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Agentes antiplaquetarios para la claudicación intermitente

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Referencias

Referencias de los estudios incluidos en esta revisión

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ADEP 1993 {published data only}

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(5):1563‐9.
Violi F, Criqui M, Longoni A, Castiglioni C. Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease. Results from the A.D.E.P. study. Atherosclerosis 1996;120(1‐2):25‐35.

Arcan 1988 {published data only}

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 complications. Angiology 1988;39(9):802‐11.

Aukland 1982 {published data only}

Aukland A, Hurlow RA, George AJ, Stuart J. Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication. Journal of Clinical Pathology 1982;35(7):740‐3.

Auteri 1995 {published data only}

Auteri A, Angaroni A, Borgatti E, Catalano M, De Vizzi GB, Forconi S, et al. Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double‐blind study vs placebo. International Journal of Clinical and Pharmacology Research 1995;15(2):57‐63.

Balsano 1989 {published data only}

Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, et al. Ticlopidine in the treatment of intermittent claudication: a 21‐month double‐blind trial. Journal of Laboratory and Clinical Medicine 1989;114(1):84‐91.

CAPRIE 1996 {published data only}

CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348(9038):1329‐39.

Coto 1989 {published data only}

Coto V, Cocozza M, Oliviero U, Lucariello A, Picano T, Coto F, et al. Clinical efficacy of picotamide in long‐term treatment of intermittent claudication. Angiology 1989;40(10):880‐5.

DAVID 2004 {published data only}

Neri Serneri GG, Coccheri S, Marubini E, Violi F and for the Committees and the Investigators of the Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2‐year mortality in diabetics with peripheral arterial disease: the DAVID study. European Heart Journal 2004;25(20):1845‐52.

EMATAP 1993 {published data only}

Blanchard J, Carreras LO, Kindermans M. Results of EMATAP: a double‐blind placebo‐controlled multicentre trial of ticlopidine in patients with peripheral arterial disease. Nouvelle Revue francaise d'hematologie 1994;35(6):523‐8.
Blanchard JF, Carreras LO, The EMATAP Group. A double‐blind, placebo‐controlled multicentre trial of ticlopidine in patients with peripheral arterial disease in Argentina. Design, organization and general characteristics of patients at entry. Nouvelle Revue Francaise d'Hematologie 1992;34(2):149‐53.

Signorini 1988 {published data only}

Signorini GP, Salmistraro G, Maraglino G. Efficacy of indobufen in the treatment of intermittent claudication. Angiology 1988;39(8):742‐6.

STIMS 1990 {published data only}

Bergqvist 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). European Journal of Vascular & Endovascular Surgery 1995;10(1):69‐76.
Fagher B. Long‐term effects of ticlopidine on lower limb blood flow, ankle/brachial index and symptoms in peripheral arterioschlerosis. A double‐blind study. The STIMS Group in Lund. Swedish Ticlopidine Multicenter Study. Angiology 1994;45(9):777‐88.
Janzon L. The STIMS trial: the ticlopidine experience and its clinical applications. Swedish Ticlopidine Multicenter Study. Vascular Medicine 1996;1(2):141‐3.
Janzon L, Bergqvist D, Boberg J, Eriksson I, Lindgarde F, Persson G, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effect of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. Journal of Internal Medicine 1990;227(5):301‐8.

Tonnesen 1993 {published data only}

Tonnesen KH, Albuquerque P, Baitsch G, Alonso AG, Ibanez F, Kester RC, et al. Double‐blind, controlled, multicenter study of indobufen versus placebo in patients with intermittent claudication. International Angiology 1993;12(4):371‐7.

Referencias de los estudios excluidos de esta revisión

Ir a:

Abrahamsen 1974 {published data only}

Abrahamsen AF, Eika C, Godal HC, Lorentsen E. Effect of acetylsalicylic acid and dipyridamole on platelet surivival and aggregation in patients with atherosclerosis obliterans. Scandinavian Journal of Haematology 1974;13(4):241‐5.

Adriaensen 1976 {published data only}

Adriaensen H. Medical treatment of intermittent claudication: a comparative double‐blind study of suloctidil, dihydroergotoxine and placebo. Current Medical Research and Opinion 1976;4(6):395‐401.

Ahn 1992 {published data only}

Ahn S, Rutherford RB. A multicenter prospective randomized trial to determine the optimal treatment of patients with claudication and isolated superficial femoral artery occlusive disease: conservative versus endovascular versus surgical therapy. Journal of Vascular Surgery 1992;15(5):889‐91.

Allegra 1993 {published data only}

Allegra C, Carlizza A, Sardina M. Long‐term effects of low‐dose calcium‐heparin versus ASA in patients with peripheral arterial occlusive disease at IIb Leriche Fontaine stage. Thrombosis & Haemostasis1993; Vol. 69, issue 6:653‐Abstract No 401.

Allegra 1994 {published data only}

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. International Journal of Clinical Pharmacology & Therapeutics 1994;32(12):646‐51.

Andreozzi 1993 {published data only}

Andreozzi GM, Signorelli SS, Cacciaguerra G, Di Pino L, Martini R, Monaco S, et al. 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(4):307‐13.

Baumgartner 1992 {published data only}

Baumgartner I, Schalch I, Bollinger A. [Double blind study of the effects of dipyridamol in patients with intermittent claudication]. Vasa 1992;21(4):387‐91.

Belcaro 1991 {published data only}

Belcaro G, De Simone P. Long‐term evaluation of indobufen in peripheral vascular disease. Angiology 1991;42(1):8‐14.

Bhatt 2000 {published data only}

Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. American Heart Journal 2000;140(1):67‐73.

Boneu 1996 {published data only}

Boneu B, Destelle G. Platelet anti‐aggregating activity and tolerance of clopidogrel in atherosclerotic patients. Thrombosis & Haemostasis 1996;76(6):939‐43.

Brass 2006 {published data only}

Brass EP, Anthony R, Cobb FR, Koda I, Jiao J, Hiatt WR. The novel phosphodiesterase inhibitor NM‐702 improves claudication‐limited exercise performance in patients with peripheral arterial disease. Journal of the American College of Cardiology 2006;48(12):2539‐45.

Canonico 1991 {published data only}

Canonico V, Ammaturo V, Guarini P, Tedeschi C, Nunziata G, Nappi A, et al. The clinico‐instrumental evaluation of the efficacy of picotamide in treating chronic obstructive arteriopathies of the lower extremities [Valutazione clinico‐strumentale della efficacia della picotamide nel trattamento delle arteriopatie croniche ostruttive degli arti inferiori]. Minerva Cardioangiologica 1991;39(3):75‐80.

Cassar 2005 {published data only}

Cassar K, Ford I, Greaves M, Bachoo P, Brittenden J. Randomized clinical trial of the antiplatelet effects of aspirin‐clopidogrel combination versus aspirin alone after lower limb angioplasty. British Journal of Surgery 2005;92(2):159‐65.

Cassar 2005a {published data only}

Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Clopidogrel has no effect on D‐dimer and thrombin‐antithrombin III levels in patients with peripheral arterial disease undergoing peripheral percutaneous transluminal angioplasty. Journal of Vascular Surgery 2005;42(2):252‐8.

Cassar 2006 {published data only}

Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Variability in responsiveness to clopidogrel in patients with intermittent claudication. European Journal of Vascular & Endovascular Surgery 2006;32(1):71‐5.

Castano 1999 {published data only}

Castano G, Mas R, Roca J, Fernandez L, Illnait J, Fernandez JC, et al. A double‐blind, placebo‐controlled study of the effects of policosanol in patients with intermittent claudication. Angiology 1999;50(2):123‐30.

Castano 2001 {published data only}

Castano G, Mas Ferreiro R, Fernandez L, Gamez R, Illnait J, Fernandez C. A long‐term study of policosanol in the treatment of intermittent claudication. Angiology 2001;52(2):115‐25.

Castano 2003 {published data only}

Castano G, Mas R, Fernandez L, Gamez R, Illnait J. Effects of policosanol and lovastatin in patients with intermittent claudication: a double‐blind comparative pilot study. Angiology 2003;54(1):25‐38.

Castano 2004 {published data only}

Castano G, Mas R, Gamez R, Fernandez L, Illnait J. Effects of policosanol and ticlopidine in patients with intermittent claudication: a double‐blinded pilot comparative study. Angiology 2004;55(4):361‐71.

Catalano 1984 {published data only}

Catalano M, Libretti A. Dipyridamole combined with acetylsalicylic acid versus acetylsalicylic acid alone in the treatment of peripheral vascular disease. International Angiology 1984;3(3):321‐2.

Cesarone 1994 {published data only}

Cesarone MR, Laurora G, De Sanctis MT, Incandela L, Belcaro G. Vasospasm in patients with intermittent claudication: Effects of defibrotide and acetylsalicylic acid. Advances in Therapy 1994;11(2):62‐9.

CHARISMA 2009 {published data only}

Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, et al. CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. Journal of the American College of Cardiology 2007;49(19):1982‐8.
Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. CHARISMA Investigators. A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. [Erratum appears in Am Heart J. 2006 Jan;151(1):247]. American Heart Journal 2005;150(3):401.
Bhatt DL, Topol EJ, Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization. Management, and Avoidance Executive Committee. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high‐risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. American Heart Journal 2004;148(2):263‐8.
Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA. CHARISMA Investigators. Patients with peripheral arterial disease in the CHARISMA trial. European Heart Journal 2009;30(2):192‐201.

Ciocon 1997 {published data only}

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(3):237‐40.

CLIPS 2007 {published data only}

Catalano M, Born, G, Peto R. Critical Leg Ischaemia Prevention Study (CLIPS) Group, et al. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double‐blind trial. Journal of Internal Medicine 2007;261(3):276‐84.

Creutzig 1994 {published data only}

Creutzig A, Ranke C, Luska G, Wagner HH, Galanski M, Bode Boger S, et al. Controlled trial of high versus low dose aspirin treatment after PTA in patients with peripheral vascular disease. Annals of Hematology1994; Vol. 68, issue Suppl 1:A74.

Davi 1985 {published data only}

Davi G, Pinto A, Francavilla G, Paterna S, Campisi D, Strano A. Inhibition of platelet functon by ticlopidine in arteriosclerosis obliterans of the lower limbs. Thrombosis Research 1985;40(2):275‐81.

Destors 1985 {published data only}

Destors JM, Arcan JC. Evaluation of oral drugs for intermittent claudication of the legs in phase III clinical trials. Options selected for the ACT study. Therapie 1985;40(6):451‐8.

Duda 2001 {published data only}

Duda SH, Tepe G, Luz O, Ouriel K, Dietz K, Hahn U, et al. Peripheral artery occlusion: treatment with abciximab plus urokinase versus with urokinase alone‐a randomized pilot trial (the PROMPT Study). Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis. Radiology 2001;221(3):689‐96.

Ehresmann 1977 {published data only}

Ehresmann U, Alemany J, Loew D. [Use of acetylsalicylic acid in the prevention of re‐occlusion following revascularization interventions. Results of a double‐ blind long term study]. Die Medizinische Welt 1977;28(26):1157‐62.

Eikelboom 2005 {published data only}

Eikelboom JW, Hankey GJ, Thom J, Claxton A, Yi Q, Gilmore G, et al. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. Journal of Thrombosis & Haemostasis 2005;3(12):2649‐55.

Elam 1998 {published data only}

Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson M, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arteriosclerosis, Thrombosis and Vascular Biology 1998;18(12):1942‐7.

Fabris 1992 {published data only}

Fabris F, Steffan A, Randi ML, Avruscio GP, Cordiano I, Girolami A. Indobufen versus dipyridamole plus aspirin in the treatment of patients with peripheral atherosclerotic disease. Journal of Medicine 1992;23(2):81‐92.

Fiotti 2003 {published data only}

Fiotti N, Altamura N, Cappelli C, Schillan M, Guarnieri G, Giansante C. Long term prognosis in patients with peripheral arterial disease treated with antiplatelet agents. European Journal of Vascular & Endovascular Surgery 2003;26(4):374‐80.

Fowkes 2010 {published data only}

Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010;303(9):841‐8.

Giansante 1990 {published data only}

Giansante C, Calabrese S, Fisicaro M, Fiotti N, Mitri E. Treatment of intermittent claudication with antiplatelet agents. The Journal of International Medical Research 1990;18(5):400‐7.

Gillot 1976 {published data only}

Gillot P. A double‐blind study comparing suloctidil and placebo in chronic peripheral arteriopathy. Current Therapeutic Research 1976;20(5):637‐44.

Gregoratti 1982 {published data only}

Gregoratti L, Redaelli G, Limido P, Ghiringhelli L. Clinical and instrumental evaluation of patients with chronic peripheral arterial occlusive disease after prolonged administration of suloctidil. La Clinica Terapeutica 1982;102(6):607‐19.

Gresele 2000 {published data only}

Gresele P, Migliacci R, Di Sante G, Nenci GG, CRAMPS Investigator Group. Effect of cloricromene on intermittent claudication. A randomized, double‐blind, placebo‐controlled trial in patients treated with aspirin: effect on claudication distance and quality of life. Vascular Medicine 2000;5(2):83‐9.

Guan 2003 {published data only}

Guan H, Wang Y, Zhang B, Ye W, Fu W, Liang W, et al. Comparison of beraprost and ticlopidine in Chinese patients with chronic peripheral arterial occlusion: a multicenter, single‐blind, randomized, controlled study. Current Therapeutic Research, Clinical and Experimental 2003;64(7):488‐503.

Harker 1999 {published data only}

Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Safety 1999;21(4):325‐35.

Hawker 1984 {published data only}

Hawker RJ, Aukland A. Platelet survival, atherosclerotic intermittent claudication and ticlopidine. Atherosclerosis 1984;50(2):147‐58.

Hess 1985 {published data only}

Hess H, Mietaschik 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;1(8426):415‐9.

Hevia 1992 {published data only}

Hevia Alonso A, Gago Angelino J, Lopez‐Valpuesta FJ, Serrano Molina JS, Fernandez‐Sanz S. The effects of ticlopidine and nifedipine on platelet aggregation in patients with obliterant artheriopathy of the lower limbs. Revista Clinica Espanola 1992;190(6):295‐8.

Hiatt 2002 {published data only}

Hiatt WR. Abciximab added to urokinase increased amputation‐free survival in peripheral arterial occlusion of the legs. ACP Journal Club 2002;137(1):12.

Holm 1984 {published data only}

Holm J, Lindblad L, Schersten T, Suurkula M. Intermittent claudication: Suloctidil vs placebo treatment. Vasa 1984;13(2):175‐8.

Hsieh 2009 {published data only}

Hsieh CJ, Wang PW. Effect of cilostazol treatment on adiponectin and soluble CD40 ligand levels in diabetic patients with peripheral arterial occlusion disease. Circulation Journal 2009;73(5):948‐54.

Jagroop 2004 {published data only}

Jagroop IA, Matsagas MI, Geroulakos G, Mikhailidis DP. The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease. Platelets 2004;15(2):117‐25.

Jones 1982 {published data only}

Jones NAG, De Haas HA, Zahavi J, Kakkar VV. A double‐blind trial of suloctidil versus placebo in intermittent claudication. British Journal of Surgery 1982;69(1):38‐40.

Kakkar 1981 {published data only}

Kakkar VV, Jones NAG, De Haas J, Zahavi J. A double blind trial ‐ suloctidil versus placebo in intermittent claudication. Thrombosis & Haemostasis1981; Vol. 46, issue 1:92.

Katsumura 1982 {published data only}

Katsumura T, Mishima Y, Kamiya K, Sakaguchi S, Tanabe T, Sakuma A. Therapeutic effect of ticlopidine, a new inhibitor of platelet aggregation, on chronic arterial occlusive diseases, a double‐blind study versus placebo. Angiology 1982;33(6):357‐67.

Labs 1999 {published data only}

Labs KH, Nehler MR, Roessner M, Jaeger KA, Hiatt WR. Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol. Vascular Medicine 1999;4(4):239‐46.

Landini 1989 {published data only}

Landini G, Poggiali C, Calacoci S, Marino N, Rosselli A. Platelet aggregation inhibitory therapy in chronic arterial occlusive disease of the lower limbs: results of short‐term clinico‐instrumental study with indobufen. Recenti Progressi in Medicina 1989;80(4):204‐7.

Leo 2007 {published data only}

Leo W, Westrych R, Bissinger A, Okraszewski J, Baj Z. [Effect of the acetylosalicyd acid (ASA) and ticlopidine therapy on clinical condition and parameters of blood platelets in patients with peripheral arterial occlusive disease (PAOD)]. Polski Merkuriusz Lekarski 2007;23(137):335‐9.

Libretti 1986 {published data only}

Libretti A, Catalano M. Treatment of claudication with dipyridamole and aspirin. International Journal of Clinical and Pharmacology Research 1986;6(1):59‐60.

Libretti 1986a {published data only}

Libretti A, Catalano M. Treatment of claudication with dipyridamole and aspirin. Monographs on Atherosclerosis 1986;14:207‐9.

Lievre 1996 {published data only}

Lievre M, Azoulay S, Lion L, Morand S, Girre JP, Boissel JP. A dose‐effect study of beraprost sodium in intermittent claudication. Journal of Cardiovascular Pharmacology 1996;27(6):788‐93.

Lievre 2000 {published data only}

Lievre M, Morand S, Besse B, Fiessinger JN, Boissel JP. Oral Beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a double‐blind, randomized, multicenter controlled trial. Circulation 2000;102(4):426‐31.

Mangiafico 2000 {published data only}

Mangiafico RA, Messina R, Attina T, Dell'Arte S, Giuliano L, Malatino LS. Impact of a 4‐week treatment with prostaglandin E1 on health‐related quality of life of patients with intermittent claudication. Angiology 2000;51(6):441‐9.

Mannarino 1991 {published data only}

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(7):513‐21.

Mannucci 1987 {published data only}

Mannucci L, Maderna P, Colli S, Lavezzari M, Sirtori CR, Tremoli E. Indobufen is a potent inhibitor of whole blood aggregation in patients with a high atherosclerotic risk. Thrombosis Research 1987;48(4):417‐26.

Mantero 1983 {published data only}

Mantero M, Bondioli A, Catenazzo G. Suloctidil: a controlled clinical and instrumental study on patients with claudicatio intermittens. Gazzetta Medica Italiana 1983;142(10):475‐8.

Marelli 1990 {published data only}

Marelli C, Belcaro G, Girardello R. Defibrotide in patients with intermittent claudication. Improvement in blood flow, fibrinolytic activity and microcirculation after six months of treatment. Current Therapeutic Research, Clinical and Experimental 1990;47(3):459‐65.

Marrapodi 1994 {published data only}

Marrapodi E, Leanza D, Giordano S, Nazzari M, Corsi C. Effects of defibrotide on physical performance and hemorheologic picture in patients with peripheral arteriopathy. Clinical Trials and Meta‐Analysis 1994;29(1):21‐30.

Miyazaki 2007 {published data only}

Miyazaki M, Higashi Y, Goto C, Chayama K, Yoshizumi M, Sanada H, et al. Sarpogrelate hydrochloride, a selective 5‐HT2A antagonist, improves vascular function in patients with peripheral arterial disease. Journal of Cardiovascular Pharmacology 2007;49(4):221‐7.

Mohler 2003 {published data only}

Mohler ER, Hiatt WR, Olin JW, Wade M, Jeffs R, Hirsch AT. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double‐blinded, randomized, controlled trial. Journal of the American College of Cardiology 2003;41(10):1679‐86.

Neirotti 1994 {published data only}

Neirotti M, Molaschi M, Ponzetto M, Macchione C, Poli L, Bonino F, et al. Hemodynamic, hemorheologic, and hemocoagulative changes after treatment with picotamide in patients affected by peripheral arterial disease (PAD) of the lower limbs. Angiology 1994;45(2):137‐41.

Nenci 1979 {published data only}

Nenci GG, Agnelli G, Berrettini M, Parise P, Ballatori E. Inhibition of spontaneous platelet aggregation by sulfinpyrazone. Thrombosis & Haemostasis 1979;42(2):621‐5.

Nenci 1982 {published data only}

Nenci GG, Berrettini M, Iadevaia V, Parise P, Ballatori E. Inhibition of spontaneous platelet aggregation and adhesion by indobufen (K 3920). A randomized, double‐blind crossover study on platelet, coagulation and fibrinolysis function tests. Pharmatherapeutica 1982;3(3):188‐94.

Norgren 2006 {published data only}

Norgren L, Jawien A, Matyas L, Riegerd H, Arita K, European MCI‐9042 Study Group. Sarpogrelate, a 5‐HT2a receptor antagonist in intermittent claudication. A Phase II European study. Vascular Medicine 2006;11(2):75‐83.

Novo 1996 {published data only}

Novo S, Abrignani MG, Pavone G, Zamueli M, Pernice C, Geraci AM, et al. Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. International Angiology 1996;15(2):169‐74.

O'Donnell 2008 {published data only}

O'Donnell ME, Badger SA, Sharif MA, Makar RR, Young IS, Lee B, et al. The effects of cilostazol on peripheral neuropathy in diabetic patients with peripheral arterial disease. Angiology 2009;59(6):695‐704.

O'Donnell 2009 {published data only}

O'Donnell ME, Badger SA, Sharif MA, Makar RR, Young IS, Lee B, et al. The vascular and biochemical effects of cilostazol in diabetic patients with peripheral arterial disease. Vascular and Endovascular Surgery 2009;43(2):132‐43.

Okadome‐Kenchiro 1992 {published data only}

Okadome‐Kenchiro, et al. Efficacy of lipo PGE1 in combination with an oral anti‐platelet agent in chronic arterial obstruction: A multicenter comparative study. Rinsho to Kenkyu 1992;69:3655‐62.

Panchenko 1997 {published data only}

Panchenko E, Eshkeeva A, Dobrovolsky A, Titaeva E, Podinovskaya Y, Hussain KM, et al. Effects of indobufen and pentoxifylline on walking capacity and hemostasis in patients with intermittent claudication: results of six months treatment. Angiology 1997;48(3):247‐54.

Pasqualini 2002 {published data only}

Pasqualini L, Pirro M, Lombardini R, Ciuffetti G, Dragani P, Mannarino E. A human model of platelet‐leucocyte adhesive interactions during controlled ischaemia in patients with peripheral vascular disease. Journal of Clinical Pathology 2002;55(12):946‐50.

Pollastri 1991 {published data only}

Pollastri M, Saccocci M, Corsi C, Monici Preti PA, Cantini L. Controlled study on the efficacy and tolerability of trapidil in the treatment of intermittent claudication of the lower extremities. One‐year review. Archivio di Medicina Interna 1991;43(4):197‐207.

POPADAD 2008 {published data only}

Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. British Medical Journal 2008;337:a1840.

Randi 1985 {published data only}

Randi ML, Fabris F, Crociani ME, Battocchio F, Girolami A. Effects of ticlopidine on blood fibrinogen and blood viscosity in peripheral atherosclerotic disease. Arzneimittel‐Forschung 1985;35(12):1847‐9.

Randi 1991 {published data only}

Randi ML, Mares M, Fabris F, Tison T, Barbone E, Girolami A. Decrease of fibrinogen in patients with peripheral atherosclerotic disease by ticlopidine. Arzneimittel‐Forschung 1991;41(4):414‐6.

Ranke 1992 {published data only}

Ranke C, Creutzig A, Luska G, Wagner H‐H, Galanski M, Frolich JC, et al. [Comparison of 50 mg and 900 mg/day acetylsalicylic acid for prevention of recurrence after percutaneous transluminal angioplasty of the lower extremities: results of the LARA study]. Vasa.Supplementum 1992;35:42‐5.

Ranke 1993 {published data only}

Ranke C, Creutzig A, Luska G, Wagner HH, Galanski M, Bode‐Boger S, et al. Dose‐dependent side effects of acetylsalicylic acid therapy. Results of a prospective randomized clinical study in patients with peripheral arterial occlusive disease. Medizinische Klinik 1993;88(10):571‐6.

Ranke 1994 {published data only}

Ranke C, Creutzig A, Luska G, Wagner HH, Galanski M, Bode‐Boger S, et al. Controlled trial of high‐ versus low‐dose aspirin treatment after percutaneous transluminal angioplasty in patients with peripheral vascular disease. The Clinical Investigator 1994;72(9):673‐80.

Regenthal 1991 {published data only}

Regenthal R, Voigt H, Reuter W, Preiss R. [The effect of oral trapidil therapy on clinical and hemorheological parameters in arteriosclerosis obliterans in comparison to pentoxifylline‐‐a pilot study]. Zeitschrift fur die Gesamte Innere Medizin und Ihre Grenzgebiete 1991;46(6):185‐90.

Rossini 1998 {published data only}

Rossini A, Tascino C, Costa F. Heparan sulphate in association with indobufen in the treatment of chronic peripheral obliterative arteriopathy of the lower extremities. Controlled clinical trial. Minerva Cardioangiologica 1998;46(11):457‐69.

Roztocil 1989 {published data only}

Roztocil K, Oliva I, Prerovsky I, Linhart J. The effect of hydroxyethylrutoside and its combination with acetylsalicylic acid in patients with obliterative atherosclerosis. Cor et Vasa 1989;31(2):128‐33.

Rudofsky 1987 {published data only}

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Singer 2006 {published data only}

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Tepe 2007 {published data only}

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Topol 2000 {published data only}

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

ADEP 1993

Methods

Randomised, double‐blinded, controlled trial, stratified by centre.

Multicentre (120 Italian centres) study.

Enrolment started in January 1989.

Power calculation: Based on detection of 25% reduction of "major and minor events" compared with untreated patients (estimated as 14% in 18 months from PACK study), the number of patients required would be 1100 for α = 0.05 and β = 0.20, one‐tailed test. The number of patients enrolled increased by 10% to account for lost to follow‐up.

ITT analysis: performed.

Single‐blinded run‐in period of one month on placebo treatment.

Follow‐up length: 18 months.

Participants

Number of patients randomised: 2304.

1150 (picotamide) versus 1154 (placebo).

Male : female ratio = 84.9% male (picotamide); 83.6% male in (placebo).

Age (mean with SD): 63.4 ± 7.31 (picotamide); 62.9 ± 7.45 (placebo).

Inclusion criteria: consecutive patients up to age of 80 suffering from PVD screened.  PVD was defined according to one or more of the following criteria: patients with claudication defined as leg pain on walking that disappeared in five minutes on standing and an ABPI by Doppler ultrasonography ≤0.85 in the posterior and anterior tibial artery of one foot; or patients with claudication with previous amputation or reconstructive vascular surgery.

Exclusion criteria: treatment with antiplatelet drugs such as aspirin, ticlopidine, dipyridamole, indobufen and other NSAIDs, anticoagulants; pain at rest; skin lesions; myocardial infarction, stroke, or survival intervention in the previous three months; stable or unstable angina requiring aortocoronary bypass or angioplasty; liver insufficiency (prothrombin activity ≤ 40%); serious renal disorders (serum creatinine ≥2.8 mg%) and other conditions resulting in a life expectancy of < 2 years.

Interventions

Intervention: picotamide 300 mg tds.

Control: placebo tds.

Outcomes

All cause mortality.

Cardiovascular mortality.

Myocardial infarction (fatal and non‐fatal).

Stroke (fatal and non‐fatal).

Adverse events leading to cessation of therapy.

Progression of disease resulting in need for revascularisation.

Amputation (above ankle).

Adverse events: adverse events leading to cessation of therapy, gastrointestinal symptoms.

Notes

Source of funding: Samil S.p.A.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomisation lists were generated by an automatic procedure developed expressly to have two balanced groups in each centre".

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind study", "placebo used", "appearance and taste of the capsules were identical".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind study", "qualitative evaluation of selected events validated under blinded conditions by an independent review committee".

Comment: it was not stated explicitly if assessors were blinded to the randomisation arm. Probably done.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Lost to follow‐up: 57/1150(4.9%) (picotamide), 59/1154 (5.1%) (placebo).

Withdrawal from study: 48/1150 (4.2%) (picotamide), 29/1154 (2.5%) (placebo).

Comment: rate of withdrawal is higher in picotamide group (P = 0.02, Chi2 test).

Rate of patients lost to follow‐up were comparable (P = 0.86, Chi2 test).

Selective reporting (reporting bias)

Low risk

Outcomes clearly listed and defined, all reported clearly in a table.
Arcan 1988

Methods

Randomised, double blinded, placebo controlled trial.

Multicentre (29 French and 1 Swiss) study.

Study period: December 1982 ‐ October 1985.

Power calculation: 204 patients required, based on a "success" rate of 30% with placebo increased to 50% with ticlopidine. The hypothesis under investigation was set one‐tailed with a type I error of 0.05 and a statistical power of 0.90.

ITT analysis: performed.

Four week, single‐blind placebo run in.

Follow‐up length: 24 weeks.

Participants

Number of patients: 169.

83 (ticlopidine) versus 86 (placebo).

Male : female ratio = 154 : 15.

Age (mean): 59.87 ± 1.03 (ticlopidine); 58.53 ± 0.98 (placebo).

Inclusion criteria: symptomatic intermittent claudication for at least 12 months and had to present a walking distance assessed by treadmill testing (3.2 km/h, 10% slope, ambient temperature 20‐24 oC) of between 50 and 300 meters. Patient was included if the relative variation of the walking distance was within 25% of initial values at the end of the run‐in period. A recent confirmation of obstructive arterial disease was required by either angiography (< 6 months) or Doppler studies (< 3 months).

Exclusion criteria: patient less than 35 or older than 75 years old, stage III or IV Fontaine disease, purely diabetic arteriopathy, vascular surgery within the past six months or planned within the next six months, severe hypertension not adequately controlled by treatment, need for treatment with anti‐inflammatory or anti‐coagulant or vasodilating agents, any contra‐indication to ticlopidine, hepatic or renal disease, and poor vital prognosis.

Interventions

Intervention: ticlopidine 250 mg bd.

Control: placebo bd.

Outcomes

All cause mortality.

Cardiovascular mortality.

Cardiovascular events (MI, stroke or TIA).

Walking distance: total and pain free walking distance (data presented in graphical form).

Adverse events: adverse events leading to cessation of therapy; GI symptoms (dyspepsia).

Need for revascularisation.

Notes

Trial enrolment terminated early because of persistence of a much slower recruitment rate than expected.

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "An academic audit centre...issued the randomisation list".

Comment: However, it was unclear how sequence generation was conducted.

Allocation concealment (selection bias)

Unclear risk

Quote: "An academic audit centre, independent of the sponsor and clinical investigators, was established, to implement an external quality control. It participated in all administrative commitment. It issued the randomisation list".

Comment: Unclear how list was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "An academic audit centre, independent of the sponsor and clinical investigators...carried out the labelling of the treatment containers", "matching placebo".

Comment: most likely participants were blinded to the treatment that they received.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "validation committee, blinded to the allocated treatment, had to validate and classify the patients' critical events and evaluate all the files to assign a final result of 'success' or 'failure'".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Patients discontinued treatment early 17/83 (20.5%) ticlopidine group, 12/86 (14.0%) placebo group, mostly (14/83 (16.9%) ticlopidine, 11/86 (12.8%) placebo) due to occurrence of critical events.

Comment: All patients fully accounted for, including those who had early withdrawals of treatment. The numbers were also balanced between arms (P = 0.26, Chi2 test) and events reported.

Selective reporting (reporting bias)

Low risk

Outcomes reported according to the method stated in the paper, and consistent with objectives of paper (earlier protocol published in French not accessed).

Aukland 1982

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Single centre (UK) study.

Power calculation: not performed.

ITT analysis: not performed.

Placebo run‐in period of four weeks.

Follow‐up length: 12 months.

Participants

Number of patients enrolled: 65.

Number of patients evaluated: 51.

25 (ticlopidine) versus 26 (placebo).

All male.

Age: Mean 59 (range 40 to 75).

Inclusion criteria: intermittent claudication for at least one year, no change in claudication distance for at least three months, no rest pain, and patients not considered for arterial surgery.

Exclusion criteria: not specified.

Interventions

Intervention: ticlopidine 250 mg bd.

Control: placebo.

Outcomes

Need for revascularisation.

Adverse events: GI symptoms.

Notes

17 patients had undergone previous vascular reconstructive surgery.

16 patients had history of angina or myocardial infarction.

Source of funding: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "one year randomised trial".

Comment: randomisation method not stated.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind, one year randomised trial".

Comment: probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind, one year randomised trial".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Drop out rates: 8/33 (24.2%) ticlopidine, 6/32 (19.0%) placebo

Comment: drop out rates comparable (P = 0.59, Chi2 test) between groups.

four withdrawals, four defaulters, two deaths, and three with non‐thrombotic medical conditions.

Selective reporting (reporting bias)

High risk

Did not present ABPI or walking results for placebo group.
Auteri 1995

Methods

Randomised, double blinded, placebo controlled trial.

Multicentre (seven Italian centres) study.

Power calculation: based on a 5% risk of error of the first type (α) and a 10% risk of error of the second type (β), on the hypothesis of a 60% frequency of success (40% increase of total walking distance over the basal level after 24 weeks of treatment with triflusal) and 30% target difference versus placebo.

ITT analysis: not performed.

Follow‐up length: 24 weeks.

Participants

Number of patients: 122.

59 (triflusal) versus 63 (placebo).

Male : female ratio = 112 : 16.

Age (mean and SD): 64 ± 7.7 (range 40 ‐ 75).

Inclusion criteria: stage II Fontaine claudicants.

Exclusion criteria: allergy or hypersensitivity to cyclo‐oxygenase inhibitors, assuming drugs that might affect coagulation or fibrinolysis, affected by hypertension, recent myocardial infarction, stroke, cranial trauma or other conditions for active bleeding, peptic ulcers or active organic dyspeptic syndromes, coagulation disorders or other conditions with haemorrhagic, neutropaenia, insulin dependent diabetes, lung, kidney, liver, neurological, psychiatric or haematological disorders or other systemic diseases of clinical importance, any type of neoplasia, surgery during the three antecedent months and use of narcotics.

Interventions

Intervention: triflusal 300 mg bd.

Control: placebo bd.

Outcomes

Walking distance: total and pain free walking distance.

Adverse events: adverse events leading to cessation of therapy, GI symptoms.

Notes

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "random oral administration".

Comment: unclear how random sequence was generated.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind versus placebo".

Comment: probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind versus placebo".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Early cessation of treatment:: 4/59 (6.8%) triflusal group, 1/63 (1.6%) placebo group.

Comment: All patients who stopped treatment early were fully accounted for. Drop out rates comparable between groups (P = 0.20, Fisher's exact test).

Selective reporting (reporting bias)

Unclear risk

Original study protocol cannot be obtained, but matches methods section.

Comment: type of outcomes reported in paper is rational compared with the objectives and length of treatment in the study.

Balsano 1989

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Multicentre (European) study.

Power calculation: not performed.

Three month single‐blind placebo run‐in period.

ITT analysis: performed.

Follow‐up length: 21 months.

Participants

Number of patients: 151.

76 (ticlopidine) versus 75 (placebo).

Male : female ratio = 110 : 42.

Age (mean): 59.5 (range 35 ‐ 75) (ticlopidine); 59.9 (range 40 ‐ 75) (placebo).

Inclusion criteria: typical intermittent claudication for at least six months, pain free walking distance of 300 m or less as determined on a treadmill (4 kph, no inclination), ankle‐arm systolic blood pressure ratio ≤0.9 at rest in the claudicating leg and further decreased three minutes after the end of the walking test.

Exclusion criteria: age > 75 years, treatment in the last six months with angioplasty, thrombolytic drugs or vascular surgery; presence of rest pain or ischaemic skin ulcer; unable to walk on the treadmill, absent ultrasound signals at any foot arteries; concomitant use of oral anti‐coagulants, aspirin, buflomedil, clofibrate, dipyridamole, ditazol, flunarizine, nicergoline, pentoxifylline, suloctidil and sulphinpyrazone.

Interventions

Intervention: ticlopidine 250 mg bd.

Control: placebo bd.

Outcomes

All cause mortality.

Vascular mortality (stroke or MI related death).

Vascular events (fatal and non‐fatal MI or stroke).

Walking distance: total and pain free walking distance (data could not be extracted).

Revascularisation.

Amputation.

ABPI: data could not be extracted.

Adverse events: adverse events resulting in cessation of study treatment; major bleeding, GI symptoms (dyspepsia).

Notes

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomly assigned".

Comment: randomisation method not stated.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind study", "all tablets were indistinguishable in appearance and taste".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind study".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Drop‐out rate: 17/76 (22.3%) ticlopidine group, 14/75 (18.7%) placebo group.

Comment: drop‐out rate comparable between groups (P = 0.57, Chi2 test). Other reasons of drop out were not clear.

Selective reporting (reporting bias)

Unclear risk

Comment: type of outcomes reported in paper is rational compared with the objectives and length of treatment in the study.

CAPRIE 1996

Methods

Randomised, double‐blinded, controlled trial

Multicentre (384 centres in 16 countries: US, Canada and Europe) study.

Power calculation: 5000 patients required in PAD subgroup, assuming a three‐year event rate of 14% for PAD, and 25% for patients with stroke or MI, study was expected to have 90% power to detect an overall relative risk reduction of 11.6%, based on the ITT analysis with a two sided α = 0.05.

ITT analysis: performed.

Study period: March 1992 to February 1996.

Follow‐up length: Varied for patients, common stop date for all. (Mean: 1.91 years).

Participants

Number of patients: 6452.

3223 (clopidogrel) versus 3229 (aspirin).

Male : female ratio = 73% male (clopidogrel); 72% male (aspirin).

Age: (mean with SD): 64.2 ± 9.6 (clopidogrel); 64.4 ± 9.7 (aspirin).

Inclusion criteria: for PAD patients ‐ intermittent claudication (WHO: leg pain on walking, disappearing in <10 min on standing) of presumed atherosclerotic origin; and ABPI ≤ 0.85 in either leg at rest (two assessments on separate days); or history of intermittent claudication with previous leg amputation, reconstructive surgery, or angioplasty with no persisting complications from intervention.

Exclusion criteria: age <21 years, scheduled for major surgery, severe co‐morbidity likely to limit life expectancy to less than three years, uncontrolled hypertension, contraindication to study drugs (severe renal or hepatic insufficiency; history of haemostatic disorder or systemic bleeding, thrombocytopaenia or neutropaenia, drug induced haematological or hepatic abnormalities; abnormal WCC, differential or platelet count; anticipated requirement for long term anticoagulant, non‐study antiplatelet drugs or NSAIDs affecting platelet function; history of aspirin sensitivity), women of childbearing age not using reliable contraception, currently receiving investigation drug, previous participation in other clopidogrel studies and geographic or other factors making study participation impractical.

Interventions

Intervention: clopidogrel 75 mg plus aspirin placebo od.

Control: aspirin 325 mg plus clopidogrel placebo od.

Outcomes

All cause mortality.

Vascular mortality.

Cardiovascular events (fatal or non‐fatal MI and ischaemic stroke).

Vascular events: amputation ‐ results could not be inferred (for PAD).

Adverse events: gastrointestinal and intracranial haemorrhage (data for PAD could not be inferred).

Notes

Source of funding: Sanofi‐Aventis and Bristol‐Myers Squibb.

Included patients with ischaemic stroke and myocardial infarction. Data was available for patients with PAD.

PAD patients included patients with previous leg amputation, reconstructive surgery or angioplasty with no persisting complications from intervention.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "computer generated blocks of four treatments, stratified by disease subgroup and treatment centre".

Allocation concealment (selection bias)

Low risk

Quote: "access to the study code restricted to Independent Statistical Centre, Chairman of External Safety and Efficacy Monitoring Committee and two independent companies responsible for preparing the study drug".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "patients allocated study drugs sequentially from supplies at the clinical centre", "supplies were in identical blister packs containing either 75 mg tablets of clopidogrel plus aspirin placebo or 325 mg aspirin plus clopidogrel placebo tablets", "initial supply of study drug had a sealed treatment code label attached which once opened, could not be resealed in its original form. This was retained by centre for emergency purposes". "At the close of the study, a representative sample of 3358 code‐break labels were retrieved...to verify that there were no unreported code‐break labels".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "external validation committee used"'

Comment: most likely done.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

42 in whole study lost to follow‐up: 22/9599(0.22%) clopidogrel group, 20/9586 (0.21%) aspirin group.

Search company hired to look for patients lost to follow‐up.

4059 (21.2%) patients in whole study had study drug permanently discontinued: 21.3% (clopidogrel) and 21.1% (aspirin).

Selective reporting (reporting bias)

Low risk

Comment: outcomes reported consistent with protocol.
Coto 1989

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Single centre (Italy) study.

Power calculation: not performed.

ITT analysis: not performed.

20 day placebo washout period.

Follow‐up length: six months.

Participants

Number of patients: 40.

19 (picotamide) versus 21 (placebo).

Male : female ratio = 25 : 15.

Age: 40 to 70 (average 63 ± 10.7).

Inclusion criteria: functional stage II Fontaine, intermittent claudication for at least six months, a pain free walking distance of less than 300 metres, and an ABPI < 0.8 at rest.

Exclusion criteria: congenital or acquired haemorrhagic diseases and uncontrolled hypertension. Patients with diabetes and with severe hepatic or renal impairment, or both, were also excluded.

Interventions

Intervention: picotamide 300mg tds.

Control: placebo tds.

Outcomes

Cardiovascular events.

Walking distance: pain free walking distance.

ABPI.

Adverse events: adverse events leading to cessation of therapy, GI symptoms (dyspepsia).

Notes

Placebo given to all patients during a washout and stabilisation period of 20 days. Only patients who had less than 20% variability in pain free walking distance and ABPI during this period were included.

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomised into two groups".

Comment: method not clearly stated.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "double‐blind fashion".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "double‐blind fashion".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Drop‐out rates: 2/19 (10.5%) picotamide, 3/21 (14.3%) placebo group (P = 0.55, Fisher's exact test).

Number of evaluable patient: 35 (five withdrawals: two in picotamide group due to gastric discomfort; three in placebo group ‐ two kept on smoking and one had gastric discomfort).

Selective reporting (reporting bias)

Unclear risk

Comment: protocol not available, and methods section in paper was brief. However, the type of outcomes was appropriate after taking into account the objectives, length of study and sample size.

DAVID 2004

Methods

Randomised, double blinded trial.

Multicentre (86 centres in Italy) study.

Study enrolment: February 1996 to October 1998.

Power calculation: 584 patients per group were required to detect an absolute reduction of mortality under picotamide of 3.5% in two years (assuming a two‐year mortality rate of 6.5% in the aspirin group), with a power of 80% and a significance level set at 0.05 (two‐sided).

ITT analysis: performed.

Follow‐up length: 24 months (IQR 1.9 to 2.1 years).

Participants

Number of patients: 1209.

603 (picotamide) versus 606 (aspirin).

Male : female ratio = 878 : 331.

Age (mean with SD): 63.8 ± 7.2 (picotamide), 64.6 ± 7.3 (aspirin).

Inclusion criteria: aged between 40 and 75 years old, and with history of type II diabetes for five years or more and PAD. PAD defined as the presence of two or more of the following: 1) history of intermittent claudication lasting more than two months; 2) loss of posterior tibial pulse in the foot; 3) ABPI < 0.90 or > 1.30 in the posterior or anterior tibial artery of the foot; 4) amputation or reconstructive surgery in patients with previous history of intermittent claudication; 5) angioplasty with no persisting complication from intervention.

Exclusion criteria: myocardial infarction, stroke or unstable angina in the six months prior to enrolment; severe neurological or mental deficits likely to make the patient non‐compliant; severe co‐morbidity likely to limit patient's life expectancy to less than two years; serum creatinine > 2.0 mg/dL; high risk of endo‐ocular bleeding; alanine aminotransferase or aspartate aminotransferase over three times the upper limit of normal; platelets < 100,000 per mm3; active peptic ulcer or gastro‐enteric bleeding in the six months prior to enrolment; pregnancy; severe, uncontrolled hypertension; total cholesterol level ≥ 300 mg/dL; picotamide or aspirin sensitivity. Patients scheduled for major surgery or requiring long term anti‐coagulant treatment were also excluded.

Interventions

Intervention: picotamide 600 mg bd.

Control: aspirin 320 mg (every morning) plus placebo (evening).

Outcomes

All cause mortality.

Cardiovascular mortality: MI or stroke related death.

Cardiovascular events: fatal and non‐fatal MI or stroke.

Amputation.

Adverse events: adverse events leading to cessation of therapy; major bleeding (requiring hospitalisation), GI symptoms.

Notes

Source of funding: Novartis S.p.a.

Number of patients available for data differ between data points.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomisation list was performed stratified by centre with treatment in balanced blocks of four patients within each centre, a 1:1 treatment allocation was used”.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "blinding was maintained by the use of indistinguishable active drugs and placebo tablets in separate bottles labelled for morning and evening intake".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Around 20% of patients in each group was lost to follow‐up for the secondary end‐points (mortality plus non‐fatal vascular events).

Lost to follow‐up : 32/603(5.3%) picotamide, 26/606 (4.3%) aspirin (P = 0.41, Chi2 test).

Treatment discontinued early: 159/603 in picotamide and 160/606 in aspirin

  • Adverse event: 11.9% picotamide, 14.4% aspirin.

  • Withdrawal of consent: 10.1 % picotamide, 8.6% aspirin.

  • Taking contraindicated medications: 1.5% picotamide, 1.3% aspirin.

  • Non compliance: 1.2% picotamide, 0.8% aspirin.

  • Others 1.7% picotamide, 1.3% aspirin.

Selective reporting (reporting bias)

Low risk

Comment: outcomes reported consistent with protocol.
EMATAP 1993

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Multicentre (21 centres in Argentina) study.

Power calculation: based on a 10% rate of outcome events in the placebo group, with an expected rate of 3.5% in the ticlopidine group, it was proposed to recruit 600 patients. This would give a 95% chance of demonstrating a significant difference in outcome between the two treatment groups at the one‐sided significance level of 5%.

ITT analysis: performed. Lost to follow‐up considered as failure, for example, occurrence of an outcome event at the date of the last visit except if investigation proves that patient was event free at the end of his planned study period.

Patients stratified into diabetic and non‐diabetic groups.

Follow‐up length: 24 weeks.

Participants

Number of patients: 615 (out of 771 patients screened).

304 (ticlopidine) versus 311 (placebo).

Male : female ratio = 521 : 94.

Patients in "diabetic" stratum: 88/304 ticlopidine, 95/311 placebo

Age (mean, range):  63.3 (ticlopidine); 62.5 (placebo) (range 42 to 76 years).

Inclusion criteria: obstructive arterial disease of the upper part (popliteal or above) of the lower limbs for at least 12 months, confirmed by angiography (< 6 months) or doppler studies (< 3 months) and intermittent claudication with a walking distance assessed by treadmill testing (3.2 km/h, 10% slope, ambient temperature 22 ± 2 oC) of between 50 and 300 m.

Exclusion criteria: < 35 or > 75 years old, disease of stage III or IV Fontaine's classification, insulin treated diabetes, vascular surgery within the past 12 months or planned for the following six months, myocardial infarction or acute stroke within the last three months, severe hypertension not adequately controlled, treatment with anti‐inflammatory or anti‐coagulant agents, contraindications to ticlopidine, aspartate aminotransferase > 50 iu/L, serum creatinine >270 μmol/L, platelets < 150 x 109 /L and granulocytes < 1.8 x 109 /L.

Interventions

Intervention: ticlopidine 250 mg bd (ratio of patients given sugar to film coated tablets 1:1).

Control: placebo bd.

Outcomes

All cause mortality.

Vascular mortality: stroke or MI related death.

Cardiovascular events: fatal and non‐fatal MI or stroke.

Walking distance: graphical data only.

Need for revascularisation.

Adverse events: adverse events leading to cessation of therapy, GI symptoms.

Notes

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomised, stratified, placebo controlled, double‐blind study", "randomisation scheme predetermined for each centre".

Comment: method of sequence generation not described. Probably done.

Allocation concealment (selection bias)

Unclear risk

Quote: "each (treatment) box was clearly labelled with random treatment number", "no codes were reported as broken".

Comment: treatment identity  contained in "sealed envelopes" (? opaque) for emergency purposes.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind trial", "placebo tablets were identical in appearance and packaging", "treatment was balanced in blocks of four tablets: ticlopidine film coated, placebo film coated,  ticlopidine sugar coated, placebo sugar coated".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind study", "validated committee unaware of the nature of the treatment allocated validated outcomes and adverse events".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "a lost to follow‐up will be considered as a failure".

17/304 (5.6%) ticlopidine versus 17/311 (5.5%) placebo did not turn up for the last follow‐up visit, but:

Quote: "it was possible after telephone or family contact or through their general practitioner to assert that none of these patients had experienced a critical event from their last visit".

Comment: this is probably low risk due to balanced rate of not turning up, and small number. Patients were also eventually followed up.

Treatment discontinued early:  42/304 (13.8%) ticlopidine group, 38/311 (12.3%) placebo group (P = 0.56, Chi2 test) due to adverse events: 20/304 (6.6%) ticlopidine, 14/311 (4.5%) placebo (P = 0.26, Chi2 test).

Comment: comparable drop out rate, low risk overall.

Selective reporting (reporting bias)

Low risk

Comment: outcomes reported consistent with protocol.
Signorini 1988

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Single centre (Italy) study.

Power calculation: not performed.

ITT analysis: not performed.

Follow‐up length: six months

Participants

Number of patients: 52.

28 (Indobufen) versus 24 (placebo), six patients dropped out "for reasons unrelated to treatment"

Male : female ratio = 39 : 13.

Age: Mean 60 (range 46 to 70).

Inclusion criteria: stage II Fontaine with disease of one to five years.

Exclusion criteria: Occlusive thromboangiitis (Buerger), congential or acquired haemorrhagic diseases, diabetes, hyperlipoproteinaemia, smokers, angina and severe hypertension requiring continuous therapy, or both. Patients were excluded if they had concomitant diseases that would have required other associated therapies.

Interventions

Intervention: indobufen 200 mg bd.

Control: placebo bd.

Outcomes

Walking distance: pain free walking distance (assessed on a treadmill at constant slope and speed (10o and 4 km/h).

Adverse events: gastrointestinal symptoms.

Notes

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Preset random design".

Allocation concealment (selection bias)

Unclear risk

Quote: "Preset random design".

Comment: did not specify.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "double‐blind study".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "double‐blind study".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "6 patients dropped out of the trial during the first month for reasons unrelated to the treatment".

Comment: did not specify attrition rate of groups.

Selective reporting (reporting bias)

Unclear risk

Brief methods section in paper

Comment: Outcomes reported is as expected from the objectives and design of the study.
STIMS 1990

Methods

Randomised, double‐blinded, placebo‐controlled trial.

Multicentre (six Swedish centres) study.

Power calculation: 90% power at 5% significance levels to detect a 50% reduction of primary end points.

ITT analysis: performed.

Study period: November 1980 to December 1987.

Stratified into presence or absence of previous leg vascular surgery.

Follow‐up length: seven years (median 5.6 years).

Participants

Number of patients: 687.

346 (ticlopidine) versus 341 (placebo).

Male : female ratio = 525 : 162.

Age (mean with SD): 60.5 ± 6.0 (ticlopidine), 60.2 ± 6.9 (placebo).

Inclusion criteria: history of intermittent claudication.

Exclusion criteria: age > 70 years; pregnant and fertile women; patients receiving treatment known to affect platelet function or anticoagulant drugs; platelet count below 100 X 109 /L; patients receiving lipid lowering drugs other than clofibrate; myocardial infarction within last three months; major surgery within the last month; diabetics who were treated with insulin or who showed evidence of advanced proliferative retinopathy or renal failure; patients with chronic disease such as malignancy signs of polyneuritis of obscure origin, uncontrolled hypertension (> 190/110 mmHg), rheumatic valvular disease with atrial fibrillation, previous bleeding peptic ulcer, or a stroke which prevented them from walking to the extent that claudication could not be experienced; renal dysfunction (serum creatinine > 150 mmol/L); or liver dysfunction (aspartate aminotransferase > 2 kat/L, alanine aminotransferase > 2 μkat/L, gamma glutamyl transferase > 3 μkat/L; 1 μkat = 1 μmol of reaction product per second).

Interventions

Intervention: ticlopidine 250 mg bd.

Control: placebo bd.

Outcomes

All cause mortality.

Vascular mortality: stroke or MI related death.

Cardiovascular events: fatal and non‐fatal MI, stroke or TIA.

Need for vascular interventions and amputations.

Adverse events: major bleeding and adverse events requiring cessation of therapy.

Notes

Patients who had undergone reconstructive surgery or amputation were also eligible for this study.

Source of funding: Sanofi‐Winthrop.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "minimisation procedure was used to balance the placebo and ticlopidine treatment group".

Allocation concealment (selection bias)

Unclear risk

Not explicitly stated.

Comment: probably used.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind placebo controlled trial", "placebo tablets were identical in appearance and packaging".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "double‐blind placebo controlled trial".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop out rate: 5/346 (1.4%) ticlopidine; 2/341 (0.59%) placebo (P = 0.26, Chi2 test) are comparable between groups.

Selective reporting (reporting bias)

Low risk

Comment: outcomes reported was as expected from the objectives and design of the study.
Tonnesen 1993

Methods

Randomised, double blinded, placebo controlled trial.

Multi‐centre (10 multinational centres ‐ Argentina, Brazil, Denmark, England, Germany, Spain and Yugoslavia) study.

Power calculation: 144 evaluable patients per study arm were required to detect an expected improvement of 30% for the placebo group and 50% for the indobufen group with a power of 0.8 using a two‐tailed test at an α level of 0.05.

ITT analysis: performed.

Single‐blinded placebo run‐in period for one month.

Follow‐up length: six months.

Participants

Number of patients: 302.

148 (indobufen) versus 154 (placebo).

Male : female ratio = 216 : 100.

Age: Median 62 years (range 43 to 78).

Inclusion criteria: stable symptomatic, moderately severe chronic occlusive PAD of the lower extremities due to atherosclerosis. Claudication was considered stable if no significant change in the severity of symptoms had occurred in the six months prior to patient enrolment. After enrolment, single blinded placebo run in was conducted for one month, and only patients who still remain within inclusion criteria were randomised.

Inclusion: intermitted claudication for at least six months prior to enrolment, ability to walk at least 50 m before complaining of pain in leg (initial claudication distance, ICD) , but no more than 300 m, as assessed on a motorised treadmill set at a slope of 8 degrees, at a speed of 3.2 km/hour. Absolute claudication distance (ACD) less than 500 m, resting ankle/arm systolic blood pressure in the arteries of the worse leg between 0.5 to 0.9.

Exclusion criteria: diabetics.

Use of antiplatelets, analgesic and anti‐inflammatory drugs other than paracetamol were disallowed.

Interventions

Intervention: indobufen 200 mg bd.

Control: placebo bd.

Outcomes

Walking distance: ICD and ACD.

Adverse events: adverse events leading to cessation of therapy, GI symptoms including dyspepsia and discomfort.

Notes

Source of funding: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients who qualified for the double‐blind phase were randomly allocated".

Allocation concealment (selection bias)

Unclear risk

Quote: "patients who qualified for the double‐blind phase were randomly allocated".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "all the patients were randomly allocated to either indobufen or placebo treatment under double‐blind conditions."

Comment: probably done.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "double blinded study".

Comment: no further description.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

All randomised patients included in data analysis‐ however there were some patients who were unaccounted for in adverse event reports.

Selective reporting (reporting bias)

Low risk

Comment: outcomes reported was as expected from the objectives and design of the study.

ABPI: ankle brachial pressure index
bd: twice a day
GI: gastrointestinal
ITT: intention‐to‐treat
IQR: interquartile range
MI: myocardial infarction
NSAID: non‐steroidal anti‐inflammatory drug
od: once a day
SD: standard deviation
tds: three times a day
TIA: transient ischaemic attack
WCC: white cell count

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Abrahamsen 1974

Cross‐over study. Patient given antiplatelet for two weeks only. No primary or secondary outcomes reported.

Adriaensen 1976

Used suloctidil and dihydroergotoxine as drugs of investigation.

Ahn 1992

Compared antiplatelet agent against surgery.

Allegra 1993

Compared antiplatelet agent against low dose heparin. See Allegra 1994.

Allegra 1994

Compared antiplatelet agent against low dose heparin.

Andreozzi 1993

Compared antiplatelet against low dose heparin.

Baumgartner 1992

No suitable results for primary and secondary outcomes.

Belcaro 1991

No mention of randomisation process. No placebo used. Control group was made up of patients who were unable to follow any kind of treatment (either because they refused it or because they had important gastrointestinal symptoms).

Bhatt 2000

Part of CAPRIE study. Outcome for PAD patients specifically not reported.

Boneu 1996

Trial to assess dose of clopidogrel only. No primary or secondary outcomes reported.

Brass 2006

Used vasodilator (NM‐702) as drug of investigation.

Canonico 1991

Cross‐over trial.

Cassar 2005

Recruited patients undergoing angioplasty.

Cassar 2005a

Recruited patients undergoing angioplasty, see Cassar 2005.

Cassar 2006

Ex‐vivo measure of platelet activation.

Castano 1999

Used policosanol as drug of investigation.

Castano 2001

Used policosanol as drug of investigation.

Castano 2003

Used policosanol as drug of investigation.

Castano 2004

Used policosanol as drug of investigation.

Catalano 1984

Unclear patient grouping.

Cesarone 1994

Used defibrotide as comparator.

CHARISMA 2009

Included asymptomatic PAD participants.

Ciocon 1997

Used pentoxifylline as comparator.

CLIPS 2007

Included asymptomatic PAD participants.

Creutzig 1994

Recruited patients undergoing angioplasty.

Davi 1985

Cross‐over trial. Patients received treatment for 60 days only.

Destors 1985

Proposal for trial.

Duda 2001

Used thrombolysis agent as comparator.

Ehresmann 1977

Patients had undergone recent revascularisation.

Eikelboom 2005

Cross‐over trial with no primary or secondary outcomes reported.

Elam 1998

Used cilostazol as drug of investigation.

Fabris 1992

Included patients with Fontaine stage III.

Fiotti 2003

Non‐randomised study.

Fowkes 2010

Included asymptomatic PAD participants.

Giansante 1990

Unusual dosing ‐ patient received antiplatelet therapy every third day.

Gillot 1976

Used suloctidil as drug of investigation.

Gregoratti 1982

Used suloctidil as drug of investigation.

Gresele 2000

Used clomicromene, an antithrombotic as part of comparator.

Guan 2003

Used beraprost as drug of investigation.

Harker 1999

Part of CAPRIE study. Outcomes for PAD patients specifically, was not reported.

Hawker 1984

No primary or secondary outcomes reported.

Hess 1985

No primary or secondary outcomes reported.

Hevia 1992

Used nifedipine as comparator.

Hiatt 2002

Used urokinase as drug of investigation.

Holm 1984

Used suloctidil as drug of investigation.

Hsieh 2009

Used cilostazol as drug of investigation. Patients also received concomitant antiplatelet.

Jagroop 2004

Patients only received 16 days of treatment.

Jones 1982

Used suloctidil as drug of investigation.

Kakkar 1981

Used suloctidil as drug of investigation.

Katsumura 1982

Included patients with ischaemic ulcers.

Labs 1999

Used beraprost as drug of investigation at varying doses.

Landini 1989

Patients followed up for one month only.

Leo 2007

Treatment duration was only two months.

Libretti 1986

No primary or secondary outcomes reported.

Libretti 1986a

No primary or secondary outcomes reported.

Lievre 1996

Used beraprost as main drug of investigation.

Lievre 2000

Used beraprost as main drug of investigation.

Mangiafico 2000

Four week treatment duration only. Used prostaglandin as drug of investigation.

Mannarino 1991

Compared antiplatelet to exercise.

Mannucci 1987

No comparator used.

Mantero 1983

Used suloctidil as drug of investigation.

Marelli 1990

Used defibrotide as drug of investigation.

Marrapodi 1994

Used defibrotide as drug of investigation.

Miyazaki 2007

Used sarpogrelate as drug of investigation.

Mohler 2003

Used beraprost as drug of investigation.

Neirotti 1994

No primary or secondary outcomes reported.

Nenci 1979

Cross‐over trial.

Nenci 1982

Cross‐over trial.

Norgren 2006

Used sarpogrelate as drug of investigation.

Novo 1996

Cross‐over trial. Used captopril as comparator.

O'Donnell 2008

Used cilostazol as drug of investigation.

O'Donnell 2009

Used cilostazol as drug of investigation.

Okadome‐Kenchiro 1992

Used vasodilator as drug of investigation.

Panchenko 1997

Used pentoxifylline as drug of investigation.

Pasqualini 2002

Only assessed walking distance after day 2 to 5 of treatment.

Pollastri 1991

Used trapidil as drug of investigation.

POPADAD 2008

Included participants with asymptomatic PAD.

Randi 1985

Not RCT. Included stage III and IV Fontaine.

Randi 1991

No primary or secondary outcomes reported.

Ranke 1992

Recruited patients following angioplasty.

Ranke 1993

Recruited patients following angioplasty.

Ranke 1994

Recruited patients following angioplasty.

Regenthal 1991

Used trapidil and pentoxifylline as drugs of investigation.

Rossini 1998

Used heparan sulphate as comparator.

Roztocil 1989

Compared antiplatelet against hydroxyethylrutoside.

Rudofsky 1987

No primary or secondary outcomes reported

Schoop 1987

No primary or secondary outcomes reported.

Schweizer 2003

Recruited patients with acute arterial thrombosis.

Singer 2006

Trial proposal only.

Smith 1981

Not RCT.

Stiegler 1984

Used angiography to determine outcome.

Tepe 2007

Trial proposal only.

Topol 2000

Included patients with coronary heart disease and cerebrovascular disease. Data for PAD patients could not be obtained.

Warfarin 2007

Used warfarin as comparator.

Wilhite 2003

Cross‐over trial.

Data and analyses

Open in table viewer
Comparison 1. Antiplatelet agent versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All cause mortality Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.60, 0.98]
Analysis 1.1
Comparison 1 Antiplatelet agent versus placebo, Outcome 1 All cause mortality.

Comparison 1 Antiplatelet agent versus placebo, Outcome 1 All cause mortality.

1.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.50, 1.66]

1.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.56, 0.96]

2 Cardiovascular mortality (fatal stroke or MI) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.32, 0.93]
Analysis 1.2
Comparison 1 Antiplatelet agent versus placebo, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

Comparison 1 Antiplatelet agent versus placebo, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

2.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.32, 0.93]

3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.63, 1.01]
Analysis 1.3
Comparison 1 Antiplatelet agent versus placebo, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

Comparison 1 Antiplatelet agent versus placebo, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

3.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.47, 1.50]

3.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.61, 1.02]

4 Myocardial infarction (fatal and non‐fatal) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.63, 1.12]
Analysis 1.4
Comparison 1 Antiplatelet agent versus placebo, Outcome 4 Myocardial infarction (fatal and non‐fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 4 Myocardial infarction (fatal and non‐fatal).

4.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.39, 1.69]

4.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.62, 1.16]

5 Myocardial infarction (fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.31, 1.05]
Analysis 1.5
Comparison 1 Antiplatelet agent versus placebo, Outcome 5 Myocardial infarction (fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 5 Myocardial infarction (fatal).

5.1 ticlopidine

4

1622

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.31, 1.05]

6 Myocardial infarction (non‐fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.48]
Analysis 1.6
Comparison 1 Antiplatelet agent versus placebo, Outcome 6 Myocardial infarction (non‐fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 6 Myocardial infarction (non‐fatal).

6.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.48]

7 Stroke (fatal and non‐fatal) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.45, 1.13]
Analysis 1.7
Comparison 1 Antiplatelet agent versus placebo, Outcome 7 Stroke (fatal and non‐fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 7 Stroke (fatal and non‐fatal).

7.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.35, 2.30]

7.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.39, 1.12]

8 Stroke (fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.07, 1.64]
Analysis 1.8
Comparison 1 Antiplatelet agent versus placebo, Outcome 8 Stroke (fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 8 Stroke (fatal).

8.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.07, 1.64]

9 Stroke (non‐fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.42, 1.30]
Analysis 1.9
Comparison 1 Antiplatelet agent versus placebo, Outcome 9 Stroke (non‐fatal).

Comparison 1 Antiplatelet agent versus placebo, Outcome 9 Stroke (non‐fatal).

9.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.42, 1.30]

10 Major bleeding Show forest plot

2

838

Risk Ratio (M‐H, Fixed, 95% CI)

1.73 [0.51, 5.83]
Analysis 1.10
Comparison 1 Antiplatelet agent versus placebo, Outcome 10 Major bleeding.

Comparison 1 Antiplatelet agent versus placebo, Outcome 10 Major bleeding.

10.1 ticlopidine

2

838

Risk Ratio (M‐H, Fixed, 95% CI)

1.73 [0.51, 5.83]

11 GI symptoms (dyspepsia) Show forest plot

9

3818

Risk Ratio (M‐H, Random, 95% CI)

2.11 [1.23, 3.61]
Analysis 1.11
Comparison 1 Antiplatelet agent versus placebo, Outcome 11 GI symptoms (dyspepsia).

Comparison 1 Antiplatelet agent versus placebo, Outcome 11 GI symptoms (dyspepsia).

11.1 indobufen

2

352

Risk Ratio (M‐H, Random, 95% CI)

3.29 [1.17, 9.27]

11.2 picotamide

2

2344

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.75, 1.18]

11.3 ticlopidine

4

1000

Risk Ratio (M‐H, Random, 95% CI)

2.40 [1.82, 3.17]

11.4 trifusal

1

122

Risk Ratio (M‐H, Random, 95% CI)

6.41 [0.79, 51.64]

12 Early cessation of treatment Show forest plot

8

4388

Risk Ratio (M‐H, Fixed, 95% CI)

2.05 [1.53, 2.75]
Analysis 1.12
Comparison 1 Antiplatelet agent versus placebo, Outcome 12 Early cessation of treatment.

Comparison 1 Antiplatelet agent versus placebo, Outcome 12 Early cessation of treatment.

12.1 indobufen

1

300

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.47, 4.49]

12.2 picotamide

2

2344

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.73, 2.84]

12.3 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

2.35 [1.66, 3.31]

12.4 trifusal

1

122

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.07, 16.69]

13 Pain Free Walking Distance Show forest plot

3

329

Mean Difference (IV, Random, 95% CI)

78.09 [12.24, 143.95]
Analysis 1.13
Comparison 1 Antiplatelet agent versus placebo, Outcome 13 Pain Free Walking Distance.

Comparison 1 Antiplatelet agent versus placebo, Outcome 13 Pain Free Walking Distance.

13.1 indobufen

2

294

Mean Difference (IV, Random, 95% CI)

196.87 [‐85.58, 479.32]

13.2 picotamide

1

35

Mean Difference (IV, Random, 95% CI)

38.70 [2.68, 74.72]

14 Revascularisation Show forest plot

5

3304

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.43, 0.97]
Analysis 1.14
Comparison 1 Antiplatelet agent versus placebo, Outcome 14 Revascularisation.

Comparison 1 Antiplatelet agent versus placebo, Outcome 14 Revascularisation.

14.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.50, 1.23]

14.2 ticlopidine

4

1000

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.13, 0.84]

15 Limb amputations Show forest plot

2

2991

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.38, 1.86]
Analysis 1.15
Comparison 1 Antiplatelet agent versus placebo, Outcome 15 Limb amputations.

Comparison 1 Antiplatelet agent versus placebo, Outcome 15 Limb amputations.

15.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.22, 2.98]

15.2 ticlopidine

1

687

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.32, 2.35]
Open in table viewer
Comparison 2. Antiplatelet agent(s) versus aspirin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All cause mortality Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.58, 0.93]
Analysis 2.1
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 1 All cause mortality.

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 1 All cause mortality.

1.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.60, 1.02]

1.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.31, 0.98]

2 Cardiovascular mortality (fatal stroke or MI) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.48, 1.15]
Analysis 2.2
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

2.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.51, 1.35]

2.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.16, 1.31]

3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.67, 0.98]
Analysis 2.3
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

3.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.64, 0.97]

3.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.57, 1.54]

4 Myocardial infarction (fatal and non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.50, 0.86]
Analysis 2.4
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 4 Myocardial infarction (fatal and non‐fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 4 Myocardial infarction (fatal and non‐fatal).

4.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.47, 0.85]

4.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.41, 1.55]

5 Myocardial infarction (fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.40, 1.15]
Analysis 2.5
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 5 Myocardial infarction (fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 5 Myocardial infarction (fatal).

5.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.37, 1.21]

5.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.23, 2.25]

6 Myocardial infarction (non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.47, 0.89]
Analysis 2.6
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 6 Myocardial infarction (non‐fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 6 Myocardial infarction (non‐fatal).

6.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.44, 0.88]

6.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.36, 1.92]

7 Stroke (fatal and non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.76, 1.34]
Analysis 2.7
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 7 Stroke (fatal and non‐fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 7 Stroke (fatal and non‐fatal).

7.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.73, 1.34]

7.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

8 Stroke (fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.05, 6.44]
Analysis 2.8
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 8 Stroke (fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 8 Stroke (fatal).

8.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Random, 95% CI)

1.38 [0.55, 3.42]

8.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

9 Stroke (non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.76, 1.39]
Analysis 2.9
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 9 Stroke (non‐fatal).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 9 Stroke (non‐fatal).

9.1 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

1.76 [0.74, 4.16]

9.2 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.69, 1.31]

10 Major bleeding Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Analysis 2.10
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 10 Major bleeding.

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 10 Major bleeding.

10.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

11 GI symptoms (dyspepsia) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 2.11
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 11 GI symptoms (dyspepsia).

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 11 GI symptoms (dyspepsia).

11.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12 Early cessation of treatment Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 2.12
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 12 Early cessation of treatment.

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 12 Early cessation of treatment.

12.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Amputation Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 2.13
Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 13 Amputation.

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 13 Amputation.

13.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 1 All cause mortality.
Figuras y tablas -
Analysis 1.1

Comparison 1 Antiplatelet agent versus placebo, Outcome 1 All cause mortality.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 2 Cardiovascular mortality (fatal stroke or MI).
Figuras y tablas -
Analysis 1.2

Comparison 1 Antiplatelet agent versus placebo, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).
Figuras y tablas -
Analysis 1.3

Comparison 1 Antiplatelet agent versus placebo, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 4 Myocardial infarction (fatal and non‐fatal).
Figuras y tablas -
Analysis 1.4

Comparison 1 Antiplatelet agent versus placebo, Outcome 4 Myocardial infarction (fatal and non‐fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 5 Myocardial infarction (fatal).
Figuras y tablas -
Analysis 1.5

Comparison 1 Antiplatelet agent versus placebo, Outcome 5 Myocardial infarction (fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 6 Myocardial infarction (non‐fatal).
Figuras y tablas -
Analysis 1.6

Comparison 1 Antiplatelet agent versus placebo, Outcome 6 Myocardial infarction (non‐fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 7 Stroke (fatal and non‐fatal).
Figuras y tablas -
Analysis 1.7

Comparison 1 Antiplatelet agent versus placebo, Outcome 7 Stroke (fatal and non‐fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 8 Stroke (fatal).
Figuras y tablas -
Analysis 1.8

Comparison 1 Antiplatelet agent versus placebo, Outcome 8 Stroke (fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 9 Stroke (non‐fatal).
Figuras y tablas -
Analysis 1.9

Comparison 1 Antiplatelet agent versus placebo, Outcome 9 Stroke (non‐fatal).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 10 Major bleeding.
Figuras y tablas -
Analysis 1.10

Comparison 1 Antiplatelet agent versus placebo, Outcome 10 Major bleeding.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 11 GI symptoms (dyspepsia).
Figuras y tablas -
Analysis 1.11

Comparison 1 Antiplatelet agent versus placebo, Outcome 11 GI symptoms (dyspepsia).

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Comparison 1 Antiplatelet agent versus placebo, Outcome 12 Early cessation of treatment.
Figuras y tablas -
Analysis 1.12

Comparison 1 Antiplatelet agent versus placebo, Outcome 12 Early cessation of treatment.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 13 Pain Free Walking Distance.
Figuras y tablas -
Analysis 1.13

Comparison 1 Antiplatelet agent versus placebo, Outcome 13 Pain Free Walking Distance.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 14 Revascularisation.
Figuras y tablas -
Analysis 1.14

Comparison 1 Antiplatelet agent versus placebo, Outcome 14 Revascularisation.

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Comparison 1 Antiplatelet agent versus placebo, Outcome 15 Limb amputations.
Figuras y tablas -
Analysis 1.15

Comparison 1 Antiplatelet agent versus placebo, Outcome 15 Limb amputations.

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 1 All cause mortality.
Figuras y tablas -
Analysis 2.1

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 1 All cause mortality.

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 2 Cardiovascular mortality (fatal stroke or MI).
Figuras y tablas -
Analysis 2.2

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).
Figuras y tablas -
Analysis 2.3

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 4 Myocardial infarction (fatal and non‐fatal).
Figuras y tablas -
Analysis 2.4

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 4 Myocardial infarction (fatal and non‐fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 5 Myocardial infarction (fatal).
Figuras y tablas -
Analysis 2.5

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 5 Myocardial infarction (fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 6 Myocardial infarction (non‐fatal).
Figuras y tablas -
Analysis 2.6

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 6 Myocardial infarction (non‐fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 7 Stroke (fatal and non‐fatal).
Figuras y tablas -
Analysis 2.7

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 7 Stroke (fatal and non‐fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 8 Stroke (fatal).
Figuras y tablas -
Analysis 2.8

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 8 Stroke (fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 9 Stroke (non‐fatal).
Figuras y tablas -
Analysis 2.9

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 9 Stroke (non‐fatal).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 10 Major bleeding.
Figuras y tablas -
Analysis 2.10

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 10 Major bleeding.

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 11 GI symptoms (dyspepsia).
Figuras y tablas -
Analysis 2.11

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 11 GI symptoms (dyspepsia).

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 12 Early cessation of treatment.
Figuras y tablas -
Analysis 2.12

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 12 Early cessation of treatment.

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Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 13 Amputation.
Figuras y tablas -
Analysis 2.13

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 13 Amputation.

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Comparison 1. Antiplatelet agent versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All cause mortality Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.60, 0.98]

1.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.50, 1.66]

1.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.56, 0.96]

2 Cardiovascular mortality (fatal stroke or MI) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.32, 0.93]

2.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.32, 0.93]

3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.63, 1.01]

3.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.47, 1.50]

3.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.61, 1.02]

4 Myocardial infarction (fatal and non‐fatal) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.63, 1.12]

4.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.39, 1.69]

4.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.62, 1.16]

5 Myocardial infarction (fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.31, 1.05]

5.1 ticlopidine

4

1622

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.31, 1.05]

6 Myocardial infarction (non‐fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.48]

6.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.69, 1.48]

7 Stroke (fatal and non‐fatal) Show forest plot

5

3926

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.45, 1.13]

7.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.35, 2.30]

7.2 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.39, 1.12]

8 Stroke (fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.07, 1.64]

8.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.07, 1.64]

9 Stroke (non‐fatal) Show forest plot

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.42, 1.30]

9.1 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.42, 1.30]

10 Major bleeding Show forest plot

2

838

Risk Ratio (M‐H, Fixed, 95% CI)

1.73 [0.51, 5.83]

10.1 ticlopidine

2

838

Risk Ratio (M‐H, Fixed, 95% CI)

1.73 [0.51, 5.83]

11 GI symptoms (dyspepsia) Show forest plot

9

3818

Risk Ratio (M‐H, Random, 95% CI)

2.11 [1.23, 3.61]

11.1 indobufen

2

352

Risk Ratio (M‐H, Random, 95% CI)

3.29 [1.17, 9.27]

11.2 picotamide

2

2344

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.75, 1.18]

11.3 ticlopidine

4

1000

Risk Ratio (M‐H, Random, 95% CI)

2.40 [1.82, 3.17]

11.4 trifusal

1

122

Risk Ratio (M‐H, Random, 95% CI)

6.41 [0.79, 51.64]

12 Early cessation of treatment Show forest plot

8

4388

Risk Ratio (M‐H, Fixed, 95% CI)

2.05 [1.53, 2.75]

12.1 indobufen

1

300

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.47, 4.49]

12.2 picotamide

2

2344

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.73, 2.84]

12.3 ticlopidine

4

1622

Risk Ratio (M‐H, Fixed, 95% CI)

2.35 [1.66, 3.31]

12.4 trifusal

1

122

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.07, 16.69]

13 Pain Free Walking Distance Show forest plot

3

329

Mean Difference (IV, Random, 95% CI)

78.09 [12.24, 143.95]

13.1 indobufen

2

294

Mean Difference (IV, Random, 95% CI)

196.87 [‐85.58, 479.32]

13.2 picotamide

1

35

Mean Difference (IV, Random, 95% CI)

38.70 [2.68, 74.72]

14 Revascularisation Show forest plot

5

3304

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.43, 0.97]

14.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.50, 1.23]

14.2 ticlopidine

4

1000

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.13, 0.84]

15 Limb amputations Show forest plot

2

2991

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.38, 1.86]

15.1 picotamide

1

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.22, 2.98]

15.2 ticlopidine

1

687

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.32, 2.35]
Figuras y tablas -
Comparison 1. Antiplatelet agent versus placebo
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Comparison 2. Antiplatelet agent(s) versus aspirin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All cause mortality Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.58, 0.93]

1.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.60, 1.02]

1.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.31, 0.98]

2 Cardiovascular mortality (fatal stroke or MI) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.48, 1.15]

2.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.51, 1.35]

2.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.16, 1.31]

3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.67, 0.98]

3.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.64, 0.97]

3.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.57, 1.54]

4 Myocardial infarction (fatal and non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.50, 0.86]

4.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.47, 0.85]

4.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.41, 1.55]

5 Myocardial infarction (fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.40, 1.15]

5.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.37, 1.21]

5.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.23, 2.25]

6 Myocardial infarction (non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.47, 0.89]

6.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.44, 0.88]

6.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.36, 1.92]

7 Stroke (fatal and non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.76, 1.34]

7.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.73, 1.34]

7.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

8 Stroke (fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.05, 6.44]

8.1 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Random, 95% CI)

1.38 [0.55, 3.42]

8.2 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

9 Stroke (non‐fatal) Show forest plot

2

7661

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.76, 1.39]

9.1 picotamide vs aspirin

1

1209

Risk Ratio (M‐H, Fixed, 95% CI)

1.76 [0.74, 4.16]

9.2 clopidogrel vs aspirin

1

6452

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.69, 1.31]

10 Major bleeding Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

10.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

11 GI symptoms (dyspepsia) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

12 Early cessation of treatment Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

12.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13 Amputation Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

13.1 picotamide vs aspirin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]
Figuras y tablas -
Comparison 2. Antiplatelet agent(s) versus aspirin
Ir a la tabla de la revisión