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CLOPIDOGREL: THE FUTURE CHOICE FOR PREVENTING PLATELET ACTIVATION DURING CORONARY STENTING?
Pharmacological Research, Vol. 40, No. 2, 1999 Article No. phrs.1999.0478, available online at http:rrwww.idealibrary.com on
CLOPIDOGREL: THE FUTURE CHOICE FOR PREVENTING PLATELET ACTIVATION DURING CORONARY STENTING? PAUL A. GURBELa , CHRISTOPHER M. O’CONNORb , CHARLES C. CUMMINGSa and VICTOR L. SEREBRUANY aU a
Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Bel¨ edere A¨ enue, Schapiro Research Building-R202, Baltimore, MD 21215, USA and b Duke Uni¨ ersity Medical Center, Durham, NC, USA Accepted 5 January 1999
Ticlopidine has become an established therapy in patients with stroke, and during stenting in patients with coronary artery disease. Clopidogrel, another thienopyridine, is a safe and promising alternative, that irreversibly inhibits ADP-induced platelet aggregation, and reduces formation of both arterial and venous thrombi. In a recent, large, well-controlled trial ŽCAPRIE., clopidogrel has been shown to be superior to aspirin in terms of prevention of ischaemic stroke, myocardial infarction and death in patients with atherosclerotic vascular disease. Clopidogrel provides a safe opportunity to enhance reperfusion when administered during stent placement, by protecting platelets from excessive activation. However, the ability of clopidogrel to be superior to ticlopidine in terms of its antiplatelet properties in the clinical setting of coronary stenting, is unknown. The effects of clopidogrel versus ticlopidine on platelet and endothelial function are yet to be determined and may strongly affect the outcome, benefits, and complications following coronary stent placement. Further clinical trials, well-designed, and carefully conducted, should elucidate possible benefits of clopidogrel during coronary interventions, especially in conjunction with new and aggressive reperfusion techniques. The benefits of clopidogrel in an expanding array of clinical conditions, including myocardial infarction, may be directly related to platelet inhibition. Moreover, marginal clinical benefits, and recently reported severe bleeding events in some patients after oral platelet glycoprotein IIbrIIIa therapy, may advance clopidogrel as a safe, and efficient alternative during coronary interventions. This review summarises the latest, and often confusing data on the effects of thienopyridines on certain haemostatic characteristics in interventional cardiology. Q 1999 Academic Press KEY
WORDS:
clopidogrel, ticlopidine, acute coronary syndromes, stents, human.
Blood platelets play a major role in normal haemostasis and in the formation of occlusive thrombotic disorders. Acquired platelet dysfunction following coronary intervention and stenting likely affects both short- and long-term outcome in patients after acute coronary interventions w1, 2x. Therefore, inhibiting platelet function is an important therapeutic goal in patients with acute coronary artery disease. Moreover, recent findings strongly suggest that glycoprotein IIbrIIIa ŽGP IIbrIIIa . receptor U
Corresponding author.
1043]6618r99r080107]05r$30.00r0
represents a common pathway for platelet activation in the acute thrombotic events w3, 4x. Aspirin, the commonly used antiplatelet drug, selectively inhibits platelet aggregation that is mediated through the blockade of the arachidonic acid}thromboxane A 2 pathway, but weakly inhibits ADP and PAF-induced platelet activation w5x. In contrast, ticlopidine acts on the platelet membrane directly and affects the aggregation of platelets induced by ADP, but has no effect on the formation of thromboxane A 2 through the cyclooxygenase pathway w6, 7x. ADP is an important platelet agonist causing shape change and aggregation required for physiological haemostasis. It Q 1999 Academic Press
108
has been demonstrated by the existence of two distinct G protein-coupled ADP receptors on platelets, one coupled to phospholipase C, P2Y1, and the other to inhibition of adenylyl cyclase, P2TAC w8x. Concomitant intracellular signalling from both the P2TAC and P2Y1 receptors is essential for ADPinduced platelet aggregation and GP IIbrIIIa heterodimer assembly w9x. The human P2Y1 receptor heterologously expressed in Jurkat cells behaves as a specific ADP receptor at which purified ATP is an ineffective agonist, but competitively antagonises the action of ADP has been recently discovered w10x. Although P2T purinoceptor was believed to be the ligand-gated cation channel for ADP in human platelets, recent patch clamp studies suggest it is P2X1 type. Indeed, such P2X1 purinoceptor has been recently cloned and characterized in human platelets w10x. ADP receptors play a key role in platelet injury after exposure of platelets to shear stress. Shearinduced platelet aggregation may occur without measurable lytic or sublytic platelet damage, and ADP liberated from platelets as a result of shear-induced release or damage may represent the major if not sole mediator of shear-induced aggregability w11x. Clopidogrel, a fast-acting novel thienopyridine, irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface w12x. In animals, clopidogrel reduces formation of both arterial w13x and venous w14x thrombi. Moreover, clopidogrel appeared to be more effective than aspirin in prevention of reocclusion after coronary thrombolysis w15x, and fibrin deposition w16x. Inhibition of platelet aggregation with clopidogrel is both dose-dependent and time-related, with the onset of activity being 12]24 h, and with maximal activity at 3]4 days after administration of a single daily Ž75 mg. dose. The terminal elimination half-life is between 8 and 12 h. Clopidogrel affects platelet activity throughout the entire life span of the cell, approximately 10 days, and prolongs bleeding time up to two to five times above normal w17, 18x. It has also been noted that clopidogrel does not exhibit a direct relationship between either plasma concentration or dose effects. Pharmacodynamic effects may be dose-, but not plasma concentrationdependent w19x. The pathophysiology of myocardial reperfusion injury is complex and not fully understood. Spontaneous decreases in coronary blood flow, distal to coronary artery occlusion may be due to episodes of platelet aggregation, which may occlude the infarctrelated artery and thus affect overall infarct size. This may have direct implications on patient survival. We have demonstrated phasic changes in platelet activity following reperfusion in an animal model w20, 21x, and in the setting of a major clinical trial w22, 23x. The data on the effects of clopidogrel on reperfusion injury are very limited for experimen-
Pharmacological Research, Vol. 40, No. 2, 1999
tal studies, and are virtually unknown in patients undergoing stent placement. Indeed, pretreatment with a high dose of clopidogrel Ž10 mg kgy1 . resulted in a decrease of myocardial damage in rats, suggesting possible protective antithrombotic effects of the drug w24x. However, clinical data challenge the ability of thienopyridines to reduce ischaemia and limit infarct size. Ticlopidine w25x and clopidogrel w26x treatment was not associated with cerebral infarct size reduction in patients with ischaemic stroke. Other reports indicate that clopidogrel, ticlopidine, and aspirin have similar moderate effects on platelets, suggesting combining strategies for future studies w27x. In short, there remains a lack of agreement between investigators on the most important issue: what are the exact effects of clopidogrel versus ticlopidine on platelets, and which drug is most advantageous for the prevention of excessive platelet activation following myocardial ischaemia-reperfusion? Highly sensitive and specific markers of thrombin generation, such as Fragment 1.2, fibrinopeptide A, and activated Protein C, have been used to evaluate haemostasis, and indirectly reflect platelet activity w28, 29x. From these studies, a hypothesis has been developed that excessive thrombin generation may play a major role in the triggering of platelet activation during coronary interventions w30x. Thrombin inhibition is an indispensable therapeutic concept in the prevention of thrombotic events after coronary interventions. However, it has been reported that while adequately suppressing thrombin activity, heparin fails to prevent existing thrombin generation w31x. A significant increase in platelet activation following intracoronary stenting in patients treated with unfractionated heparin has been consistently reported w32, 33x. Activation of platelets by heparin may explain the increased rate of stent thrombosis in patients treated with anticoagulant therapy. Interestingly, thrombin triggering of platelet activation can be blocked by increased levels of bradykinin, secondary to treatment with ACE inhibitors w34, 35x. Recent clinical study suggests that thienopyridines may ameliorate the cytotoxicity associated with myocardial reperfusion via thrombin generation blockade w36x. Several studies indicate that stenting may affect platelet function. First, the mechanical action of the interventional procedures themselves has been indirectly shown to result in damage to platelets by increasing thromboxane production w37, 38x. Second, the physical action of the stent and angioplasty procedure may damage the endothelium, thus interfering with prostacyclin and nitric oxide production and thus render the traumatised area susceptible to platelet deposition w39x. It has been suggested that stenting could increase platelet aggregation in patients with coronary artery disease, which may adversely affect outcome w40x.
Pharmacological Research, Vol. 40, No. 2, 1999
The elective placement of stents in coronary arteries decreases the risk of restenosis in comparison to balloon angioplasty w41x. This advancement is hindered by the complications of subacute stent thrombosis w37x. The conventional approach of treatment with heparin, coumadin, and warfarin has been replaced by combined antiplatelet therapy with ticlopidine and aspirin w42, 43x. However, a recent study denies the advantages of the combined aspirin and ticlopidine therapy, claiming that aspirin use alone is sufficient in preventing stent thrombosis w44x. It has been demonstrated that patients treated with anticoagulant agents show progressive activation of platelets after coronary stenting as opposed to patients on antiplatelet therapy who exhibit a decrease in surface expression of the activated fibrinogen receptor, shortly after stenting w45x. The effect of thienopyridines on platelet receptors other than glycoprotein IIbrIIIa is unknown. Interestingly, there are some data available suggesting that shear stress and ADP are key elements of aspirin resistance, and that thienopyridines may, to some extent, help overcome this phenomena w46, 47x. Although early clinical results were promising, there are obvious concerns about serious flaws in the design and the logistics of small trials including out of date methodology, absence of control groups, and possible observer bias due to unblinded data collection. One major clinical trial has assessed the clinical efficacy of clopidogrel ¨ s aspirin in patients at risk of ischaemic events} Ž C lopidogrel ¨ s Aspirin in Patients at Risk of Ischaemic E vents, CAPRIE. w48x. This trial focused on the comparison of Plavix W Žclopidogrel bisulphate, 75 mg daily. and aspirin Ž325 mg daily. in a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death. Results indicated risk reduction with clopidogrel Ž9599 patients. as compared to aspirin Ž9586 patients. for all outcome events. Also, the rates of fatal and non-fatal vascular events at 3 years showed a moderate, but significant Ž Ps 0.045., risk reduction with clopidogrel therapy as compared to aspirin. One of the limitations of this trial might be an absence of the combined clopidogrel and aspirin group. Recognising the fact that ticlopidine is almost invariably used as an addition to aspirin in a clinical setting of coronary stenting, it is quite difficult to conclude for certain, whether or not clopidogrel alone would have the same degree of efficacy. The CAPRIE trial also assessed the overall safety profile of clopidogrel, and found it at least as good as that of medium-dose aspirin. These data may represent a major clinical advantage of clopidogrel over ticlopidine, which is known to suppress bonemarrow, resulting in neutropenia w49x. Even if both drugs exhibit similar antiplatelet properties, as suggested by anecdotal in ¨ itro experiments w50x, clopidogrel is expected to reduce the incidence of complications since smaller doses are sufficient to sup-
109
presses platelet aggregation compared to ticlopidine w51x. Moreover, medication side effects occurred in 1.9% of patients treated with ticlopidine, which were absent in the aspirin-treated group, in a well controlled large trial w36x. Innovative stent designs may also permit changes in antithrombotic regiments w52x. In summary, ticlopidine is an established medication which reduces the incidence of stroke, myocardial ischaemia, or vascular death. It is currently the drug of choice in the prophylaxis of subacute stent thrombosis. However, despite good treatment tolerance, and rare major complications, ticlopidine have several shortcomings, including reported cases of cholestatic jaundice, gastrointestinal dysfunctions, skin rash, and mainly}suppression of bone marrow with resultant neutropenia, or even severe cases of aplastic anaemia, and agranulocytosis. These side effects have stimulated a search for new adjunctive agents. Future coronary interventions must consider better strategies to protect platelets from extensive activation. On the other hand, bleeding events after uniform adjunctive strategies could be related to decreased or normal baseline platelet characteristics observed in some patients w23, 53x. Moreover, marginal clinical benefits, severe bleeding events in association with the substantial inter-individual optimal dose finding variability in some patients after oral platelet GP IIbrIIIa inhibition may limit future chronic use of this class of agents. All of the above may advance clopidogrel as a safe, and efficient alternative during interventions in patients with acute coronary syndromes.
REFERENCES 1. Mak KH, Belli G, Ellis SG, Moliterno DJ. Subacute stent thrombosis: evolving issues and current concepts. J Am Coll Cardiol 1996; 27: 494]503. 2. Eeckhout E, Kappenberger L, Goy JJ. Stents for intracoronary placement: status and future direction. J Am Coll Cardiol 1996; 27: 757]65. 3. Coller BS. GPIIbrIIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemostasis 1997; 78: 730]5. 4. Peter K, Schwarz M, Ylanne J, Kohler B, Moser M, Nordt T, Salbach P, Kubler W, Bode C. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIbrIIIa ŽIIb b 3. inhibitors. Blood 1998; 92: 3240]9. 5. Boger RH, Bode-Boger SM, Gutzki FM, Tsikas D, Weskott HP, Frolich JC: Rapid and selective inhibition of platelet aggregation and thromboxane formation by intravenous low dose aspirin in man. Clin Sci 1993; 84: 517]24. 6. Saltiel E, Ward A. Ticlopidine: a review of the pharmacodynamics and pharmokinetics properties, and therapeutic efficacy in platelet-dependent states. Drugs 1987; 34: 222]67. 7. Desager JP. Clinical pharmokinetics of ticlopidine. Clin Pharm 1994; 26: 347]55. 8. Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U. Ligand specificity and ticlopidine effects distin-
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47. Schror K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemostasis 1997; 23: 349]56. 48. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events ŽCAPRIE.. Lancet 1996; 348: 1329]39. 49. Verstraete M. New developments in antiplatelet and antithrombotic therapy. Eur Heart J 1995; 16(Suppl L): 16]23. 50. Defreyn G, Gachet C, Savi P, Driot F, Casenave JP, Maffrand JP. Ticlopidine and clopidogrel ŽSR 25990C. selectively neutralize ADP inhibition of PGE1-activated platelet adenylate cyclase in rats and rabbits. Thromb Haemostasis 1991; 65: 186]90. 51. Uchiyama S, Yamazaki M, Maruyama S. Antiplatelet effect of clopidogrel. Jpn J Clin Med 1992; 50: 372]8. 52. Zidar JP. Rationale for low-molecular weight heparin in coronary stenting. Am Heart J 1997; 134: S81]7. 53. Serebruany VL, Gurbel PA, Shustov AR, Ohman EM, Topol EJ. Heterogeneity of platelet aggregation and major surface receptor expression in patients presenting with acute myocardial infarction. Am Heart J 1998; 136: 398]405.
CLOPIDOGREL: THE FUTURE CHOICE FOR PREVENTING PLATELET ACTIVATION DURING CORONARY STENTING? PAUL A. GURBELa , CHRISTOPHER M. O’CONNORb , CHARLES C. CUMMINGSa and VICTOR L. SEREBRUANY aU a
Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Bel¨ edere A¨ enue, Schapiro Research Building-R202, Baltimore, MD 21215, USA and b Duke Uni¨ ersity Medical Center, Durham, NC, USA Accepted 5 January 1999
Ticlopidine has become an established therapy in patients with stroke, and during stenting in patients with coronary artery disease. Clopidogrel, another thienopyridine, is a safe and promising alternative, that irreversibly inhibits ADP-induced platelet aggregation, and reduces formation of both arterial and venous thrombi. In a recent, large, well-controlled trial ŽCAPRIE., clopidogrel has been shown to be superior to aspirin in terms of prevention of ischaemic stroke, myocardial infarction and death in patients with atherosclerotic vascular disease. Clopidogrel provides a safe opportunity to enhance reperfusion when administered during stent placement, by protecting platelets from excessive activation. However, the ability of clopidogrel to be superior to ticlopidine in terms of its antiplatelet properties in the clinical setting of coronary stenting, is unknown. The effects of clopidogrel versus ticlopidine on platelet and endothelial function are yet to be determined and may strongly affect the outcome, benefits, and complications following coronary stent placement. Further clinical trials, well-designed, and carefully conducted, should elucidate possible benefits of clopidogrel during coronary interventions, especially in conjunction with new and aggressive reperfusion techniques. The benefits of clopidogrel in an expanding array of clinical conditions, including myocardial infarction, may be directly related to platelet inhibition. Moreover, marginal clinical benefits, and recently reported severe bleeding events in some patients after oral platelet glycoprotein IIbrIIIa therapy, may advance clopidogrel as a safe, and efficient alternative during coronary interventions. This review summarises the latest, and often confusing data on the effects of thienopyridines on certain haemostatic characteristics in interventional cardiology. Q 1999 Academic Press KEY
WORDS:
clopidogrel, ticlopidine, acute coronary syndromes, stents, human.
Blood platelets play a major role in normal haemostasis and in the formation of occlusive thrombotic disorders. Acquired platelet dysfunction following coronary intervention and stenting likely affects both short- and long-term outcome in patients after acute coronary interventions w1, 2x. Therefore, inhibiting platelet function is an important therapeutic goal in patients with acute coronary artery disease. Moreover, recent findings strongly suggest that glycoprotein IIbrIIIa ŽGP IIbrIIIa . receptor U
Corresponding author.
1043]6618r99r080107]05r$30.00r0
represents a common pathway for platelet activation in the acute thrombotic events w3, 4x. Aspirin, the commonly used antiplatelet drug, selectively inhibits platelet aggregation that is mediated through the blockade of the arachidonic acid}thromboxane A 2 pathway, but weakly inhibits ADP and PAF-induced platelet activation w5x. In contrast, ticlopidine acts on the platelet membrane directly and affects the aggregation of platelets induced by ADP, but has no effect on the formation of thromboxane A 2 through the cyclooxygenase pathway w6, 7x. ADP is an important platelet agonist causing shape change and aggregation required for physiological haemostasis. It Q 1999 Academic Press
108
has been demonstrated by the existence of two distinct G protein-coupled ADP receptors on platelets, one coupled to phospholipase C, P2Y1, and the other to inhibition of adenylyl cyclase, P2TAC w8x. Concomitant intracellular signalling from both the P2TAC and P2Y1 receptors is essential for ADPinduced platelet aggregation and GP IIbrIIIa heterodimer assembly w9x. The human P2Y1 receptor heterologously expressed in Jurkat cells behaves as a specific ADP receptor at which purified ATP is an ineffective agonist, but competitively antagonises the action of ADP has been recently discovered w10x. Although P2T purinoceptor was believed to be the ligand-gated cation channel for ADP in human platelets, recent patch clamp studies suggest it is P2X1 type. Indeed, such P2X1 purinoceptor has been recently cloned and characterized in human platelets w10x. ADP receptors play a key role in platelet injury after exposure of platelets to shear stress. Shearinduced platelet aggregation may occur without measurable lytic or sublytic platelet damage, and ADP liberated from platelets as a result of shear-induced release or damage may represent the major if not sole mediator of shear-induced aggregability w11x. Clopidogrel, a fast-acting novel thienopyridine, irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface w12x. In animals, clopidogrel reduces formation of both arterial w13x and venous w14x thrombi. Moreover, clopidogrel appeared to be more effective than aspirin in prevention of reocclusion after coronary thrombolysis w15x, and fibrin deposition w16x. Inhibition of platelet aggregation with clopidogrel is both dose-dependent and time-related, with the onset of activity being 12]24 h, and with maximal activity at 3]4 days after administration of a single daily Ž75 mg. dose. The terminal elimination half-life is between 8 and 12 h. Clopidogrel affects platelet activity throughout the entire life span of the cell, approximately 10 days, and prolongs bleeding time up to two to five times above normal w17, 18x. It has also been noted that clopidogrel does not exhibit a direct relationship between either plasma concentration or dose effects. Pharmacodynamic effects may be dose-, but not plasma concentrationdependent w19x. The pathophysiology of myocardial reperfusion injury is complex and not fully understood. Spontaneous decreases in coronary blood flow, distal to coronary artery occlusion may be due to episodes of platelet aggregation, which may occlude the infarctrelated artery and thus affect overall infarct size. This may have direct implications on patient survival. We have demonstrated phasic changes in platelet activity following reperfusion in an animal model w20, 21x, and in the setting of a major clinical trial w22, 23x. The data on the effects of clopidogrel on reperfusion injury are very limited for experimen-
Pharmacological Research, Vol. 40, No. 2, 1999
tal studies, and are virtually unknown in patients undergoing stent placement. Indeed, pretreatment with a high dose of clopidogrel Ž10 mg kgy1 . resulted in a decrease of myocardial damage in rats, suggesting possible protective antithrombotic effects of the drug w24x. However, clinical data challenge the ability of thienopyridines to reduce ischaemia and limit infarct size. Ticlopidine w25x and clopidogrel w26x treatment was not associated with cerebral infarct size reduction in patients with ischaemic stroke. Other reports indicate that clopidogrel, ticlopidine, and aspirin have similar moderate effects on platelets, suggesting combining strategies for future studies w27x. In short, there remains a lack of agreement between investigators on the most important issue: what are the exact effects of clopidogrel versus ticlopidine on platelets, and which drug is most advantageous for the prevention of excessive platelet activation following myocardial ischaemia-reperfusion? Highly sensitive and specific markers of thrombin generation, such as Fragment 1.2, fibrinopeptide A, and activated Protein C, have been used to evaluate haemostasis, and indirectly reflect platelet activity w28, 29x. From these studies, a hypothesis has been developed that excessive thrombin generation may play a major role in the triggering of platelet activation during coronary interventions w30x. Thrombin inhibition is an indispensable therapeutic concept in the prevention of thrombotic events after coronary interventions. However, it has been reported that while adequately suppressing thrombin activity, heparin fails to prevent existing thrombin generation w31x. A significant increase in platelet activation following intracoronary stenting in patients treated with unfractionated heparin has been consistently reported w32, 33x. Activation of platelets by heparin may explain the increased rate of stent thrombosis in patients treated with anticoagulant therapy. Interestingly, thrombin triggering of platelet activation can be blocked by increased levels of bradykinin, secondary to treatment with ACE inhibitors w34, 35x. Recent clinical study suggests that thienopyridines may ameliorate the cytotoxicity associated with myocardial reperfusion via thrombin generation blockade w36x. Several studies indicate that stenting may affect platelet function. First, the mechanical action of the interventional procedures themselves has been indirectly shown to result in damage to platelets by increasing thromboxane production w37, 38x. Second, the physical action of the stent and angioplasty procedure may damage the endothelium, thus interfering with prostacyclin and nitric oxide production and thus render the traumatised area susceptible to platelet deposition w39x. It has been suggested that stenting could increase platelet aggregation in patients with coronary artery disease, which may adversely affect outcome w40x.
Pharmacological Research, Vol. 40, No. 2, 1999
The elective placement of stents in coronary arteries decreases the risk of restenosis in comparison to balloon angioplasty w41x. This advancement is hindered by the complications of subacute stent thrombosis w37x. The conventional approach of treatment with heparin, coumadin, and warfarin has been replaced by combined antiplatelet therapy with ticlopidine and aspirin w42, 43x. However, a recent study denies the advantages of the combined aspirin and ticlopidine therapy, claiming that aspirin use alone is sufficient in preventing stent thrombosis w44x. It has been demonstrated that patients treated with anticoagulant agents show progressive activation of platelets after coronary stenting as opposed to patients on antiplatelet therapy who exhibit a decrease in surface expression of the activated fibrinogen receptor, shortly after stenting w45x. The effect of thienopyridines on platelet receptors other than glycoprotein IIbrIIIa is unknown. Interestingly, there are some data available suggesting that shear stress and ADP are key elements of aspirin resistance, and that thienopyridines may, to some extent, help overcome this phenomena w46, 47x. Although early clinical results were promising, there are obvious concerns about serious flaws in the design and the logistics of small trials including out of date methodology, absence of control groups, and possible observer bias due to unblinded data collection. One major clinical trial has assessed the clinical efficacy of clopidogrel ¨ s aspirin in patients at risk of ischaemic events} Ž C lopidogrel ¨ s Aspirin in Patients at Risk of Ischaemic E vents, CAPRIE. w48x. This trial focused on the comparison of Plavix W Žclopidogrel bisulphate, 75 mg daily. and aspirin Ž325 mg daily. in a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death. Results indicated risk reduction with clopidogrel Ž9599 patients. as compared to aspirin Ž9586 patients. for all outcome events. Also, the rates of fatal and non-fatal vascular events at 3 years showed a moderate, but significant Ž Ps 0.045., risk reduction with clopidogrel therapy as compared to aspirin. One of the limitations of this trial might be an absence of the combined clopidogrel and aspirin group. Recognising the fact that ticlopidine is almost invariably used as an addition to aspirin in a clinical setting of coronary stenting, it is quite difficult to conclude for certain, whether or not clopidogrel alone would have the same degree of efficacy. The CAPRIE trial also assessed the overall safety profile of clopidogrel, and found it at least as good as that of medium-dose aspirin. These data may represent a major clinical advantage of clopidogrel over ticlopidine, which is known to suppress bonemarrow, resulting in neutropenia w49x. Even if both drugs exhibit similar antiplatelet properties, as suggested by anecdotal in ¨ itro experiments w50x, clopidogrel is expected to reduce the incidence of complications since smaller doses are sufficient to sup-
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presses platelet aggregation compared to ticlopidine w51x. Moreover, medication side effects occurred in 1.9% of patients treated with ticlopidine, which were absent in the aspirin-treated group, in a well controlled large trial w36x. Innovative stent designs may also permit changes in antithrombotic regiments w52x. In summary, ticlopidine is an established medication which reduces the incidence of stroke, myocardial ischaemia, or vascular death. It is currently the drug of choice in the prophylaxis of subacute stent thrombosis. However, despite good treatment tolerance, and rare major complications, ticlopidine have several shortcomings, including reported cases of cholestatic jaundice, gastrointestinal dysfunctions, skin rash, and mainly}suppression of bone marrow with resultant neutropenia, or even severe cases of aplastic anaemia, and agranulocytosis. These side effects have stimulated a search for new adjunctive agents. Future coronary interventions must consider better strategies to protect platelets from extensive activation. On the other hand, bleeding events after uniform adjunctive strategies could be related to decreased or normal baseline platelet characteristics observed in some patients w23, 53x. Moreover, marginal clinical benefits, severe bleeding events in association with the substantial inter-individual optimal dose finding variability in some patients after oral platelet GP IIbrIIIa inhibition may limit future chronic use of this class of agents. All of the above may advance clopidogrel as a safe, and efficient alternative during interventions in patients with acute coronary syndromes.
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