title: Antiplatelet agents for intermittent claudication.
abstract: BACKGROUND
  Peripheral arterial disease (PAD) is common and is a marker of systemic atherosclerosis. Patients with symptoms of intermittent claudication (IC) are at increased risk of cardiovascular events (myocardial infarction (MI) and stroke) and of both cardiovascular and all cause mortality.
  
  
  OBJECTIVE
  To determine the effectiveness of antiplatelet agents in reducing mortality (all cause and cardiovascular) and cardiovascular events in patients with intermittent claudication.
  
  
  METHODS
  The Cochrane Peripheral Vascular Diseases group searched their Specialised Register (last searched April 2011) and CENTRAL (2011, Issue 2) for publications on antiplatelet agents and IC. In addition reference lists of relevant articles were also searched.
  
  
  METHODS
  Double-blind randomised controlled trials comparing oral antiplatelet agents versus placebo, or versus other antiplatelet agents in patients with stable intermittent claudication were included. Patients with asymptomatic PAD (stage I Fontaine), stage III and IV Fontaine PAD, and those undergoing or awaiting endovascular or surgical intervention were excluded.
  
  
  METHODS
  Data on methodological quality, participants, interventions and outcomes including all cause mortality, cardiovascular mortality, cardiovascular events, adverse events, pain free walking distance, need for revascularisation, limb amputation and ankle brachial pressure indices were collected. For each outcome, the pooled risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) was calculated.
  
  
  RESULTS
  A total of 12 studies with a combined total of 12,168 patients were included in this review. Antiplatelet agents reduced all cause (RR 0.76, 95% CI 0.60 to 0.98) and cardiovascular mortality (RR 0.54, 95% CI 0.32 to 0.93) in patients with IC compared with placebo. A reduction in total cardiovascular events was not statistically significant (RR 0.80, 95% CI 0.63 to 1.01). Data from two trials (which tested clopidogrel and picotamide respectively against aspirin) showed a significantly lower risk of all cause mortality (RR 0.73, 95% CI 0.58 to 0.93) and cardiovascular events (RR 0.81, 95% CI 0.67 to 0.98) with antiplatelets other than aspirin compared with aspirin. Antiplatelet therapy was associated with a higher risk of adverse events, including gastrointestinal symptoms (dyspepsia) (RR 2.11, 95% CI 1.23 to 3.61) and adverse events leading to cessation of therapy (RR 2.05, 95% CI 1.53 to 2.75) compared with placebo; data on major bleeding (RR 1.73, 95% CI 0.51, 5.83) and on adverse events in trials of aspirin versus alternative antiplatelet were limited. Risk of limb deterioration leading to revascularisation was significantly reduced by antiplatelet treatment compared with placebo (RR 0.65, 95% CI 0.43 to 0.97).
  
  
  CONCLUSIONS
  Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC. Treatment with antiplatelet agents in this patient group however is associated with an increase in adverse effects, including GI symptoms, and healthcare professionals and patients need to be aware of the potential harm as well as the benefit of therapy; more data are required on the effect of antiplatelets on major bleeding. Evidence on the effectiveness of aspirin versus either placebo or an alternative antiplatelet agent is lacking. Evidence for thienopyridine antiplatelet agents was particularly compelling and there is an urgent need for multicentre trials to compare the effects of aspirin against thienopyridines.
authors.affiliation: Department of Vascular Surgery, Freeman Hospital, Newcastle upon Tyne, UK. pwong23@hotmail.com
authors.forename: Peng F
authors.initials: PF
authors.lastname: Wong
authors.forename: Lee Yee
authors.initials: LY
authors.lastname: Chong
authors.forename: Dimitris P
authors.initials: DP
authors.lastname: Mikhailidis
authors.forename: Peter
authors.initials: P
authors.lastname: Robless
authors.forename: Gerard
authors.initials: G
authors.lastname: Stansby
mesh_terms: D002423:Cause of Death; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy* / Q000401:mortality; D009203:Myocardial Infarction / Q000401:mortality / Q000517:prevention & control*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000401:mortality / Q000517:prevention & control*
chemical_list: D010975:Platelet Aggregation Inhibitors
references.citation: Vasa Suppl. 1987;20:165-8
references.pmid: 3321492
references.citation: Angiology. 1993 Apr;44(4):307-13
references.pmid: 8457082
references.citation: Int J Clin Pharmacol Res. 1995;15(2):57-63
references.pmid: 8593974
references.citation: Br J Surg. 2005 Feb;92(2):159-65
references.pmid: 15609386
references.citation: J Int Med Res. 1990 Sep-Oct;18(5):400-7
references.pmid: 2147914
references.citation: Med Welt. 1977 Jul 1;28(26):1157-62
references.pmid: 886967
references.citation: Med Klin (Munich). 1993 Oct 15;88(10):571-6
references.pmid: 8272018
references.citation: Angiology. 1994 Sep;45(9):777-88
references.pmid: 8092543
references.citation: Angiology. 1994 Feb;45(2):137-41
references.pmid: 8129189
references.citation: Vasc Med. 1999;4(4):239-46
references.pmid: 10613628
references.citation: J Vasc Surg. 2007 Apr;45(4):645-654; discussion 653-4
references.pmid: 17398372
references.citation: J Lab Clin Med. 1989 Jul;114(1):84-91
references.pmid: 2661700
references.citation: Vasc Endovascular Surg. 2009 Apr-May;43(2):132-43
references.pmid: 19131370
references.citation: Arzneimittelforschung. 1991 Apr;41(4):414-6
references.pmid: 1859515
references.citation: Circulation. 2004 Aug 10;110(6):738-43
references.pmid: 15262830
references.citation: JAMA. 2008 Jul 9;300(2):197-208
references.pmid: 18612117
references.citation: Minerva Cardioangiol. 1991 Mar;39(3):75-80
references.pmid: 1881558
references.citation: N Engl J Med. 1990 Jan 25;322(4):213-7
references.pmid: 2294448
references.citation: Int Angiol. 1996 Jun;15(2):169-74
references.pmid: 8803643
references.citation: Eur J Vasc Endovasc Surg. 1995 Jul;10(1):69-76
references.pmid: 7633972
references.citation: Curr Ther Res Clin Exp. 1976 Nov;20(5):637-44
references.pmid: 825349
references.citation: J Atheroscler Thromb. 2011;18(6):431-42
references.pmid: 21427504
references.citation: J Med. 1992;23(2):81-92
references.pmid: 1512524
references.citation: Pharmatherapeutica. 1981;2(9):597-600
references.pmid: 7267676
references.citation: BMJ. 2002 Nov 16;325(7373):1139
references.pmid: 12433762
references.citation: Eur J Vasc Endovasc Surg. 2003 Oct;26(4):374-80
references.pmid: 14511998
references.citation: J Clin Pathol. 1982 Jul;35(7):740-3
references.pmid: 7047575
references.citation: Am J Med. 2004 Feb 15;116(4):236-40
references.pmid: 14969651
references.citation: N Engl J Med. 2007 Jul 19;357(3):217-27
references.pmid: 17634457
references.citation: Helv Chir Acta. 1954 Dec;21(5-6):499-533
references.pmid: 14366554
references.citation: Angiology. 1997 Mar;48(3):247-54
references.pmid: 9071201
references.citation: J Vasc Surg. 1992 May;15(5):889-91
references.pmid: 1533686
references.citation: Int J Epidemiol. 1991 Jun;20(2):384-92
references.pmid: 1917239
references.citation: Vasc Med. 1996;1(2):141-3
references.pmid: 9546929
references.citation: Circ J. 2009 May;73(5):948-54
references.pmid: 19282610
references.citation: ACP J Club. 2002 Jul-Aug;137(1):12
references.pmid: 12093211
references.citation: Angiology. 2003 Mar-Apr;54(2):155-61
references.pmid: 12678189
references.citation: J Cardiovasc Pharmacol. 1994;23 Suppl 3:S8-16
references.pmid: 7517479
references.citation: Scand J Haematol. 1974;13(4):241-5
references.pmid: 4614427
references.citation: J Am Coll Cardiol. 2007 May 15;49(19):1982-8
references.pmid: 17498584
references.citation: Angiology. 1988 Aug;39(8):742-6
references.pmid: 3048153
references.citation: J Intern Med. 1990 May;227(5):301-8
references.pmid: 2187948
references.citation: Thromb Haemost. 1979 Aug 31;42(2):621-5
references.pmid: 505369
references.citation: Vasa. 1992;21(4):387-91
references.pmid: 1485474
references.citation: Angiology. 2004 Jul-Aug;55(4):361-71
references.pmid: 15258682
references.citation: Clin Ter. 1982 Sep 30;102(6):607-19
references.pmid: 6291844
references.citation: Angiology. 2003 Jan;54(1):25-38
references.pmid: 12593493
references.citation: Am Heart J. 2004 Aug;148(2):263-8
references.pmid: 15308995
references.citation: Angiology. 1982 Jun;33(6):357-67
references.pmid: 7046521
references.citation: Lancet. 1985 Feb 23;1(8426):415-9
references.pmid: 2857803
references.citation: JAMA. 2009 May 13;301(18):1909-19
references.pmid: 19436018
references.citation: Vasa. 1984;13(2):175-8
references.pmid: 6331019
references.citation: Thromb Haemost. 2010 Apr;103(4):766-73
references.pmid: 20174763
references.citation: Am J Cardiol. 1994 Jul 1;74(1):64-5
references.pmid: 8017309
references.citation: Lancet. 1996 Nov 16;348(9038):1329-39
references.pmid: 8918275
references.citation: Am Heart J. 2000 Jul;140(1):67-73
references.pmid: 10874265
references.citation: Nouv Rev Fr Hematol (1978). 1994;35(6):523-8
references.pmid: 8152898
references.citation: J Vasc Surg. 2005 Aug;42(2):252-8
references.pmid: 16102623
references.citation: Cochrane Database Syst Rev. 2011 Nov 09;(11):CD001272
references.pmid: 22071801
references.citation: J Am Coll Cardiol. 2006 Dec 19;48(12):2539-45
references.pmid: 17174195
references.citation: Circulation. 1993 May;87(5):1563-9
references.pmid: 8491012
references.citation: Curr Med Res Opin. 1976;4(6):395-401
references.pmid: 793778
references.citation: Monogr Atheroscler. 1986;14:207-9
references.pmid: 3526127
references.citation: N Engl J Med. 2007 Dec 13;357(24):2482-94
references.pmid: 18077812
references.citation: Angiology. 1999 Feb;50(2):123-30
references.pmid: 10063942
references.citation: J Intern Med. 2007 Mar;261(3):276-84
references.pmid: 17305650
references.citation: Dtsch Med Wochenschr. 1984 Aug 17;109(33):1240-3
references.pmid: 6381015
references.citation: Angiology. 2001 Feb;52(2):115-25
references.pmid: 11228084
references.citation: Arch Intern Med. 1999 Nov 22;159(21):2524-8
references.pmid: 10573042
references.citation: Atherosclerosis. 1996 Feb;120(1-2):25-35
references.pmid: 8645368
references.citation: Pol Merkur Lekarski. 2007 Nov;23(137):335-9
references.pmid: 18361314
references.citation: Br J Surg. 1982 Jan;69(1):38-40
references.pmid: 6274471
references.citation: Drug Saf. 1999 Oct;21(4):325-35
references.pmid: 10514023
references.citation: Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000123
references.pmid: 17943736
references.citation: JAMA. 2010 Mar 3;303(9):841-8
references.pmid: 20197530
references.citation: Arzneimittelforschung. 1985;35(12):1847-9
references.pmid: 4096744
references.citation: Pharmatherapeutica. 1982;3(3):188-94
references.pmid: 7134226
references.citation: Angiology. 1989 Oct;40(10):880-5
references.pmid: 2679241
references.citation: Angiology. 1997 Mar;48(3):237-40
references.pmid: 9071199
references.citation: J Vasc Surg. 2007 Jan;45 Suppl S:S5-67
references.pmid: 17223489
references.citation: Eur J Vasc Endovasc Surg. 2006 Jul;32(1):71-5
references.pmid: 16549375
references.citation: Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1942-7
references.pmid: 9848888
references.citation: J Cardiovasc Pharmacol. 1996 Jun;27(6):788-93
references.pmid: 8761844
references.citation: Curr Ther Res Clin Exp. 2003 Jul;64(7):488-503
references.pmid: 24944399
references.citation: Am Heart J. 2005 Sep;150(3):401
references.pmid: 16169314
references.citation: BMJ. 2010 Aug 18;341:c3920
references.pmid: 20719825
references.citation: Circulation. 2000 Jul 25;102(4):426-31
references.pmid: 10908215
references.citation: J Thromb Haemost. 2005 Dec;3(12):2649-55
references.pmid: 16359503
references.citation: Circulation. 1993 Sep;88(3):837-45
references.pmid: 8353913
references.citation: Rev Clin Esp. 1992 Apr;190(6):295-8
references.pmid: 1598427
references.citation: Cochrane Database Syst Rev. 2008 Oct 08;(4):CD000990
references.pmid: 18843614
references.citation: Arch Intern Med. 2003 Apr 28;163(8):884-92
references.pmid: 12719196
references.citation: Z Gesamte Inn Med. 1991 Apr;46(6):185-90
references.pmid: 2063598
references.citation: Vasa. 2006 Aug;35(3):174-7
references.pmid: 16941406
references.citation: Therapie. 1985 Nov-Dec;40(6):451-8
references.pmid: 4089787
references.citation: Atherosclerosis. 1984 Feb;50(2):147-58
references.pmid: 6712768
references.citation: BMJ. 2002 Jan 12;324(7329):71-86
references.pmid: 11786451
references.citation: Platelets. 2004 Mar;15(2):117-25
references.pmid: 15154604
references.citation: Thromb Res. 1985 Oct 15;40(2):275-81
references.pmid: 2933846
references.citation: BMJ. 2008 Oct 16;337:a1840
references.pmid: 18927173
references.citation: Eur J Pharmacol. 1998 Aug 14;355(1):77-83
references.pmid: 9754941
references.citation: Thromb Res. 1987 Nov 15;48(4):417-26
references.pmid: 3445229
references.citation: Minerva Cardioangiol. 1998 Nov;46(11):457-69
references.pmid: 10207294
references.citation: Radiology. 2001 Dec;221(3):689-96
references.pmid: 11719664
references.citation: J Vasc Surg. 2003 Oct;38(4):710-3
references.pmid: 14560218
references.citation: Angiology. 1993 Apr;44(4):300-6
references.pmid: 8457081
references.citation: Eur Heart J. 2009 Jan;30(2):192-201
references.pmid: 19136484
references.citation: Thromb Haemost. 1996 Dec;76(6):939-43
references.pmid: 8972014
references.citation: Recenti Prog Med. 1989 Apr;80(4):204-7
references.pmid: 2762658
references.citation: Angiology. 2008 Dec-2009 Jan;59(6):695-704
references.pmid: 18796444
references.citation: Diabetes Care. 1999 Mar;22(3):453-8
references.pmid: 10097928
references.citation: Angiology. 2000 Jun;51(6):441-9
references.pmid: 10870853
references.citation: JAMA. 1995 Sep 27;274(12):975-80
references.pmid: 7674529
references.citation: Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):403-12
references.pmid: 18174460
references.citation: Vasc Med. 2000;5(2):83-9
references.pmid: 10943584
references.citation: Angiology. 1991 Jan;42(1):8-14
references.pmid: 1992862
references.citation: Angiology. 1991 Jul;42(7):513-21
references.pmid: 1863010
references.citation: Nouv Rev Fr Hematol (1978). 1992;34(2):149-53
references.pmid: 1502021
references.citation: Int J Epidemiol. 1996 Dec;25(6):1172-81
references.pmid: 9027521
references.citation: Circulation. 2000 Mar 14;101(10):1206-18
references.pmid: 10715270
references.citation: Angiology. 1985 May;36(5):310-4
references.pmid: 4025940
references.citation: Circulation. 1970 May;41(5):875-83
references.pmid: 5444530
references.citation: Eur Heart J. 2004 Oct;25(20):1845-52
references.pmid: 15474700
references.citation: JAMA. 2007 Mar 21;297(11):1197-206
references.pmid: 17374814
references.citation: J Intern Med. 2002 Mar;251(3):193-206
references.pmid: 11886478
references.citation: N Engl J Med. 1992 Feb 6;326(6):381-6
references.pmid: 1729621
references.citation: Int J Clin Pharmacol Res. 1986;6(1):59-60
references.pmid: 3514494
references.citation: Eur J Vasc Endovasc Surg. 2008 Jun;35(6):701-8
references.pmid: 18375152
references.citation: Am Heart J. 2000 Jun;139(6):927-33
references.pmid: 10827369
references.citation: J Cardiovasc Pharmacol. 2007 Apr;49(4):221-7
references.pmid: 17438407
references.citation: Int Angiol. 1993 Dec;12(4):371-7
references.pmid: 8207316
references.citation: J Clin Pathol. 2002 Dec;55(12):946-50
references.pmid: 12461065
references.citation: Cor Vasa. 1989;31(2):128-33
references.pmid: 2663343
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1679-86
references.pmid: 12767646
references.citation: Vasc Med. 2006 May;11(2):75-83
references.pmid: 16886837
references.citation: Vasa Suppl. 1992;35:42-5
references.pmid: 1481057
references.citation: Clin Trials Metaanal. 1994 Apr;29(1):21-30
references.pmid: 10150182
references.citation: Clin Investig. 1994 Sep;72(9):673-80
references.pmid: 7849445
references.citation: Int J Clin Pharmacol Ther. 1994 Dec;32(12):646-51
references.pmid: 7881702
references.citation: Ital Heart J. 2003 Oct;4(10):677-84
references.pmid: 14664280
references.citation: Cochrane Database Syst Rev. 2009 Oct 07;(4):CD001246
references.pmid: 19821273
references.citation: Chest. 2004 Sep;126(3 Suppl):234S-264S
references.pmid: 15383474
references.citation: Angiology. 1988 Sep;39(9):802-11
references.pmid: 3048155
references.citation: J Am Coll Cardiol. 2002 Jan 2;39(1):9-14
references.pmid: 11755280