 2 were double reportss 1415 of other publications,1617 and 1 did not evaluate clinical outcomes.18 Thus,, 54 studies were further evaluated. Among these, 44 assessed the efficacy off an active drug in comparison with placebo or no treatment (Table i);16171960

Tablee 1 - Studies on the efficacy of antithrombotic drugs in the primary medical treat- mentment of intermittent claudication

Author r Level l Sample e Runn in Activee Drug Duration n * * t t t t Regimenn § II I

Aspirinn ( Dipyridamole) Schoop,, 1983 ,9T* 1 1 200/100 0 -- 990 0 5y y Hess,, 1985 20 ft 1 1 160/80 0 -- 990 0 33 m n Roztocil,, 1989 $$ 1 1 34/35 5 -- 1200 0 iy y Mannarino,19911 " §§ 2 2 10/10 0 Yes s 330 0 66 m Belcaro,, 1991 " 3 3 57/22 2 -- 1000 0 iy y Dipyridamole e Libretti,, 1986 ,6 1 1 27/27 7 -- 2255 Hu 66 m Ticlopidine e Aukland,, 1982 ^ 33/32 2 11 m, p 500 0 iy y Cloarec,, 1985 25 ** 11 32 (?/?) -- 500 0 66 m Arcan,, 1988" 83/86 6 11 m, p 500 0 66 m 2b Balsano,, 1989 76/75 5 33 m, p 500 0 Vy y Janzon,, 1990 "HI 346/341 1 -- 500 0 5,66 y Fagher,, 1993'8Cfl1 9/9 9 -- 500 0 3y y Blanchard,, 1993 29 304/311 1 -- 1000 0 66 m 50 Fagher,, 1994 f{ 51/50 0 -- 500 0 5y y Bergqvist,, 1995 " 11 346/341 1 -- 500 0 7y y Suloctidil l Adriaensen,, 1976 " 15/15 5 -- 3000 *** 2m m Gillot,, 1976" 15/12 2 11 m, p 300 0 2m m

158 8 Verhaeghe,, 1981 lA ttt 23/22 2 33 m, p 300 0 66 m Jones,, 1982 3S 14/17 7 -- 300 0 66 m Holm,, 1984 56 20/20 0 -- 300 0 99 m Picotamide e Coto,, 1989 }7 20/20 0 200 d, p 900 0 66 m 38 Balsano,, 1993 1150/11544 30 d, p 900 0 1,55 y Neirotti,, 1994 w 10/10 0 40d,p p 900 0 1,55 y Indobufen n Signorini,, 1988 40 28/24 4 -- 400 0 66 m Tönnensen,, 1993 41 148/154 4 11 m, p 400 0 66 m Belcaro,, 1991 " 3 3 125/22 2 -- 400 0 iy y Cilostazol l Money,, 1998 n 104/108 8 -- 200 0 166 w Triflusal l Auteri,, 1995 Ai 55/62 2 -- 600 0 66 m LMWH H Palmieri,, 198844 28/27 7 11 w 8.0000 IU aXa sc #$ 66 m Tesi,, 198945** 10/10 0 22 w 8.0000 IU aXa sc ttt 66 m Mannarino,, 1991 46 22/22 2 11 m 15.0000 UaXasc 66 m Calabró,, 1993 47 18/18 8 11 m 15.0000 UaXasc 66 m

Sulodexide e Palmieri,, 198448 15/15 5 22 m 6000 LU im / 600 LU os §§§ 20/700 d Dii Stefano, 1984 49 15/15 5 -- 6000 LU im / 600 LU os 20/700 d Corsi,, 1985 50 15/15 5 -- 6000 LRU im / 600 LRU os 20/700 d Bonalumi,, 198651 15/15 5 -- 6000 LU im / 600 LU os 20/700 d Palmieri,, 1987" 20/20 0 2ww 1200 LRU im / 600 LRU os ||||| 20/700 d Caramelli,, 1988" 30/30 0 -- 6000 LRU im 200 d Crepaldi,, 1990 54 **

159 9 ** Study level (see methods), t Included patients (active drug / placebo). | Run in: duration of the wash outt period from antithrombotic and vasoactive agents, of all included patients before the administration off the active drug; d: days; w: weeks; m: months; oral, unless differently stated; p: placebo. § Active drug regimen,, expressed in oral daily milligrams, unless differently stated; sc: subcutaneous; im: intramuscu- larly;; LU: lipasaemic units; LRU: Lipoproteinlipase Releasing Units. || Duration of treatment; d: days; w: weeks;; m: months; y: years. 1 300 patients were randomised to aspirin, aspirin plus dipyridamole, placebo;; the first two groups were considered together for the final analysis. ** From this study raw data could nott be extracted for the final analysis, tt 240 patients were randomised to: aspirin, aspirin plus dipyri- damolee (225 mg daily), or placebo; the first two groups were considered together for the final analysis, ttt 105 patients were randomised to: 7-mono-hydroxyethylrutoside (300 mg die) plus aspirin (34 patients),, 7-mono-hydroxyethylrutoside (300 mg die) alone (35 patients), placebo (36 patients); only thee first two groups were considered in the analysis. §§ 30 patients were randomised to physical training,, physical training plus aspirin (330 mg daily) and dipyridamole (225 mg daily), aspirin (330 mg daily)) and dipyridamole (225 mg die); only the first two groups were considered in the analysis (20 patients).. ||| Both groups received also aspirin 600 mg daily. 11 STIMS: Swedish Ticlopidine Multicenter Study;; these four studies reported data partly overlapping, on the same group of patients: outcome dataa were considered once only in the analysis. *** 45 patients were randomised to suloctidil, placebo orr dihydroergotoxine; the first two groups were considered in the analysis, ttt After a double blind phase,, a cross over and a 4 month single blind period followed; in this second phase the active group receivedd 600 mg daily of suloctidil; from the second part of the study no intention to treat data were available,, ttt equal to 15.000 aXa U. §§§ out of 30 included patients, 23 were dislipidaemic; all patients receivedd a hypocaloric and hypolipidic diet before active treatment. |||||| 600 LRU are equivalent to 2.600 aXaaXa IU and to 11.000 aXa U. Ill Cross over study; after cross over, patients received oral drug in an uncontrolledd fashion for a total observation period of 8 months. **** 149 patients were randomised to placebo,, acenocumarol, pentoxifylline, both drugs; only the first two groups are considered in the analysis,, tttt 30% of the included patients underwent to revascularisation procedures before enrolment; phenprocoumonn was the index drug.

33 of these233256 as well as 10 other studies6170 compared 2 or more active drugs (Tablee 2).

ActiveActive treatment versus control Includedd studies evaluated the effect of antiplatelet drugs, i.e. of aspirin and dipyridamole,1619233 ticlopidine,172431 suloctidil,3236 picotamide,3739 indobufen,2340411 cilostazol42 and triflusal.43 With regard to anticoagulant drugs, includedd studies evaluated the efficacy of low molecular weight heparins,4447 sulodexide,48555 vitamin K inhibitors,5657 and defibrotide (Table I).5860 Thee difference in effect of aspirin,22 ticlopidine,1730 suloctidil,3336 picotamide,37 indobufen,40411 low molecular weight heparins,444647 sulodexide,4853 and defi- brotide588 on pain-free walking distance, compared to control at the end of treatmentt period, is reported in Figure 1. A statistically significant improvement wass observed with picotamide (difference of the means, 38.7 m; 95% CI, 2.2 too 75.2 m),37 indobufen (difference of the means in two distinct studies, 450.8

160 0 " rü t2"xs s «« 2 S< o D y c >ï ï £ £ E E >> >E E E E >s s £ £ £ £ £ £ E E E E E E : § y

m m i\ \ .. NO O NO O NO O -- NO O NO O m m fN N year <-- 'O. . fN N ;; nt bo 55 mboti OO QJ Oi vo ££ * E c uo o U1 1 5 5 3 3 ccrara Q_ +-ï:1 *-i_ .»» >*- (LI "o. . uo o CD D o o *->TO TO *->EEr s o 2 n

UO O E E f o o *T *T o t ^TO TO^ o o O O oo -5 c s o CM M o o o o o o co o CM M in n fN N O O 3 3 o o LH H NO O og g o o 4-J J

o o mo rsi i CM M ou o o m m : CM M c" " o o a> > CM M o o aT T Cd Cd O O h m m

cf f .. O O > > E E o o was

O) ) e k. . O» » ro ro 'a. . ai i c c 'Q. . o o 'ö. . X X 'o. . X X o o o o to o o o o o Onl th tO O 'i_ _ ui i I/O O *

cf f f o o o o Ol/l) l ) TO TO weeks cX Xc o o : uo o < < CC C o o a> > < < Q. . * ai i CJ) ) o i-- o» » .. CU U 2 2 w < < b b c c o o t t X X ai i ;; c c CC C ai i o o nn ays tio inate 'Q. . 5 5 ocutaneously

T3 3 u

to o : :

2^33 3c

^ ^ c d d : ; s

< < u u ni o o b b ; u u 3 3 to o l l/l l o o a: : o o i/> > in o o o o _i i o o fN N Z) ) n o o Z> > UO O o o Z) ) o o o o o o o o O O o o TO TO drugs UO O aT T Units Ru uo o O O CM M +J J O O o o e CM M o o 00 0 X X g o o o o PO O

m m X aT T TO TO o o TO TO oT T LD D . Q. . cf f cf f xanthino

U0 0 f 'x x C C m T3 3 O O IS) IS) T3 3 o o TO TO «3 3 o o l_ _ TO TO ee o dd <-o o yy Q. . < < +-1 1 TO TO Q. . x" " i-- (Li i U U c c Q Q a> > nn

ai i =3 3 dail con a> > o X X CL. . X X 2 2 lipas oo o X X 1 1 && '-5 c o .TT 2 « o SS 'S 0\ i

Q. . | JO JO 5 5 CL L 33r .E o ; U1 U1 1 1 o o 1 1 m w c c E E E E ' ' d 1 1 tt ad dd

oo o Lipo 3 3 2 2 rsi i CM M :: ee U (firs ate h __ +J QC CU ££ ï Tl ' ON N a>> o jlf JS _0J J CM M * * o o * * fN N 5 NO O oo o CM M NO O r\ \ rsi i o o co o uo o '™™ 1 ^ o o m m u0 0 oo o oo o UO O fN N fN N ro o fN N ! ! -^r r r>. . ! ! "OO 4-f ^3 "c fN N O O m m LD D NO O rsT T O O oo o r^ ^ U0 0 o o rN N CM M UO O oo o oo o UO O fN N fN N fN N CM M O»» c ^ t , rN N TT T e o o 33h ~ 9 B

oo o p pa 6 stat Inc dd 9 tt yy ff e l i o i d no o (NI I CM M CM M CNJ J CM M CM M m m . " " " " " " " " " " pp inclu ll grou , ethods) different al d n

m m m £ £ s i e

^ ^ ^ ^ « « CO O NO O s

ro o thir o o ON N CO O ON N ON N ON N -3-- ON N ON N

rv. . A unles ON N ON N NO O r*v v (se ON N l ON N O O , ON N ON N ON N ON N oo o ON N 1

ON N . ON N ON N ON N ON N ON N c" " agent o" " ON N ON N ON N o" " a> > > C C C C to o y

C C "3 3 TO~ TO~ y O O O O u-T T cf f ai i >** * TO" TO" TO TO C C TO TO O O H— — ai i L_ _ i/i i O O -C C O O 6" " a> > CU CU O O *-> *-> C C a; ; _TO O ro ro c c U U u u +-> +-> 1/1 1 L_ _ CD D dail ll u u ro ro T3 3 O O c c TO TO OO O months :: 3 3 ai i Stud Ol l c c < < TO TO TO TO o o

CL. . ** m < < CO O a a ü ü < < 5 5 < < vasoactiv ora <

Treated/Control l Treatmentt better

Aspirin n Mannarino,, 1991 (22) 10/10 0 i

Ticlopidine e Arcan,, 1988(17) 75/81 Faghcr.. 1994 (30)25'22 Totall 100/103 i i

Suloctidil l Gillot,, 1976(33) 15/12 ii Holm,, 1984(36) 16/16 ** 1 Totall 31/28 1

Picotamide e Coto,, 1989(37) 18/17

Indobufcn n Signorini,, 1988(40) 28/24 Tonnesen,, 1993(41) 148/154

Loww molecular weight heparin Palmieri,, 1988(44) 28/27 Mannarino.. 1991 (46) 22/22 Calabró.. 1993(47) 18/18 1 Totall 68/67 i-B-i i

Sulodexide e Palmieri.. 1984 (48) 11 ] 10 ii i DiStefano,, 1984(49) 15/15 5 ii Corsi,, 1985(50) 15/15 5 ii Bonalumi.. 1986(51) 15/15 5 Palmieri,, 1987(52) 19/11 o 1-*H H Caratnclli,, 1988(53) 30/30 0 II 1 Total l 105/104 4

Defibrotide e Morelli,, 1990(58)

1000 0 100 200 300 400 500 600

Painn free walking distance (meters)

m;; 95% CI, 363.5 to 538.2 m; and, 74.8 m, 95% CI, 40.2 to 109 m),4041 low molecularr weight heparins (common difference of the means, 53.3 m; 95% CI, 20.33 to 86.7 m),444647 sulodexide (common difference of the means, 112.6 m; 95%% CI, 76.9 to 148.3 m)4853 and defibrotide (difference of the means, 238 m; 95%% CI, 228.8 to 247.2 m).58 In 1 level 1 study, triflusal increased pain-free walkingg distance of 46.8 m compared to placebo (P=.07).43 In 1 study42 the differencee in effect could not be calculated. Totall walking distance was assessed with aspirin,22 ticlopidine,1730 suloctidil,3436 indobufen,411 and defibrotide,5860 and results were similar to those observed for

162 2 pain-freee walking distance, but did not reach statistical significance, except for indobufenn and defibrotide, which increased total walking distance for a (common)) difference of the means egual to 98.3 m (95% CI, 49.2 to 147 m), and too 88.8 m (95% CI, 45.0 to 1 32.6 m), respectively.4'5860 In 1 study, triflusal increasedd total walking distance of 53.2 meters compared to placebo (P=.05).43 Cilostazoll improved total walking distance of 51.5 m (95% CI, -3.1 to 106).42 Thee number of arterial occlusion or of revascularisation procedures performed inn the arteries of the lower limbs, was assessed in trials with aspirin20 and ticlopidine.293'' The results expressed as odds ratios (OR) are presented in Figure 2.

Figuree 2 - Effect of antithrombotic drugs on arterial occlusions, number of revascularisation proceduress performed and mortality in patients with peripheral arterial obstructive disease at Fontainee stage I! of disease. End of treatment differences results between treated and con- troll patients are reported, expressed as odds ratios with 95% confidence intervals, for each study,, and combined for each drug

Author,, year Treated d Control l Treatmentt better Control better

Occlusions s

Aspirin n Hess,, 1985 (20) & 30/1838 8 34/972 2

Ticlopidine e Blanchard,, 1993 (29) && 1/304 4 8/311 1 » » Bergqvist,, 1995 (31) && 42/346 6 57/341 1 Totall && 43/650 0 65/652 2 i-B-i i

Mortality y

Aspirin n Hess,, 1985 (20) 5/160 0 0/80 0 ii *

Roztocil,, 1989(21) 0/34 4 1/35 5 * * Total l 5/194 4 1/115 5 ii

Dipyridamole e Libretti,, 1986(16) 1/27 7 2/27 7

Ticlopidine e Aukland,, 1982(24) 1/33 3 1/32 2 < < Arcan,, 1988(17) 1/83 3 1/86 6 1 1 Balsano,, 1989 (26) 1/76 6 3/75 5 1 Janzon,, 1990 (27) 64/346 6 89/341 1 -- Blanchard,, 1993(29) 7/304 4 67311 1 ii ' Total l 74/842 2 100/845 5

Picotamide e Balsano,, 1993 (38) 20/1150 0 22/1154 4 i—«—I I

Vitaminn K inhibitors Dettori.. 1989(56) 0/36 6 2/37 7 - 1

0,11 1 10 Oddss ratio && occluded artery segments / total segments analysed &&& revascularisation procedures performed / patients

163 3 AA statistically significant reduction in the number of revascularisation proceduress performed was observed in patients treated with ticlopidine (common OR,, 0.62; 95% CI, 0.41 to 0.93).2931 With regard to aspirin, results in arterial segmentss rather than in patients were reported: the number of lower limb arte- riall occlusions was statistically significantly reduced (OR, 0.46; 95% CI, 0.27 to 0.77)) in a small study.20 Mortalityy was reported only in studies evaluating aspirin,2021 dipyridamole,16 ticlopidine,17242627299 picotamide,38 and vitamin K inhibitors.56 Results are present- edd in Figure 2. A statistically significant reduction in mortality was observed only forr ticlopidine treated patients (common OR, 0.68; 95% CI, 0.49 to 0.95).17242627299 In one large study on picotamide, vascular events (death, stroke, myocardiall infarction and amputation) were not significantly reduced in treat- edd patients compared to control (OR, 0.86; 95% CI, 0.57 to 1.29).38 Att least one haemodynamic measure (ankle-brachial index or calf blood flow, at restt or after exercise) was assessed with all drugs.'6212224303234 3739444650515355565860 Inn general, no differences in favour of actively treated patients were detected comparedd to control, except for patients receiving aspirin (calf blood flow after exercise:: common difference of the means, in mL/100 mL per min, 2.6; 95% CI,, 0.28 to 4.91 mL/100 mL per min),2122 vitamin K inhibitors (ankle-brachial indexx at rest or after exercise: difference of the means, 0.1; 95% CI, 0.01 to 0.19;; and 0.09; 95% CI, 0.02 to 0.2, respectively),56 defibrotide (ankle-brachial indexx at rest: difference of the means, 0.04; 95% CI, 0.01 to 0.07; calf blood floww at rest: difference of the means, 1.1 mL/100mL/units; 95% CI, 0.76 to 1.4 mL/100mL/units).S859 9

ComparativeComparative studies Mainn comparisons regarded ticlopidine, aspirin, clopidogrel (Table 2). Outcome resultss of the 1 3 included studies23 3256617 are shown in Table 3. Clopidogrel, a ticlopidinee derived drug, was compared to aspirin in 1 large level 1 study.63 The mainn outcome measured was the rate of vascular events (any vascular death, stroke,, myocardial infarction). Superiority of clopidogrel in comparison with aspirinn was reported (OR 0.76; 95% CI, 0.63 to 0.92; P=.004). The OR for vascularr death at the end of treatment period was 0.77; 95% CI, 0.58 to 1.03 (P=.075).

Discussion n Althoughh intermittent claudication is frequent in the western society and antithromboticc drugs are frequently used in this group of patients, data on the

164 4 efficacyy of these agents are relatively scarce. Our systematic review clearly showss that data on the effectiveness of aspirin in this group of patients are poor. Althoughh aspirin was reported to reduce the number of peripheral arterial occlusions,, it should be realised that this observation is based on a single study thatt considered artery segments rather than patients. However, the use of aspirinn could be defended by the analogy with its documented benefit in patientss with atherosclerosis of coronary and cerebral arteries5 and the benefi- ciall effects observed in patients with peripheral arterial disease after revascular- isationn procedures.6 Currently,, the best evidence on the efficacy of antithrombotic agents in patients withh intermittent claudication is available for ticlopidine. Five level 1 stud- ies17242627299 showed a reduction of mortality of approximately 30%, while revas- cularisationn procedures were shown to be less frequently indicated in 2 level 1 studies.29311 Furthermore, in 1 large level 1 study,53 an analogue of ticlopidine, clopidogrel,, resulted in a significant reduction of major vascular events in patientss with atherosclerotic vascular disease compared to aspirin, and the advantagee was most prominent in the subgroup of patients with peripheral arte- riall disease. Other antithrombotic drugs were less extensively evaluated in small samplee studies and conclusions about their effectiveness would be premature. In fact,, with a sensitivity analysis it can be demonstrated that the positive effects observedd on walking distances, become statistically not significant by adding a studyy with true zero effect with less than 50 patients in the case of picotamide andd low molecular weight heparin, and of 180 patients in the case of defibrotide,, suggesting the possibility of a publication bias. With regard to the resultss observed with indobufen on walking distance, the heterogeneity test was positivee and results were not pooled. Therefore, these drugs should be evaluat- edd in larger proper studies, assessing also the effects on the prevention of arteri- all occlusions and on survival. On the contrary, the positive results observed with sulodexidee become not statistically significant by adding a study with more than 8000 hundred patients. The gain in walking distance is of more than one 100 m comparedd to control and is twice compared to that obtained with pentoxifylline orr nafronyl;7374 however, in a small study directly comparing sulodexide and pentoxifyllinee (Table 2),6S no significant differences were observed in terms of walkingg distance and ankle-brachial index (Table 3). Furthermore, no data are avail- ablee on the effect on survival in these patients. Finally, picotamide in 1 large level 11 study was ineffective on mortality (Figure 2).38 Ourr meta-analysis was limited to English language studies; in general, a poten- tiall error due to a language bias is extremely low and, if present, is trivial

165 5 Tablee 3 - Comparative studies on antithrombotic drugs in the primary medical treatmentt of intermittent claudication: summary of results

Comparison n Author r Level l

Indobufenn vs Aspirin Belcaro,Belcaro, 1991 "

Ticlopidinee vs Aspirin Giansante,, 199061 1 Clopidogrell vs Aspirin CAPRIE,, 1996" 1

Pentoxifyllinee vs Aspirin Ciocon,, 1997

Indobufenn vs Pentoxifylline Panchenko,, 199765

Sulodexidee vs Pentoxifylline Shustov,, 1997

Calciumm heparin vs Aspirin Allegra,, 1994

Calciumm heparin vs Ticlopidine Andreozzi,, 1993

Pentoxifyllinee vs Warfarin Dettori,, 1989 56 2 Heparann Sulphate vs Mesoglycan Strano,, 199068 1

Defibrotidee vs Mesoglycan Laurora,, 1994 67 1 1

LMWHH vs Calcium heparin Dii Stefano, 1988

Suloctidill v Diydroergotoxine methylate Adriaensen,, 1976

** Study level (see methods). CI confidence interval; v: versus

166 6 Resultss (expressed as relative effect of first versus second drug) painn free and total walking distance were significantly increased by 210 m (95% C.I., 118-302)) and 185 m (95% C.I., 76-294), respectively noo difference in ankle brachial index or side effects 23.8%% risk reduction (95% C.I., 8.9-36.2%; p = 0.0028) of vascular events (vascular death,, myocardial infarction, stroke) totall walking distance significantly improved in the pentoxifylline treated group (differencee of the means, 1287 m, p<0.05); ankle brachial index was not different significantt increase of pain free and total walking distance, equal to 91 m (95% C.I., 34.4-148)) and 119 m (95% CI, 54.2-184), respectively; no significant difference in terms off stroke incidence (odds ratio 0.14, 95% C.I., 0.01-2.2) noo significant differences in terms of pain free and total walking distance and ankle brachiall index noo statistically significant difference in terms of pain free and total walking distance and anklee brachial index at rest; after exercise, ankle brachial index was significantly changed (differencee of the means, 0.07, 95% C.I., 0.03-0.11) noo significant differences in terms of pain free and total walking distance, and ankle brachiall index noo differences in terms of pain free walking distance and ankle brachial index significantt improvement in pain free walking distance (difference of the means, 56.1 m, 95%C.I.,, 28.7-83.5) painn free and total walking distance were significantly increased by defibrotide (differencee of the means, 262 m, 95% C.I., 194-330; and, 319 m, 95% C.I., 241-397, respectively);; distal tibial pressure was increased in the defibrotide group of 21 mm Hg (95% C.I.,, 12.2-29.8) noo significant differences in terms of reduction of leg symptoms, side effects, pain free walkingg distance, blood flow significantt improvement of calf blood flow both at rest (0.74 ml/min/kg, 95% C.I., 0.45- 1.03)) or after exercise (0.75, 95% C.I., 0.46-1.05)

167 7 ("Towerr of Babel Error").71 Therefore, aware of the aforementioned limitation, wee are confident our results can be generalised to patients at stage II of disease. Whatt do the results of our systematic review imply for the primary medical managementt of patients with intermittent claudication? In the light of previous analysis,, patients with peripheral arterial disease should be advised to practice physicall training and firmly discouraged to smoke7273 The use of vasoactive drugss is associated with a statistically significant, but small improvement in pain freee walking distance and therefore their clinical usefulness is questionable.7374 Inn particular, pentoxifylline (in 6 level 1 studies) and nafronyl (in 4 level 1 trials) determinedd an increase in pain free walking distance of 21.0 m (95% CI, 0.7 to 41.33 m) and 58.6 m (95% CI, 30.4 to 86.8 m), respectively.73 Since the effect onn mortality and vascular events, as well on quality of life, was not assessed, the prescriptionn of these vasoactive drugs to patients at Fontaine stage II of disease iss clinically questionable. Thee current analysis suggests that the antiplatelet drugs clopidogrel and ticlopidinee do modify the natural course of the disease. It is important to note that thee incidence of adverse effects (specifically neutropenia) associated with clopidogrell (0.1%) is lower than with ticlopidine (2.4%)."75 These observations wouldd lead to the suggestion to add clopidogrel, 75 mg once daily, to the pri- maryy medical management of patients with intermittent claudication. Alternatively,, ticlopidine could be given, with appropriate measures for the timelyy detection of neutropenia or of the recently described ticlopidine induced thromboticc thrombocytopenic purpura (76-78). In current clinical practice, aspirinn is the first choice option for these patients; however, direct evidence of itss efficacy is lacking. Only based on the aforementioned analogy, it could be arguedd that aspirin is a reasonable choice for these patients, less expensive but lesss effective, compared to clopidogrel.

References s 1.. Dormandy J, Mahir M, Acsady G, Balsano F, De Leeuw P, Blombery P, Bousser MG, Clementt D, Coffman J, Deutshinoff A, Blétry O, Hampton J, Mahlen F, Ohlin P, Riegerr H, Stranden E, Turpie AGG, Urai L, Verstraete M. Fate of the patient with chronicc leg ischaemia: a review article. J Cardiovasc Surg (Torino) 1989; 30: 50-7. 2.. Balkau B, Vray M, Eschwege E. Epidemiology of peripheral arterial disease. J Cardiovascc Pharmacol 1994; 23 (Suppl. 3): S8-S16. 3.. Kannel WB, Skinner J), Schwartz MJ, Shurtleff D. Intermittent claudication: incidence inn the Framingham study. Circulation 1970; 41: 875-83. 4.. Verstraete M. Current therapy for intermittent claudication. Drugs 1982; 24: 240-7.

168 8 5.. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelett therapy - I: Prevention of death, myocardial infarction, and stroke by prolongedd antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81 - 106. . 6.. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelett therapy - II: Maintenance of vascular graft or arterial patency by antiplatelett therapy. BMj 1994; 308: 159-68. 7.. Clagett GP, Krupski WC. Antithrombotic therapy in peripheral arterial occlusive disease.. Chest 1995; 108 (Suppl.): 431 S-443S. 8.. Fontaine VR, Kim M, Kicny R. Die chirurgische Behandlung der peripheren Durchblutungsstörungen.. Helv Chir Acta. 1954; 5/6: 499-533. 9.. Rao CR. Linear statistical inference and its applications. New York, John Wiley and Sons,, eds., 1973; 389-91. 10.. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studiess of disease. J Natl Cancer Inst 1959; 22: 719-48. 11.. Kirtstein P, Jogestrand T, Johnsson H, Olsson AC. Antiaggregatory, physiological and clinicall effects of ticlopidine in subjects with peripheral atherosclerosis. Atherosclerosiss 1980; 36: 471-80. 12.. Craveri A, Tornaghi G, Ranieri R, Stanzani M, Landi G, Paganardi L, Passaretti B, Galloo E. Effects of defibrotide after oral and parenteral administration in patients withh peripheral obliterative arterial disease (PAOD). Int Angiol 1990; 9: 274-7. 11 3. Belcaro G. Vasospasm in intermittent claudication: effects of indobufen, defibrotide andd combination treatment. Curr Ther Res 1990; 48: 667-75. 14.. Libretti A, Catalano M. Treatment of claudication with dipyridamole and aspirin. Monogrr Atheroscl 1986; 14: 207-9. 15.. Arcan JC, Destors JM, on behalf of the ACT Research Group. Controlled clinical trial off ticlopidine in patients suffering from intermittent claudication. Thromb Res 1986; Suppl.. VI: 159 (abstract 315). 16.. Libretti A, Catalano M. Treatment of claudication with dipyridamole and aspirin. Int jj Clin Pharmacol Res 1986; 6: 59-60. 11 7. Arcan JC, Blanchard J, Boissel JP, Destors JM, Panak E. Multicenter double-blind studyy of ticlopidine in the treatment of intermittent claudication and the prevention off its complications. Angiology 1988; 39: 802-11. 18.. Castelluccio A, Bologna E. Effect of sulodexide on blood viscosity in patients with peripherall vascular disease. Curr Med Res Opin 1991; 12: 325-31. 19.. Schoop W, Levy H. Prevention of peripheral arterial occlusive disease with antiag- gregants.. Thromb Haemost 1983; 50: 137 (abstract 416). 20.. Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progressionn of peripheral occlusive arterial disease: a prospective double-blind arte- riographicallyy controlled trial. Lancet 1985; 23: 415-19.

169 9 21.. Roztocil K, Oliva I, Prerovsk_ I, Linhart J. The effect of hydroxyethylrutoside and its combinationn with acetylsalicylic acid in patients with obliterative atherosclerosis Corr Vasa 1989; 31: 128-33. 22.. Mannarino E, Pasqualini L, Innocente S, Scricciolo V, Rignanese A, Ciuffetti C. Physicall training and antiplatelet treatment in stage II peripheral arterial occlusive disease:: alone or combined? Angiology 1991; 42: 51 3-21. 23.. Belcaro G, De Simone P. Long-term evaluation of indobufen in peripheral vascular disease.. Angiology 1991; 42: 8-14. 24.. Aukland A, Hurlow RA, George AJ, Stuart J. Platelet inhibition with Ticlopidine in ath- eroscleroticc intermittent claudication. J Clin Pathol 1982; 35: 740-3. 25.. Cloarec M, Caillard P, Mouren X. Double-blind clinical trial of ticlopidine versus placeboo in peripheral atherosclerotic disease of the legs. Thromb Res 1985; Suppl VI:: 160 (abstract 316). 26.26. Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violii F, Hellemans H, Vanhove P. Ticlopidine in the treatment of intermittent claudication:: a 21 -month double-blind trial. J Lab Clin Med 1989; 114: 84-91. 27.27. Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G. Preventionn of myocardial infarction and stroke in patients with intermittent claudication;; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentree Study, j Intern Med 1990; 227: 301-8. 28.. Fagher B, Persson S, Persson G, Larsson H. Blood viscosity during long-term treatmentt with ticlopidine in patients with intermittent claudication. A double-blind study.. Angiology 1993; 44: 300-6. 29.. Blanchard J, Carreras LO, Kindermans M, and the EMATAP group. Results of EMAT- AP:: a double-blind placebo-controlled multicentre trial of ticlopidine in patients withh peripheral arterial disease. Nouv Rev Fr Hematol 1993; 35: 523-8. 30.. Fagher B, on behalf og the STIMS group in Lund. Long term effects of ticlopidine onn lower limb blood flow, ankle/brachial index and symptoms in peripheral arte- riosclerosis.. A double-blind study. Angiology 1994; 45: 777-88. 31.. Berqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery dur- ingg long-term treatment of claudicant patients with Ticlopidine: results from the Swedish Ticlopidinee Multicentre Study (STIMS). Eur j Vase Endovasc Surg 1995; 10: 69-76. 32.. Adriaensen H. Medical treatment of intermittent claudication: a comparative double-blindd study of suloctidil, dihydroergotoxine and placebo. Curr Med Res Opin 1976;; 4: 395-401. 33.. Gillot P. A double-blind study comparing suloctidil and placebo in chronic peripherall arteriopathy. CurrTher Res Clin Exp 1976; 20: 637-44. 34.. Verhaeghe R, Van Hoof A, Beyens G. Controlled trial of suloctidil in intermittent claudication.. J Cardiovasc Pharmacol 1981; 3: 279-86. 35.. Jones NAG, De Haas H, Zahavi J, Kakkar W. A double-blind trial of suloctidil v. placeboo in intermittent claudication. Br J Surg 1982; 69: 38-40.

170 0 36.. Holm J, Lindblad L, Scherstén T, Suurkula M. Intermittent claudication: Suloctidil v.s. placeboo treatment. Vasa 1984; 1 3: 1 75-8. 37.. Coto V, Cocozza M, Oliviero U, Lucariello A, Picano T, Coto F, Cacciatore L. Clinical efficacyy of picotamide in long-term treatment of intermittent claudication. Angiologyy 1989; 40: 880-5. 38.. Balsano F, Violi F, and the ADEP Group. Effect of picotamide on the clinical progressionn of peripheral vascular disease. A double-blind placebo-controlled study. Circulationn 1993; 87: 1563-9. 39.. Neirotti M, Malaschi M, Ponzetto M, Macchione C, Poli L, Bonino F, Fabris F. Hemodynamic,, hemorheologic, and hemocoagulative changes after treatment with picotamidee in patients affected by peripheral arterial disease (PAD) of the lower limbs.. Angiology 1994; 45: 137-41. 40.. Signorini GP, Salmistraro G, Maraglino G. Efficacy of indobufen in the treatment of intermittentt claudication. Angiology 1988; 39: 742-6. 41.. Tonnesen KH, Albuquerque P, Baitsch G, Gomez Alonso A, Ibanez F, Kester RC, Levesonn S, Poredos P. Double-blind, controlled, multicenter study of indobufen ver- suss placebo in patients with intermittent claudication. Int Angiol 1993; 12: 371-7. 42.. Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heekman J, Forbes WP. Effectt of cilostazol on walking distances in patients with intermittent claudication causedd by peripheral vascular disease. J Vase Surg 1998; 27: 267-75. 43.. Auteri A, Angaroni A, Borgatti E, Catalano M, De Vizzi GB, Forconi S, Fossati L, Girardelloo R, Ambrosoli L, Poli A, Di Perri T. Triflusal in the treatment of patients with chronicc peripheral arteriopaty: multicentre double-blind clinical study vs placebo. Intt J Clin Pharmacol Res 1995; 15: 57-63. 44.. Palmieri G, Ambrosi G, Agrati AM, Ferraro G, Marcozzi S. A new low molecular weightt heparin in the treatment of peripheral arterial disease. Int Angiol 1988; 7 (Suppl.. 3): 41-7. 45.. Tesi M, Bronchi GF, Carini A, Morfini M, Cinotti S, Fiüberti E. Efficacy and safety of aa new low molecular weight heparin in the medium-term treatment of atheroscle- roticc arteriopathy of the lower limbs. J Drug Dev 1989; 2: 73-82. 46.. Mannarino E, Pasqualini L, Innocente S, Orlandi U, Scricciolo V, Lombardini R, Ciuffettii G. Efficacy of low-molecular-weight heparin in the management of intermittentt claudication. Angiology 1991; 42: 1-7. 47.. Calabró A, Piarulli F, Milan D, Rossi A, Coscetti G, Crepaldi G. Clinical assessment of loww molecular weight heparin effects in peripheral vascular disease. Angiology 1993;; 44: 188-95. 48.. Palmieri J, Nazzari M, Ambrosi G, Campiotti A, Palazzini E. Sulodexide in the treatmentt of peripheral arterial disease. Clin Trials J 1984; 21: 411-27. 49.. Di Stefano F, Patane' S, Vinci M, Giglio A, Raciti T, Salanitri G, Di Stefano B. Medical treatmentt of atherosclerosis: controlled clinical trial with new glycosaminoglycan: sulodexide.. Eur Rev Med Pharmacol Sci 1984; VI: 525-32.

171 1 50.. Corsi C, Bocci L, Cipriani C, Gazzini A, Marrapodi E. The effectiveness of gly- cosaminoglycanss in peripheral vascular disease therapy: a clinical and experimental trial,, j Int Med Res 1985; 1 3: 40-7. 51.. Bonalumi F, Sarcina A, Bonadeo P, Maddinelli L. A randomized protocol for the managementt of chronic peripheral arterial diseases by means of sulodexide. Eur Rev Medd Pharmacol Sci 1986; VIII: 123-9. 52.. Palmieri G, Ambrosi G, Cantoni S, Agrati AM, Palazzini E. Clinical evaluation of a nativee low molecular weight heparin in the management of symptomatic peripherall vasculopathy in the elderly. Curr Ther Res 1987; 41: 998-1009. 53.. Caramelli L, Mirchioni R, Carini A. Effectiveness of short-term sulodexide treatment onn peripheral vascular disease clinical manifestations. Eur Rev Med Pharmacol Sci 11 988; 1 0: 55-8. 54.. Crepaldi G, Fellin R, Calabro' A, Rossi A, Ventura A, Mannarino E, Senin U, Ciuffetti G,, Descovich GC, Gaddi A, Rimondi S, Pozza G, Vicari A, Carandente O, Mancini M, Rubbaa P, Postiglione A, Strano A, Avellone G, Davi G, Novo S, Pinto A, Capurso A, Restaa F, Mogavero AM, Bucci A, Antonini R, Lalloni L. Double-blind multicenter trial onn a new medium molecular weight glycosaminoglycan: current therapeutic effects andd perspectives for clinical use. Atherosclerosis 1990; 81: 233-43. 55.. Catania G, Salanitri T. Pharmacological treatment of intermittent claudication: doublee blind controlled study of Sulodexide vs placebo. Eur Rev Med Farmacol Sci 1992;; 14: 149-57. 56.. Dettori AG, Pini M, Moratti A, Paolicelli M, Basevi P, Quintavalla R, Manotti C, Di Leccee C, and the APIC Study Group. Acenocoumarol and pentoxifylline in intermittentt claudication. A controlled clinical study. Angiology 1989; 40: 237-48. 57.. de Smit P, van Urk H. Dutch oral anticoagulation trial. Acta Chir Austriaca 1992; 24: 5-7. 5-7. 58.. Marelli C, Belcaro G, Girardello R. Defibrotide in patients with intermittent claudication.. Improvement in blood flow, fibrinolytic activity, and microcirculation after sixx months of treatment. Curr Ther Res 1990; 47: 459-65. 59.. Strano A, Fareed J, Sabba' C, Albano O, Allegra C, Carlizza A, Binaghi F, Fronteddu F,, Del Guercio R, Arpaia MR, Pinto A, Alletto G, Walenga JM, Hoppensteadt D, Nazzarii M, Ferrari PA. A double-blind, multicenter, placebo-controlled, dose com- parisonn of orally administred defibrotide: preliminary results in patients with peripherall arterial disease. Semin Thromb Hemost 1991; 17: 228-34. 60.. Sabba C, Zupo V, Dina F, Nazzari M, Albano O. A pilot evaluation ofthe effect of defibrotidee in patients affected by peripheral arterial occlusive disease. Int J Clin Pharmacoll Ther Toxicol 1988; 26: 249-52. 61.. Giansante C, Calabrese S, Fisicaro M, Fiotti N, Mitri E. Treatment of intermittent claudicationn with antiplatelet agents. J Int Med Res 1990; 18: 400-7. 62.62. Andreozzi GM, Signorelli SS, Cacciaguerra G, Di Pino L, Martini R, Monaco S, Buttó G,, Sardina M. Three-month therapy with calcium-heparin in comparison with ticlo-

172 2 pidinee in patients with peripheral arterial occlusive disease at Leriche-Fontaine lib class.. Angiology 1993; 44: 307-13. 63.. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirinn in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1 329-39. 64.. Ciocon JO, Calindo-Ciocon D, Galindo DJ. A comparison between aspirin and pentoxifyllinee in relieving claudication due to peripheral vascular disease in the elderly. Angiologyy 1997; 48: 237-40. 65.. Panchenko E, Eshkeeva A, Dobrovolsky A, Titaeva E, Podinovskaya Y, Hussain KMA, Karpovv Y. Effects of indobufen and pentoxifylline on walking capacity and hemo- stasiss in patients with intermittent claudication: results of six months of treatment. Angiologyy 1997; 48: 247-54. 66.. Shustov SB. Controlled clinical trial on the efficacy and safety of oral sulodexide in patientss with peripheral occlusive arterial disease. Curr Med Res Opin 1997; 13: 573-82. . 67.67. Laurora C, Ambrosoli L, Cesarone MR, De Sanctis MT, Incandela L, Marelli C, Belcaroo G. Treatment of intermittent claudication with defibrotide or mesoglycan: a doublee blind study. PanMinerva Med 1994; 36: 83-6. 68.. Strano A, Pinto A, Galati D. Double-blind controlled study of the efficacy and pharmacologicall properties of heparan sulfate in patients with occlusive arterial disease off the lowers limbs. Drugs Exp Clin Res 1990; 16: 543-50. 69.. Allegra C, Pollari G, Carioti B, Sardina M. Thrombin and platelet inhibition with low- dosee calcium-heparin in comparison with ASA in patients with peripheral arterial occlusivee disease at Leriche-Fontaine lib class. Int J Clin Pharmacol Ther 1994; 12: 646-51. . 70.. Di Stefano F, Giglio A, Vinci M, Romano M, Salanitri G, Cossarizza A, lani P, Di Stefanoo VA. Low molecular weight heparins for long-term therapy of peripheral vascularr disease: results of a controlled study. Curr Ther Res 1988; 44: 1-10. 71.. Grégorie G, Derderian F, Le Lorier J. Selecting the language of the publications includedd in a meta-analysis: is there a Tower of Babel bias? J Clin Epidemiol 1995; 48:: 159-63. 72.. Housley E. Treating claudication in five words. BMj 1988; 296: 1483-4. 73.. Girolami B, Bernard! E, Prins MH, ten Cate JW, Hetttarachchi R, Prandoni P, Girolami A,, Büller HR. Treatment of intermittent claudication with physical training, smoking cessation,, pentoxifylline or nafronyl: a meta-analysis. Accepted for publication in the Archivess of Internal Medicine. 74.. Girolami B, Bernardi E, Koelemay M, Prandoni P, Girolami A, Prins MH. Pharmacologicall treatment of peripheral arterial occlusive disease (Fontaine's stage II):: a meta-analysis of randomised clinical trials. Thromb Haemost 1995; 6: 1386 (abstractt 1864). 75.. Moloney BA. An analysis of the side-effects of ticlopidine. In: Ticlopidine, platelets and vascularr disease. Hass WK, Easton JD, eds. New York: Spinger-Verlag 1993; 99-116.

173 3 76.. Kovacs MJ, Soong PY, Chin-Yee IH. Thrombotic thrombocytopenic purpura associ- atedd with ticlopidine. Ann Pharmacother 1993; 27: 1060-1. 77.77. Ariyoshi K, Shinohara K, Ruirong X. Thrombotic thrombocytopenic purpura caused by ticlopidine,, successfully treated by plasmapheresis. Am J Hematol 1997; 54: 1 75-6. 78.. Centurioni R, Candela M, Leoni P, Minnucci ML, Danieli C. Is ticlopidine really responsiblee for thrombotic thrombocytopenic purpura (TTP)? Haematologica 1993; 78:: 196-7.

174 174