Antithrombotic Drugs in the Primary Medical Management of Intermittent Claudication: A Meta-analysis
Bruno Girolami
,
Enrico Bernardi
,
Martin H. Prins
1
From the Institute of Medical Semeiotics, University Hospital of Padua, Italy the Department of Clinical Epidemiology, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands
,
Jan Wouter ten Cate
2
Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands
,
Paolo Prandoni
,
Rohan Hettiarachchi
1
From the Institute of Medical Semeiotics, University Hospital of Padua, Italy the Department of Clinical Epidemiology, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands
,
Elena Marras
,
Piero Maria Stefani
,
Antonio Girolami
,
Harry R. Büller
2
Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands
Background. There is no consensus on the efficacy of the antithrombotic drugs available for patients with intermittent claudication. Methods. A Medline and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). Mortality, cerebro- or cardiovascular events, amputations, arterial occlusions or number of revascularization procedures performed in the lower limbs, pain-free and total walking distance, ankle brachial index and calf blood flow, were the main outcomes considered. When feasible, end of treatment results, either continuous or binary, were combined with appropriate statistical methods. Results. Mortality was significantly decreased by ticlopidine compared to placebo (common odds ratio 0.68, 95% C.I., 0.49 - 0.95); clopidogrel decreased vascular events in comparison to aspirin (odds ratio 0.76, 95% C.I., 0.63 - 0.92) in level 1 studies. Arterial occlusions and the number of revascularization procedures performed were statistically significantly decreased by aspirin and ticlopidine, respectively. A small but statistically significant improvement in pain-free walking distance was determined by picotamide, indobufen, low molecular weight heparins, sulodexide and defibrotide, in small studies. Conclusions. Clopidogrel and ticlopidine do reduce clinically important events in patients with intermittent claudication and could be added to the primary medical treatment of these patients. The use of aspirin in these patients cannot be based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis, where it has documented efficacy. Other antithrombotic drugs were not properly evaluated in patients with intermittent claudication.
References
1
Dormandy J,
Mahir M,
Acsady G,
Balsano F,
De Leeuw P,
Blombery P,
Bousser MG,
Clement D,
Coffman J,
Deutshinoff A,
Blétry O,
Hampton J,
Mahlen F,
Ohlin P,
Rieger H,
Stranden E,
Turpie AGG,
Urai L,
Verstraete M.
Fate of the patient with chronic leg ischaemia: a review article.. J Cardiovasc Surg (Torino) 1989; 30: 50-7.
5 Antiplatelet Trialists" Collaboration Collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:: 81-106.
12
Craveri A,
Tornaghi G,
Ranieri R,
Stanzani M,
Landi G,
Paganardi L,
Passaretti B,
Gallo E.
Effects of defibrotide after oral and parenteral administration in patients with peripheral obliterative arterial disease (PAOD).. Int Angiol 1990; 9: 274-7.
15
Arcan JC,
Destors JM.
on behalf of the ACT Research Group. Controlled clinical trial of ticlopidine in patients suffering from intermittent claudication.. Thromb Res 1986; VI Suppl. 159 (abstract 315).
17
Arcan JC,
Blanchard J,
Boissel JP,
Destors JM,
Panak E.
Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications.. Angiology 1988; 39: 802-11.
18
Castelluccio A,
Bologna E.
Effect of sulodexide on blood viscosity in patients with peripheral vascular disease.. Curr Med Res Opin 1991; 12: 325-31.
20
Hess H,
Mietaschk A,
Deichsel G.
Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease: a prospective double-blind arteriographically controlled trial.. Lancet 1985; 23: 415-9.
21
Roztocil K,
Oliva I,
Prerovský I,
Linhart J.
The effect of hydroxyethylruto-side and its combination with acetylsalicylic acid in patients with obliterative atherosclerosis.. Cor Vasa 1989; 31: 128-33.
22
Mannarino E,
Pasqualini L,
Innocente S,
Scricciolo V,
Rignanese A,
Ciuffetti G.
Physical training and antiplatelet treatment in stage II peripheral arterial occlusive disease: alone or combined?. Angiology 1991; 42: 513-21.
24
Aukland A,
Hurlow RA,
George AJ,
Stuart J.
Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication.. J Clin Pathol 1982; 35: 740-3.
25
Cloarec M,
Caillard P,
Mouren X.
Double-blind clinical trial of ticlopidine versus placebo in peripheral atherosclerotic disease of the legs.. Thromb Res 1985; VI Suppl 160 (abstract 316).
26
Balsano F,
Coccheri S,
Libretti A,
Nenci GG,
Catalano M,
Fortunato G,
Grasselli S,
Violi 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
Janzon L,
Bergqvist D,
Boberg J,
Boberg M,
Eriksson I,
Lindgarde F,
Persson G.
Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study.. J Intern Med 1990; 227: 301-8.
28
Fagher B,
Persson S,
Persson G,
Larsson H.
Blood viscosity during longterm treatment 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 EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease.. Nouv Rev Fr Hematol 1993; 35:: 523-8.
30
Fagher B.
on behalf of the STIMS group in Lund. Long term effects of ticlopidine on lower limb blood flow, ankle/brachial index and symptoms in peripheral arteriosclerosis. A double-blind study.. Angiology 1994; 45: 777-88.
31
Berqvist D,
Almgren B,
Dickinson JP.
Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with Ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS).. Eur J Vasc Endovasc Surg 1995; 10: 69-76.
32
Adriaensen H.
Medical treatment of intermittent claudication: a comparative double-blind study of suloctidil, dihydroergotoxine and placebo.. Curr Med Res Opin 1976; 4: 395-401.
37
Coto V,
Cocozza M,
Oliviero U,
Lucariello A,
Picano T,
Coto F,
Cacciatore L.
Clinical efficacy of picotamide in long-term treatment of intermittent claudication.. Angiology 1989; 40: 880-5.
38
Balsano F,
Violi F.
and the ADEP Group. Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study.. Circulation 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 picotamide in patients affected by peripheral arterial disease (PAD) of the lower limbs.. Angiology 1994; 45: 137-41.
41
Tönnesen KH,
Albuquerque P,
Baitsch G,
Gomez Alonso A,
Ibanez F,
Kester RC,
Leveson S,
Poredos P.
Double-blind, controlled, multicenter study of indobufen versus placebo in patients with intermittent claudication.. Int Angiol 1993; 12: 371-7.
43
Auteri A,
Angaroni A,
Borgatti E,
Catalano M,
De Vizzi GB,
Forconi S,
Fossati L,
Girardello R,
Ambrosoli L,
Poli A,
Di Perri T.
Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo.. Int J Clin Pharmacol Res 1995; 15: 57-63.
44
Palmieri G,
Ambrosi G,
Agrati AM,
Ferraro G,
Marcozzi S.
A new low molecular weight heparin in the treatment of peripheral arterial disease.. Int Angiol 1988; 7 (Suppl. 03) (Suppl) 41-7.
45
Tesi M,
Bronchi GF,
Carini A,
Morfini M,
Cinotti S,
Filiberti E.
Efficacy and safety of a new low molecular weight heparin in the medium-term treatment of atherosclerotic 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,
Ciuffetti G.
Efficacy of low-molecular-weight heparin in the management of intermittent claudication.. Angiology 1991; 42: 1-7.
47
Calabró A,
Piarulli F,
Milan D,
Rossi A,
Coscetti G,
Crepaldi G.
Clinical assessment of low 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 treatment of peripheral arterial disease.. Clin Trials J 1984; 21: 411-27.
49
Di Stefano F,
Patané S,
Vinci M,
Giglio A,
Raciti T,
Salanitri G,
Di Stefano B.
Medical treatment of atherosclerosis: controlled clinical trial with new glycosaminoglycan: sulodexide.. Eur Rev Med Pharmacol Sci 1984; VI: 525-32.
50
Corsi C,
Bocci L,
Cipriani C,
Gazzini A,
Marrapodi E.
The effectiveness of glycosaminoglycans in peripheral vascular disease therapy: a clinical and experimental trial.. J Int Med Res 1985; 13: 40-7.
51
Bonalumi F,
Sarcina A,
Bonadeo P,
Maddinelli L.
A randomized protocol for the management of chronic peripheral arterial diseases by means of sulodexide.. Eur Rev Med Pharmacol Sci 1986; VIII: 123-9.
52
Palmieri G,
Ambrosi G,
Cantoni S,
Agrati AM,
Palazzini E.
Clinical evaluation of a native low molecular weight heparin in the management of symptomatic peripheral vasculopathy in the elderly.. Curr Ther Res 1987; 41: 998-1009.
54
Crepaldi G,
Fellin R,
Calabró 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,
Rubba P,
Postiglione A,
Strano A,
Avellone G,
Daví G,
Novo S,
Pinto A,
Capurso A,
Resta F,
Mogavero AM,
Bucci A,
Antonini R,
Lalloni L.
Double-blind multicenter trial on a new medium molecular weight glycosaminoglycan: current therapeutic effects and perspectives for clinical use.. Atherosclerosis 1990; 81: 233-43.
55
Catania G,
Salanitri T.
Pharmacological treatment of intermittent claudication: double 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 Lecce C.
and the APIC Study Group. Acenocoumarol and pentoxifylline in intermittent claudication. A controlled clinical study.. Angiology 1989; 40:: 237-48.
58
Marelli C,
Belcaro G,
Girardello R.
Defibrotide in patients with intermittent claudication. Improvement in blood flow, fibrinolytic activity, and micro-circulation after six months of treatment.. Curr Ther Res 1990; 47: 459-65.
60
Sabbá C,
Zupo V,
Dina F,
Nazzari M,
Albano O.
A pilot evaluation of the effect of defibrotide in patients affected by peripheral arterial occlusive disease.. Int J Clin Pharmacol Ther Toxicol 1988; 26: 249-52.
61
Giansante C,
Calabrese S,
Fisicaro M,
Fiotti N,
Mitri E.
Treatment of intermittent claudication with antiplatelet agents.. J Int Med Res 1990; 18: 400-7.
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 ticlopidine in patients with peripheral arterial occlusive disease at Leriche-Fontaine IIb class.. Angiology 1993; 44: 307-13.
63 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).. Lancet 1996; 348:: 1329-39.
64
Ciocon JO,
Galindo-Ciocon D,
Galindo DJ.
A comparison between aspirin and pentoxifylline in relieving claudication due to peripheral vascular disease in the elderly.. Angiology 1997; 48: 237-40.
65
Panchenko E,
Eshkeeva A,
Dobrovolsky A,
Titaeva E,
Podinovskaya Y,
Hussain KMA,
Karpov Y.
Effects of indobufen and pentoxifylline on walking capacity and hemostasis in patients with intermittent claudication: results of six months of treatment.. Angiology 1997; 48: 247-54.
66
Shustov SB.
Controlled clinical trial on the efficacy and safety of oral sulodexide in patients with peripheral occlusive arterial disease.. Curr Med Res Opin 1997; 13: 573-82.
67
Laurora G,
Ambrosoli L,
Cesarone MR,
De Sanctis MT,
Incandela L,
Marelli C,
Belcaro G.
Treatment of intermittent claudication with defibro-tide or mesoglycan: a double blind study.. PanMinerva Med 1994; 36: 83-6.
68
Strano A,
Pinto A,
Galati D.
Double-blind controlled study of the efficacy and pharmacological properties of heparan sulfate in patients with occlusive arterial disease of 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-dose calcium-heparin in comparison with ASA in patients with peripheral arterial occlusive disease at Leriche-Fontaine IIb class.. Int J Clin Pharmacol Ther 1994; 12: 646-51.
70
Di Stefano F,
Giglio A,
Vinci M,
Romano M,
Salanitri G,
Cossarizza A,
Iani P,
Di Stefano VA.
Low molecular weight heparins for long-term therapy of peripheral vascular 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 included in a meta-analysis: is there a Tower of Babel bias?. J Clin Epidemiol 1995; 48: 159-63.
73
Girolami B,
Bernardi E,
Prins MH,
ten Cate JW,
Hettiarachchi R,
Prandoni P,
Girolami A,
Büller HR.
Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline or nafronyl: a meta-analysis.. Arch Intern Med 1999; 159: 337-45.
75
Moloney BA.
An analysis of the side-effects of ticlopidine. In Ticlopidine, platelets and vascular disease..
Hass WK,
Easton JD.
eds. New York: Spinger-Verlag; 1993: 99-116.
