Download PDF
Thromb Haemost 1998; 80(03): 512-518
DOI: 10.1055/s-0037-1615238
Rapid Communications
Schattauer GmbH

The Antiaggregating and Antithrombotic Activity of Clopidogrel Is Potentiated by Aspirin in Several Experimental Models in the Rabbit

Jean-Marc Herbert
1   From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
Frédérique Dol
1   From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
André Bernat
1   From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
Robert Falotico
1   Johnson & Johnson, Pharmaceutical Research, Warren, NJ, USA
,
Alain Lalé
1   From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
,
Pierre Savi
1   From the Sanofi Recherche, Haemobiology Research Department, Toulouse, France
› Author Affiliations
Further Information

Publication History

Received 08 December 1997

Accepted after resubmission 13 May 1998

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

It is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1–20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1–10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP‘s effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.

 

  • References

  • 1 Sigwart U, Puel J, Mirkowitch V. Intravascular stents to prevent occlusion or restenosis after transluminal angioplasty. N Engl J Med 1987; 316: 701-6.
    CrossrefPubMedGoogle Scholar
  • 2 Hermann HC, Hirshfeld JW, Buchbinder M. Emergent coronary artery stenting for failed PTCA. Circulation 1991; 84 (suppl II) II-590 (abstract).
    PubMedGoogle Scholar
  • 3 Schatz RA, Baim DS, Leon M. Clinical experience with the Palmaz-Schatz coronary stent. Circulation 1991; 83: 148-61.
    CrossrefPubMedGoogle Scholar
  • 4 Puel J, Joffre F, Rousseau H. Endoprothèses coronarienes auto-expansives dans la prévention des resténoses après angioplastie transluminale. Arch Mal Coeur 1987; 80: 1311-2.
    PubMedGoogle Scholar
  • 5 Haude M, Herber R, Straub U. Results of intracoronary stents for management of coronary dissection after balloon angioplasty. Am J Cardiol 1991; 67: 691-6.
    CrossrefPubMedGoogle Scholar
  • 6 Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione A, Goldberg SL, Tobis J. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995; 91: 1676-88.
    CrossrefPubMedGoogle Scholar
  • 7 Neumann F-J, Gawaz M, Dickfeld T, Wehinger A, Walter H, Blasini R, Schömig A. Antiplatelet effect of ticlopidine after coronary stenting. J Am Coll Cardiol 1997; 29: 1515-9.
    CrossrefPubMedGoogle Scholar
  • 8 Goods CM, Al-Shaibi KF, Liu NW, Yadav JS, Dean LS, Iyer SS, Parks JM, Roubin GS. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary stenting. Am J Cardiol 1996; 78: 1042-4.
    CrossrefPubMedGoogle Scholar
  • 9 Lecompte TP, Lecrubier C, Bouloux C, Horellou M-H, Galleyrand J, Maffrand J-P, Samama MM. Antiplatelet effects of the addition of acetylsalicylic acid 40 mg daily to ticlopidine in human healthy volunteers. Clin Appl Thromb Haemost 1997; 3: 245-50.
    CrossrefPubMedGoogle Scholar
  • 10 Herbert JM, Bernat A, Samama M, Maffrand JP. The antiaggregating and antithrombotic activity of Ticlopidine is potentiated by aspirin in the rat. Thromb Haemost 1996; 76: 94-8.
    PubMedGoogle Scholar
  • 11 Moloney BA. An analysis of the side-effects of ticlopidine. In: Ticlopidine, platelets and vascular disease. Hass WK, Easton JD (eds). New York: Springer-Verlag; 1993. p 117.
    Google Scholar
  • 12 Herbert JM, Frehel D, Vallée E, Berger Y, Gouy D, Necciari Defreyn G Maffrand JP. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovasc Drug Rev 1993; 11: 180-98.
    CrossrefPubMedGoogle Scholar
  • 13 CAPRIE Steering Committee.. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemia. Lancet 1996; 348: 1329-39.
    CrossrefPubMedGoogle Scholar
  • 14 Born GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-95.
    CrossrefPubMedGoogle Scholar
  • 15 Umetzu T, Sanai K. Effect of 1-Methyl-2Mercapto-5-(3-Pyridyl)-Imidazole (KC-6141), an anti-aggregating compound, on experimental thrombosis in rabbits. Thromb Haemost 1978; 39: 74-83.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Hladovec I. Experimental arterial thrombosis in rats with continuous registration. Thromb Diathes Haemorrh 1971; 26: 407-10.
    PubMedGoogle Scholar
  • 17 Fishman J, Ryan GB, Karnovsky MJ. Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of intimal thickening. Lab Invest 1975; 32: 339-51.
    PubMedGoogle Scholar
  • 18 Sarembock IJ, La Veau PJ, Sigal SL, Timms I, Sussman J, Haudenschild C, Ezekowitz MD. Influence of inflation pressure and balloon size on the development of intimal hyperplasia after balloon angioplasty. Circulation 1989; 80: 1029-40.
    CrossrefPubMedGoogle Scholar
  • 19 Maffrand JP, Bernat A, Delebassée D, Defreyn G, Cazenave JP, Gordon JL. ADP plays a key role in thrombogenesis in rats. Thromb Haemost 1988; 59: 225-30.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Dongay B, Dol-Gleizes F, Herbert JM. Effect of fantofarone, a new calcium channel antagonist on angioplasty-induced vasospasm in an atherosclerotic rabbit model. Biochem Pharmacol, in press.
    PubMedGoogle Scholar
  • 21 McTavish D, Faulds D, Goa KL. Ticlopidine: an updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40: 238-59.
    CrossrefPubMedGoogle Scholar
  • 22 Gent M, Easton JD, Hachinski VC, Panak E, Sicurella J, Blakely JA, Ellis DJ, Harbinson JW, Roberts RS, Turpie AGG. the CATS Group. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-20.
    PubMedGoogle Scholar
  • 23 Hass WK, Easton JD, Harold P, Adams Jr, Pryse-Phillips W, Molonu BA, Anderson S, Kamm B. for the Ticlopidine Aspirin Stroke Study. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-7.
    CrossrefPubMedGoogle Scholar
  • 24 Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, Persson G. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. Scand J Int Med 1990; 227: 301-8.
    PubMedGoogle Scholar
  • 25 Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini G, Ferraro M, Colombo A. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996; 93: 215-22.
    CrossrefPubMedGoogle Scholar
  • 26 Morice MC, Zemour G, Benveniste E, Biron Y, Bourdonnec C, Faivre R, Fajadet J, Gaspard P, Glatt B, Joly P, Labrunie P, Lienhart Y, Marco J, Petiteau PY, Royer T, Valeix B. Intracoronary stenting without coumadin: one month results of a French multicenter study. Catheter Cardiovasc Diagn 1995; 35: 1-7.
    CrossrefPubMedGoogle Scholar
  • 27 Baragan P, Sainsous J, Silvestri M, Bouvier JL, Comet B, Simeoni JB, Charmasson C, Bremondy M. Ticlopidine and subcutaneous heparin as an alternative regimen following coronary stenting. Catheter Cardiovasc Diagn 1994; 32: 133-6.
    CrossrefPubMedGoogle Scholar
  • 28 Van Belle E, Mc Fadden EP, Lablanche JM, Bauters C, Hamon M, Bertrand ME. Two-ranged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation. Coronary Artery Disease 1995; 6: 341-5.
    CrossrefPubMedGoogle Scholar
  • 29 Serruys PW, de Jaegere P, Kiemeneij F. for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331: 489-95.
    CrossrefPubMedGoogle Scholar
  • 30 Herbert JM, Tissinier A, Defreyn G, Maffrand JP. Inhibitory effect of clopidogrel on platelet adhesion and intimal proliferation after arterial injury in rabbits. Atherioscl Thromb 1993; 13: 1171-9.
    PubMedGoogle Scholar
  • 31 Tallarida RJ. Statistical analysis of drug combinations for synergism. Pain 1992; 49: 93-7.
    CrossrefPubMedGoogle Scholar
  • 32 Clowes AW, Karnovsky MJ. Failure of certain antiplatelet drugs to affect myointimal thickening following arterial endothelial injury in the rat. Lab Invest 1977; 36: 452-62.
    PubMedGoogle Scholar
  • 33 Dejana R, Cazenave JP, Groves HM, Kinlough-Rathbone RL, Richardson M, Packham MA, Mustard JF. The effect of aspirin inhibition of PGI2 production on platelet adherence to normal and damaged rabbit aortae. Thromb Res 1980; 17: 453-8.
    CrossrefPubMedGoogle Scholar
  • 34 Reece AH, Walton PL. Inhibition of intimal proliferation of rabbit aorta by ticlopidine. Thromb Haemost 1979; 42: 367.
    PubMedGoogle Scholar
  • 35 Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest 1992; 89: 507-11.
    CrossrefPubMedGoogle Scholar