Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

Summary

Ticlopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B₂ generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB₂ (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

• References

• 1 Lewis DL, Davis JW, Archibald DC. et al Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396-403
• 2 Cairns J, Gent M, Singer J, Finnie KJ. et al Aspirin, sulfinpyrazone or both in unstable angina. N Engl J Med 1985; 313: 1369-1375
• 3 Antiplatelet Trialist’s Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-331
• 4 Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978; 61: 314-319
• 5 De Caterina R, Giannessi D, Gazzetti P, Bernini W. Inhibition of platelet aggregation and thromboxane B2 production during aspirin treatment: dependence on the dose of the aggregating agent. Thromb Res 1985; 37: 337-342
• 6 Saltiel E, Ward A. Ticlopidine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. Drugs 1987; 34: 222-262
• 7 McTavish D, Faulds D, Goa KL. Ticlopidine: an updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs (in press)
• 8 Hass WK, Easton JD, Adams JHP, Pryse-Phillips W, Molony BA. et al A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507
• 9 Thebault J, Blatrix CE, Blanchard JF, Panak EA. The interactions of ticlopidine and aspirin in normal subjects. J Int Med Res 1977; 5: 405-411
• 10 De Caterina R, Giannessi D, Bernini W, Gazzetti P, Michelassi C, L’Abbate A, Donato L, Patrignani P, Filabozzi P, Patrono C. Selective inhibition of thromboxane-related platelet function by low-dose aspirin in patients after myocardial infarction. Am J Cardiol 1985; 55: 589-590
• 11 De Caterina R, Giannessi D, Bernini W, Gazzetti P, Michelassi C, L’Abbate A, Donato L, Patrignani P, Filabozzi P, Patrono C. Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function. Eur Heart J 1985; 9: 409-417
• 12 De Caterina R, Giannessi D, Boem A, Bernini W, Battaglia D, Michelassi C, Dell’Amico F, L’Abbate A, Patrignani P, Patrono C. Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction. Thromb Haemostas 1985; 54: 528-532
• 13 De Caterina R, Boem A, Gazzetti P, Sicari R, Giannessi D, Ciabattoni G, Patrono C. Long-term maintenance of thromboxane inhibition by two different aspirin regimens in patients with unstable angina. Thromb Res 1990; 60: 169-175
• 14 De Caterina R, Giannessi D, Bernini W, Mazzone A. Organic nitrates: direct antiplatelet effects and synergism with prostacyclin. Thromb Haemostas 1988; 59: 207-211
• 15 Giannessi D, De Caterina R, Gazzetti P, Bernini W, Masini S, Zucchelli GC. Methodological assessment and applications of a radioimmunoassay for thromboxane (TX) B₂ to measurement of TXB₂ release by platelets. J Nucl Med All Sci 1982; 26: 25-33
• 16 Mielke CH. International Committee Communications - Measurement of the bleeding time. Thromb Haemostas 1984; 52: 210-211
• 17 De Caterina R, Sicari R, Buti Strata G. Bleeding time and bleeding: a reappraisal. Submitted for publication
• 18 Snedecor GW, Cochrane WG. Statistical Methods. Seventh Edition Iowa State University Press; Ames, IA: 1980. pp 233-237
• 19 Balsano F, Rizzon P, Violi F, Scrutinio D, Cimminiello C, Aguglia F, Pasotti C, Rudelli G. and the S T A I group Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical study. Circulation 1990; 82: 17-26
• 20 Defreyn G, Bernat A, Delebassee D, Maffrand JP. Pharmacology of ticlopidine: a review. Semin Thromb Hemostas 1989; 15: 159-166
• 21 Di Minno G, Cerbone AM, Mattioli PL, Turco S, Iovine C. et al Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest 1985; a 75: 328-338
• 22 Uchiyama S, Sone R, Shibagaki Y, Nagayama T, Tsutsumi Y. et al Antiplatelet effects of combination therapy with low doses of aspirin and ticlopidine in cerebral ischemia. Abstract. Blood Vessels 1988; 19: 390-393
• 23 FitzGerald GA. Dipyridamole. N Engl J Med 1987; 316: 1247-1257
• 24 Coller BS. Report of the working party on hybridoma-derived monoclonal antibodies to platelets. Thromb Haemostas 1984; 51: 169-173
• 25 Petersen E, Handin RI. Production of recombinant glycoprotein IB alpha fragments with antiplatelet activity. Thromb Haemostas 1989 62. 319 (Abstr)
• 26 Marguerie G. Synthetic peptides with antithrombotic activity. Thromb Haemostas 1989 62. 318 (Abstr)
• 27 Huang TF, Holt JC, Lukasiewicz H, Niewiarowski S. Trigramin: a low-molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. J Biol Chem 1987; 262: 16157-16163
• 28 Liu MW, Roubin GS, King SB. III Restenosis after coronary angioplasty: Potential biological determinants and role of intimal hyperplasia. Circulation 1989; 79: 1374-1387