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Antiplatelet Drugs — Do We Need New Options?

With a Reappraisal of Direct Thromboxane Inhibitors

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Abstract

This review describes the current status of antiplatelet therapy in prevention of cardiovascular events of an atherothrombotic nature. The efficacy of aspirin clearly outweighs bleeding risk in secondary prevention, with the relevant exception of patients with peripheral arterial disease (PAD). In trials of primary prevention, aspirin has a limited advantage, which is challenged by the risk of major bleeding. A typical example is primary prevention in type 2 diabetes mellitus, in which a number of trials and a recent meta-analysis have confirmed these limitations.

In various settings, clopidogrel has been shown to be marginally more effective than aspirin. Despite a non-negligible bleeding risk, the combination of aspirin-clopidogrel has provided satisfactory results in conditions at high thrombotic risk but rather disappointing results in the long-term treatment of chronic stable cardiovascular disease. The combination of aspirin-dipyridamole was shown to be superior to aspirin alone and equivalent to clopidogrel alone for secondary prevention in cerebrovascular patients.

Limitations in the efficacy of antiplatelet agents are partly inherent in their mechanism of action and should not be considered simply as ‘treatment failures’. Among other factors, individual variability of response to antiplatelet drugs also plays a meaningful role. Variability of response and ‘resistance’ may result from drug interactions, baseline and residual platelet hyperactivity, increased platelet turnover, pharmacogenetic factors and others. Poor biological response to aspirin and/or clopidogrel is also frequent in clinical settings such as diabetes, obesity and acute coronary syndromes. The correlation between biological resistance and impaired clinical efficacy of aspirin, and especially clopidogrel, is currently accepted, although with limitations due to the different methods used to assess platelet response. Indeed, the concept of individual ‘tailoring’ of antiplatelet regimens on the basis of previous laboratory or ‘point of care’ platelet function tests has been validated in a number of recent trials.

The search for and validation of new antiplatelet agents with already known, or totally new, mechanisms of action have also been undertaken with increasing eagerness. Among new adenosine diphosphate receptor antagonists, prasugrel is already registered, and ticagrelor and cangrelor are being developed. New mechanisms being explored are blockade of thrombin-induced platelet aggregation (vorapaxar [SCH 530398]), and inhibition of collagen and ristocetin-mediated platelet functions (DZ-697b).

Reappraisal of the neglected class of direct thromboxane A2 antagonists was followed with less interest. Besides blocking the effects of thromboxane produced from platelets, drugs of this class (such as terutroban sodium and picotamide) may also protect cells from thromboxane produced by sources other than platelets, and some of them may preserve or enhance prostacyclin production. Terutroban is presently being tested in PAD and stroke prevention. Picotamide, marketed in Italy, was shown to reduce cardiovascular events and mortality in studies of PAD patients with diabetes. The results available with thromboxane inhibitors are particularly interesting because they are being obtained in conditions, such as type 2 diabetes and PAD, which are known to be refractory to aspirin.

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References

  1. Davì G, Patrono C. Platelet activation and athero-thrombosis. N Engl J Med 2007; 357: 2482–94

    Article  PubMed  Google Scholar 

  2. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86

    Article  Google Scholar 

  3. Maulaz AB, Bezerra DC, Michel P. Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2005; 62: 1217–220

    Article  PubMed  Google Scholar 

  4. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008; 121: 43–9

    Article  PubMed  CAS  Google Scholar 

  5. Dalen JE. Aspirin to prevent heart attack and stroke: what’s the right dose? Am J Med 2006; 119: 198–202

    Article  PubMed  CAS  Google Scholar 

  6. Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention of cardiovascular events in patients with peripheral artery diseases: a meta-analysis of randomized trials. JAMA 2009; 301: 1909–19

    Article  PubMed  CAS  Google Scholar 

  7. Berger JS, Brown DL, Burke GL, et al. Aspirin use, dose and clinical outcomes in postmenopausal women with stable cardiovascular disease: the Women’s Health Initiative Observational Study. Circ Cardiovasc Qual Outcomes 2009; 2: 78–87

    Article  PubMed  Google Scholar 

  8. Hebert PR, Hennekens CH. An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease. Arch Intern Med 2000; 160: 3123–7

    Article  PubMed  CAS  Google Scholar 

  9. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293–304

    Article  PubMed  CAS  Google Scholar 

  10. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295: 306–13

    Article  PubMed  CAS  Google Scholar 

  11. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 150: 396–404

    Google Scholar 

  12. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Antithrombotic Trialists’ (ATT) Collaboration. Lancet 2009; 373: 1849–60

    Article  PubMed  CAS  Google Scholar 

  13. Fowkes FG, Price JF, Stewart MC, 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: 841–8

    Article  PubMed  CAS  Google Scholar 

  14. Giampaoli S, Palmieri M, Donfrancesco C, et al. Cardiovascular risk assessment in Italy: the CUORE Project risk score and risk chart. Ital J Public Health 2007; 4: 102–9

    Google Scholar 

  15. Coccheri S. Approaches to prevention of cardiovascular complications and events in diabetes mellitus. Drugs 2007; 67: 997–1026

    Article  PubMed  CAS  Google Scholar 

  16. de Gaetano G, and the Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89–95

    Article  PubMed  Google Scholar 

  17. Sacco M, Pellegrini F, Roncaglioni MC, et al. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 3264–72

    Article  PubMed  CAS  Google Scholar 

  18. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300: 2134–41

    Article  PubMed  CAS  Google Scholar 

  19. Nicolucci A. Aspirin for primary prevention of cardiovascular events in diabetes: still an open question. JAMA 2008; 300: 2180–1

    Article  PubMed  CAS  Google Scholar 

  20. Catalano M, Born G, Peto R, Critical Leg Ischaemia Prevention Study (CLIPS) Group. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med 2007; 261: 276–84

    Article  PubMed  CAS  Google Scholar 

  21. Belch J, MacCuish A, Campbell I, 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. BMJ 2008; 337: a1840

    Article  PubMed  Google Scholar 

  22. De Berardis G, Sacco M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 333: b4531

    Article  Google Scholar 

  23. Ong G, Davis TM, Davis WA, et al. Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting the Fremantle Diabetes study. Diabetes Care 2010; 33: 317–21

    Article  PubMed  CAS  Google Scholar 

  24. American Diabetes Association. Standard of medical care in diabetes: 2010. Diabetes Care 2010; 33 Suppl. 1: S1 1-61

    Article  Google Scholar 

  25. Mehta SR. Aspirin for prevention and treatment of cardiovascular disease. Ann Intern Med 2009; 150: 414–6

    PubMed  Google Scholar 

  26. Laine L. Gastrointestinal bleeding with low-dose aspirin: what’s the risk? Aliment Pharmacol Ther 2006; 24: 897–908

    Article  PubMed  CAS  Google Scholar 

  27. Gent M, Easton JD, Ellis DJ, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 19: 442–3

    Google Scholar 

  28. Hass WK, Easton DJ, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321: 501–7

    Article  PubMed  CAS  Google Scholar 

  29. De Caterina R, Sicari R, Bernini W, et al. Benefit/risk profile of combined antiplatelet therapy with ticlopidine and aspirin. Thromb Haemost 1991; 65: 504–10

    PubMed  Google Scholar 

  30. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the Full Anticoagulation vs Aspirin and Ticlopidine (FANTASTIC) Study. Circulation 1998; 98: 1597–603

    Article  PubMed  CAS  Google Scholar 

  31. Urban P, Macaya C, Rupprecht H-J, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998; 98: 2126–32

    Article  PubMed  CAS  Google Scholar 

  32. Faxon DP, Freedman JE. Facts and controversies of aspirin and clopidogrel therapy. Am Heart J 2009; 157: 412–22

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  34. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev 2000; CD001246

  35. Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682–7

    Article  PubMed  CAS  Google Scholar 

  36. Aronow HD, Steinhubl SR, Brennan DM, et al. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2009; 157: 369–74

    Article  PubMed  CAS  Google Scholar 

  37. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: a placebo-controlled trial. Lancet 2005; 366: 1607–21

    Article  PubMed  CAS  Google Scholar 

  38. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7

    Article  PubMed  CAS  Google Scholar 

  39. Bhatt DL, Fox KA, Hacke W, et al., and the CHARISMA investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–17

    Article  PubMed  CAS  Google Scholar 

  40. Keller TT, Squizzato A, Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev 2007; (3): CD005158

  41. Steinhubl SR, Bhatt DL, Brennan DM, et al. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009; 150: 379–86

    PubMed  Google Scholar 

  42. Blasco-Colmenares E, Peri TM, Guallar E, et al. Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 2009; 169: 788–96

    Article  PubMed  Google Scholar 

  43. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin [letter]. J Neurol Neurosurg Psychiatry 1999; 66: 255

    Article  PubMed  CAS  Google Scholar 

  44. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13

    Article  PubMed  CAS  Google Scholar 

  45. Halkes PH, van Gijn J, Kappelle LJ, et al.,ESPRIT study group. Aspirin plus dipyridamole versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665–73

    Article  PubMed  CAS  Google Scholar 

  46. Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke 2008; 39: 1358–63

    Article  PubMed  CAS  Google Scholar 

  47. Sacco RL, Diener HC, Yusuf S, et al., and PROFESS study group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238–51

    Article  PubMed  CAS  Google Scholar 

  48. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol 2009; 103 Suppl.: 27A–34A

    Article  PubMed  CAS  Google Scholar 

  49. Kuliczkowski W, Witkowski A, Polonski L, et al. Inter-individual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009; 30: 426–35

    Article  PubMed  Google Scholar 

  50. Gupta S, Gupta MM. Aspirin and clopidogrel resistance — myth or reality: an update. Indian Heart J 2008; 60: 245–53

    PubMed  Google Scholar 

  51. Samama MM, Elalamy I. Study of variability in response to aspirin and clopidogrel: clinical and/or biological resistance? [In French]. Ann Pharm Fr 2009; 67: 265–71

    Article  PubMed  CAS  Google Scholar 

  52. Snoep JD, Hovens MM, Eikenboom JC, et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 1593–9

    Article  PubMed  Google Scholar 

  53. Krasopoulos G, Brister SJ, Beattie WS, et al. Aspirin “resistance” and risk of cardiovascular morbidity: a systematic review and meta-analysis. BMJ 2008; 336: 195–8

    Article  PubMed  CAS  Google Scholar 

  54. Snoep JD, Hovens MM, Eikenboom JC, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221–31

    Article  PubMed  CAS  Google Scholar 

  55. Sofi F, Marcucci R, Gori AM, et al. Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events: a meta-analysis. Int J Cardiol 2008; 128: 166–71

    Article  PubMed  Google Scholar 

  56. Combescure C, Fontana P, Mallouk N, et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost. Epub 2010 Feb 12

  57. Crescente M, De Castelnuovo A, Iacoviello L, et al. Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100: a systematic review. Thromb Haemost 2008; 99: 14–26

    PubMed  CAS  Google Scholar 

  58. Patrono C, Rocca B. Aspirin, 110 years later. J Thromb Haemost 2009; 7 Suppl. 1: 258–61

    Article  PubMed  CAS  Google Scholar 

  59. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007; 115: 2196–207

    Article  PubMed  Google Scholar 

  60. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301: 937–44

    Article  PubMed  CAS  Google Scholar 

  61. Siller-Matula JM, Lang I, Christ G, et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52: 1557–63

    Article  PubMed  CAS  Google Scholar 

  62. Motovska Z, Widimsky P, Petr R, et al., on behalf of the PRAGUE-8 Study Investigators. Factors influencing clopidogrel efficacy in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention: statin’s advantage and the smoking “paradox”. J Cardiovasc Pharmacol 2009; 53: 368–72

    Article  PubMed  CAS  Google Scholar 

  63. Malmström RE, Ostergren J, Jørgensen L, et al. Influence of statin treatment on platelet inhibition by clopidogrel: a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment. J Intern Med 2009; 266: 457–66

    Article  PubMed  CAS  Google Scholar 

  64. Maree AO, Curtin RJ, Chubb A, et al. Cycloxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3: 2340–5

    Article  PubMed  CAS  Google Scholar 

  65. Clappers N, van Oijen MG, Sundaresan S, et al. The C50T polymorphism of the cycloxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl-salicylic acid. Thromb Haemost 2008; 100: 70–5

    PubMed  CAS  Google Scholar 

  66. Frelinger 3rd AL, Li Y, Linden MD, et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009; 120: 2586–96

    Article  PubMed  CAS  Google Scholar 

  67. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354–62

    Article  PubMed  CAS  Google Scholar 

  68. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363–75

    Article  PubMed  CAS  Google Scholar 

  69. Sibbing D, Stengherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916–22

    Article  PubMed  CAS  Google Scholar 

  70. Motovska Z, Widimsky P, Kvasnicka J, et al. High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism: a genetic substudy of PRAGUE-8 trial. Blood Coagul Fibrinolysis 2009; 20: 257

    Article  PubMed  CAS  Google Scholar 

  71. Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP34A4 IVS10+ 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genom 2007; 17: 1057–64

    Article  CAS  Google Scholar 

  72. Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effects (ASPECT) study. Circulation 2007; 115: 3156–64

    Article  PubMed  CAS  Google Scholar 

  73. Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol 2008; 51: 1829–43

    Article  PubMed  CAS  Google Scholar 

  74. Patrono C, Fitzgerald GA. Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 1997; 17: 2309–15

    Article  PubMed  CAS  Google Scholar 

  75. Lordkipanidzè M, Diodati JG, Schampaert E, et al. Prevalence of unresponsiveness to aspirin and/or clopidogrel in patients with stable coronary heart disease. Am J Cardiol 2009; 104: 1189–93

    Article  PubMed  CAS  Google Scholar 

  76. Feher G, Koltai K, Papp E, et al. Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables. Drugs Aging 2006; 23: 559–67

    Article  PubMed  CAS  Google Scholar 

  77. Cuisset T, Frere C, Quilici J, et al. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597–603

    Article  PubMed  CAS  Google Scholar 

  78. Serebruany V, Pokov I, Kuliczkowski W, et al. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 76–82

    PubMed  CAS  Google Scholar 

  79. Watala C, Pluta J, Golanski J, et al. Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin. J Mol Med 2005; 83: 148–58

    Article  PubMed  CAS  Google Scholar 

  80. Shantsila E, Lip GY. Beyond glucose levels in diabetic patients with coronary artery disease: platelet activity and non-responsiveness to antiplatelet therapy. Thromb Haemost 2008; 100: 7–8

    PubMed  CAS  Google Scholar 

  81. Anfossi G, Russo I, Trovati M. Resistance to aspirin and thienopyridines in diabetes mellitus and metabolic syndrome. Curr Vasc Pharmacol 2008; 6: 313–28

    Article  PubMed  CAS  Google Scholar 

  82. Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298–304

    Article  PubMed  CAS  Google Scholar 

  83. van Werkum JW, Topcu Y, Postma S, et al. Effects of diabetes mellitus on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel. Thromb Haemost 2008; 99: 637–9

    PubMed  Google Scholar 

  84. Michelson AD, Linden MD, Furman MI, et al. Evidence that pre-existent variability in platelet response to ADP accounts for ’’clopidogrel resistance’’. J Thromb Haemost 2007; 5: 75–81

    Article  PubMed  CAS  Google Scholar 

  85. Erlinge D, Varenhorst C, Braun OO, et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008; 52: 1968–77

    Article  PubMed  CAS  Google Scholar 

  86. Duzenil MA, Ozdemir K, Aygul N, et al. Comparison of increased aspirin dose versus combined aspirin plus clopidogrel therapy in patients with diabetes mellitus and coronary heart disease and impaired antiplatelet response to low-dose aspirin. Am J Cardiol 2008; 102: 396–400

    Article  CAS  Google Scholar 

  87. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708–16

    Article  PubMed  CAS  Google Scholar 

  88. Angiolillo DJ, Costa MA, Shoemaker SB, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol 2008; 101: 440–5

    Article  PubMed  CAS  Google Scholar 

  89. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) study. Circulation 2005; 111: 2099–106

    Article  PubMed  CAS  Google Scholar 

  90. Jung JH, Min PK, Lee SH, et al. Clopidogrel pretreatment before primary percutaneous coronary stenting in patients with acute ST-segment elevation myocardial infarction: comparison of high loading dose (600 mg) versus low loading dose (300 mg). Coron Artery Dis 2009; 20: 150–4

    Article  PubMed  Google Scholar 

  91. Eikelboom JW, Hankey GJ, Thom J, et al. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. J Thromb Haemost 2005; 3: 2649–55

    Article  PubMed  CAS  Google Scholar 

  92. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27–33

    Article  PubMed  CAS  Google Scholar 

  93. Holmes Jr DR, Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009; 54: 95–109

    Article  PubMed  CAS  Google Scholar 

  94. Golanski J, Muchova J, Golanski R, et al. Does pycnogenol intensify the efficacy of acetylsalicylic acid in the inhibition of platelet function? Invitroexperience. Postepy Hig Med Dosw (Online) 2006; 60: 316–21

    Google Scholar 

  95. Angiolillo DJ, Capranzano P, Goto S, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J 2008; 29: 2202–11

    Article  PubMed  CAS  Google Scholar 

  96. Jeong YH, Lee SW, Choi BR, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol versus High Maintenance Dose Clopidogrel in Patients with Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009; 53: 1101–9

    Article  PubMed  CAS  Google Scholar 

  97. Singh I, Shafiq N, Pandhi P, et al. Triple antiplatelet therapy vs dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: an evidence-based approach to answering a clinical query. Br J Clin Pharmacol 2009; 68: 4–13

    Article  PubMed  Google Scholar 

  98. Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849–56

    Article  PubMed  CAS  Google Scholar 

  99. Patti G, Nusca A, Mangiacapra F, et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity predicts Outcome) study. J Am Coll Cardiol 2008; 52: 1128–33

    Article  PubMed  CAS  Google Scholar 

  100. Valgimigli M, Campo G, de Cesare N, et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel study. Circulation 2009; 199: 3215–22

    Article  CAS  Google Scholar 

  101. Bonello L, Camoin-Jau L, Armero S, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5–10

    Article  PubMed  CAS  Google Scholar 

  102. Bonello L, Palot-Bonello N, Armero S, et al. Impact of loading dose adjustment on platelet reactivity in homozygotes of the 2C192 loss of function polymorphism. Int J Cardiol. Epub 2009 Aug 25

  103. Bonello-Palot N, Armeno S, Paganelli F, et al. Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 104: 1511–5

    Article  PubMed  CAS  Google Scholar 

  104. Gladding P, Webster M, Zeng L, et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1: 620–7

    Article  PubMed  Google Scholar 

  105. Trenk D, Hochoholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925–34

    Article  PubMed  CAS  Google Scholar 

  106. Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 8(2): 250–6

    Article  PubMed  CAS  Google Scholar 

  107. Price MJ, Berger PB, Angiolillo DJ, et al. Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 157: 818–24

    Article  PubMed  CAS  Google Scholar 

  108. Turnbull CM, Cena C, Fruttero R, et al. Mechanism of action of novel NO-releasing furoxan derivatives of aspirin in human platelets. Br J Pharmacol 2006; 148: 517–26

    Article  PubMed  CAS  Google Scholar 

  109. Momi S, Pitchford SC, Alberti PF, et al. Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. Thromb Haemost 2005; 93: 535–43

    PubMed  CAS  Google Scholar 

  110. Murdoch D, Plosker GL. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. Drugs 2006; 66: 671–92

    Article  PubMed  CAS  Google Scholar 

  111. Cattaneo M. New P2Y12 blockers. J Thromb Haemost 2009;7 Suppl. 1: 262–5

    Article  PubMed  CAS  Google Scholar 

  112. Angiolillo DJ, Bhatt DL, Gurbel PA, et al. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol 2009; 103 Suppl.: 40A–51A

    Article  PubMed  CAS  Google Scholar 

  113. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic and clinical outcomes. Circulation 2009; 119: 2553–60

    Article  PubMed  CAS  Google Scholar 

  114. Montalescot G, Wiviott SD, Braunwald E, and the TRITON-TIMI 38 Investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double blind, randomized controlled trial. Lancet 2009; 373: 723–31

    Article  PubMed  CAS  Google Scholar 

  115. Morrow DA, Wiviott SD, White HD, et al. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction. Circulation 2009; 119: 2758–64

    Article  PubMed  CAS  Google Scholar 

  116. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626–36

    Article  PubMed  CAS  Google Scholar 

  117. Harrington RA, Stone GW, McNully S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318–29

    Article  PubMed  CAS  Google Scholar 

  118. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330–41

    Article  PubMed  CAS  Google Scholar 

  119. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57

    Article  PubMed  CAS  Google Scholar 

  120. Shinohara Y, Nishimaru K, Sawada T, for SACCESS Study Group. Sarpogrelate-SarpoAspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin controlled trial. Stroke 2008; 39: 1827–33

    Article  PubMed  CAS  Google Scholar 

  121. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing nonurgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. TRA-PCI Investigators. Lancet 2009; 373: 872–3

    Article  Google Scholar 

  122. Zafar MU, Ibanez B, Chol BG, et al. A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel in a randomized phase I study. Thromb Haemost 2010; 103: 205–12

    Article  PubMed  CAS  Google Scholar 

  123. Fitzgerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68: 11B-5B

    Article  Google Scholar 

  124. Golino P, Ambrosio G, Gresele P, et al. The vivo antiplatelet effects of thromboxane A2 synthase inhibitors are potentiated by simultaneous thromboxane A2/prostaglandin H2 receptor blockade. J Pharmacol Exp Ther 1993; 266: 511–7

    PubMed  CAS  Google Scholar 

  125. Gresele P, Deckmyn H, Arnout J, et al. Characterization of N,N′-bis (3picolyl)-4-methoxy-isophtalate (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. Thromb Haemost 1989; 61: 479–84

    PubMed  CAS  Google Scholar 

  126. Neri Serneri GG, Gensini GF, Poggesi L, et al. The role of extraplatelet thromboxane A2 in unstable angina investigated with a dual thromboxane A2 inhibitor: importance of activated monocytes. Coron Artery Dis 1994; 5: 137–45

    Article  PubMed  CAS  Google Scholar 

  127. Watts IS, Wharton KA, White BP, et al. Thromboxane (Tx)A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti-aggregatory efficacy in human platelets. Br J Pharmacol 1991; 102: 497–505

    Article  PubMed  CAS  Google Scholar 

  128. Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers: a review. Circulation 1990; 81 Suppl.: 169–78

    Google Scholar 

  129. Yao SK, Ober JC, Ferguson JJ, et al. Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries. Circulation 1992; 86: 1993–9

    Article  PubMed  CAS  Google Scholar 

  130. The RAPT Investigators. Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction: the Ridogrel Versus Aspirin Patency Trial (RAPT). Circulation 1994; 89: 588–95

    Article  Google Scholar 

  131. Tranchesi B, Pileggi F, Vercammen E, et al. Ridogrel does not increase the speed and rate of coronary recanalization in patients with myocardial infarction treated with alteplase and heparin. Eur Heart J 1994; 15: 660–4

    PubMed  CAS  Google Scholar 

  132. van der Wieken LR, Simoons ML, Laarman GJ, et al. Ridogrel as an adjunct to thrombolysis in acute myocardial infarction. Int J Cardiol 1995; 52: 125–34

    Article  PubMed  Google Scholar 

  133. Cimitière B, Dubuffet T, Muller O, et al. Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as thromboxane receptor antagonists. Bioorg Med Chem Lett 1998; 8: 1375–80

    Article  Google Scholar 

  134. Cayatte AJ, Du Y, Oliver-Krasinski J, et al. The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20: 1724–8

    Article  PubMed  CAS  Google Scholar 

  135. Egan KM, Wang M, Fries S, et al. Cyclooxygenase, thromboxane, and atherosclerosis: plaque destabilization by cycloxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 2005; 111: 334–42

    Article  PubMed  CAS  Google Scholar 

  136. Hong TT, Huang J, Driscoll E, et al. Preclinical evaluation of S18886 in an experimental model of coronary arterial thrombosis. Cardiovasc Pharmacol 2006; 48: 239–48

    Article  CAS  Google Scholar 

  137. Vilahur G, Casani L, Badimon L. A thromboxane H2 receptor antagonist (S1 8886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis. Thromb Haemost 2007; 98: 662–9

    PubMed  CAS  Google Scholar 

  138. Xu S, Jiang B, Maitland KA, et al. The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice. Diabetes 2006; 55: 110–9

    Article  PubMed  CAS  Google Scholar 

  139. Viles-Gonzales JF, Fuster V, Corti R, et al. Atherosclerosis regression and TP receptor inhibition: effect of S 18886 on plaque size and composition — a magnetic resonance imaging study. Eur Heart J 2005; 26: 1557–61

    Article  CAS  Google Scholar 

  140. Fiessinger JN, TAIPAD Study Group. S18886, a new specific TP receptor antagonist is safe and as effective as aspirin in inhibiting platelet aggregation in patients with peripheral arterial disease. Eur Heart J 2004; 25: 89–90

    Google Scholar 

  141. Bousser MG, Amarenco P, Chamorro A, et al. Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study. Cerebrovasc Dis 2009; 27: 509–18

    Article  PubMed  CAS  Google Scholar 

  142. Modesti PA. Picotamide: an inhibitor of the formation and effects of TxA2. Cardiovasc Drug Rev 1995; 4: 353–64

    Article  Google Scholar 

  143. Buccellati C, Ciceri P, Ballerio R, et al. Evaluation of the effects of anti-thromboxane agents in platelet-vessel wall interaction. Eur J Pharmacol 2002; 443: 133–41

    Article  PubMed  CAS  Google Scholar 

  144. Ratti S, Quarato P, Casagrande C, et al. Picotamide, an antithromboxane agent, inhibits the migration and proliferation of arterial myocytes. Eur J Pharmacol 1998; 355: 77–83

    Article  PubMed  CAS  Google Scholar 

  145. Giustina A, Perini P, Desenzani P, et al. Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients. Diabetes 1998; 47: 423–30

    Article  PubMed  CAS  Google Scholar 

  146. Coto V, Oliviero U, Cocozza M, et al. Long-term safety and efficacy of picotamide, a dual-action antithromboxane agent, in diabetic patients with carotid atherosclerosis: a 6-year follow-up study. J Int Med Res 1998; 26: 200–5

    PubMed  CAS  Google Scholar 

  147. Davi G, Gresele P, Violi F, et al. Diabetes mellitus, hyper-cholesterolemia and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo: evidence derived from the study of peripheral arterial disease. Circulation 1997; 96: 69–75

    Article  PubMed  CAS  Google Scholar 

  148. Coto V, Cocozza M, Oliviero U, et al. Clinical efficacy of picotamide in long-term treatment of intermittent claudication. Angiology 1989; 40: 880–5

    Article  PubMed  CAS  Google Scholar 

  149. Canonico V, Ammaturo V, Guarini P, et al. The clinico-instrumental evaluation of the efficacy of picotamide in treating chronic obstructive arteriopathies of the lower extremities. Minerva Cardioangiol 1991; 39: 75–80

    PubMed  CAS  Google Scholar 

  150. Neirotti M, Molaschi M, Ponzetto M, 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: 137–41

    Article  PubMed  CAS  Google Scholar 

  151. Lechat P, Priollet P. Prevention of major ischemic events in lower limb arterial disease: does aspirin play a role? J Mal Vasc 2006; 31: 129–34

    Article  PubMed  CAS  Google Scholar 

  152. Balsano F, Violi F. Effect of picotamide on the clinical progression of peripheral vascular disease: a double-blind placebo-controlled study. The ADEP Group. Circulation 1993; 87: 1563–9

    Article  PubMed  CAS  Google Scholar 

  153. Violi F, Hiatt W. A critical review of antiplatelet treatment in peripheral arterial disease. Intern Emerg Med 2007; 2: 84–7

    Article  PubMed  CAS  Google Scholar 

  154. Milani M, Longoni A, Maderna M. Effects of picotamide, an antiplatelet agent, on cardiovascular events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study. Br J Clin Pharmacol 1996; 42: 782–5

    Article  PubMed  CAS  Google Scholar 

  155. Neri Serneri GG, Coccheri S, Marubini E, et al. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur Heart J 2004; 25: 1845–52

    Article  PubMed  CAS  Google Scholar 

  156. Gresele P, Migliacci R. Picotamide versus aspirin in diabetic patients with peripheral arterial disease: has David defeated Goliath? Eur Heart J 2004; 25: 1769–71

    Article  PubMed  CAS  Google Scholar 

  157. Celestini A, Violi F. A review of picotamide in the reduction of cardiovascular events in diabetic patients. Vasc Health Risk Manag 2007; 3: 93–8

    PubMed  CAS  Google Scholar 

  158. Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650–5

    Article  PubMed  CAS  Google Scholar 

  159. Cipollone F, Ciabattoni G, Patrignani P. Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina. Circulation 2000; 102: 1007–13

    Article  PubMed  CAS  Google Scholar 

  160. Bertel`e V, Falanga A, Tomisiak M, et al. Platelet thromboxane synthetase inhibitors with low doses of aspirin: possible resolution of the “aspirin dilemma”. Science 1983; 220: 517–9

    Article  CAS  Google Scholar 

  161. Cyrus T, Yao Y, Ding T, et al. A novel thromboxane receptor antagonist and synthase inhibitor, BM-573, reduces development and progression of atherosclerosis in LDL receptor deficient mice. Eur J Pharmacol 2007; 561: 105–11

    Article  PubMed  CAS  Google Scholar 

  162. Vetrano A, Milani M, Corsini G. Effects of aspirin or picotamide, an antithromboxane agent, in combination with low-intensity oral anticoagulation in patients with acute myocardial infraction: a controlled randomized pilot trial. G Ital Cardiol 1999; 29: 524–8

    PubMed  CAS  Google Scholar 

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Acknowledgements

Professor Coccheri did not receive specific funding for the preparation of this manuscript. During the last 5 years he received occasional fees for consultancy or reports regarding direct thromboxane inhibition from Teofarma, Milan and Evolva, Basel.

Professor Coccheri is deeply grateful to Dr Donatella Orlando, his scientific secretary, for her outstanding collaboration and unfailing support in literature search, organization of the work and editing of the manuscript.

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    Sergio Coccheri

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Coccheri, S. Antiplatelet Drugs — Do We Need New Options?. Drugs 70, 887–908 (2010). https://doi.org/10.2165/11536000-000000000-00000

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