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Platelet ADP receptor antagonists: ticlopidine and clopidogrel
Best Practice & Research Clinical Haematology Vol. 17, No. 1, pp. 55–64, 2004 doi:10.1016/j.beha.2004.03.002 available online at http://www.sciencedirect.com
3 Platelet ADP receptor antagonists: ticlopidine and clopidogrel Alan K. Jacobson*
MD, FACC
Associate Chief of Staff/Research Research Service (151), Loma Linda VA Medical Center, 11201 Benton Street, Loma Linda, CA 92354, USA
The central role of platelets in the pathophysiology of arterial vascular disease has focused attention on the development of effective platelet inhibitor modalities to mitigate the clinical consequences of atherothrombotic disease. Aspirin has been the gold standard of therapy and is effective in cerebral, coronary and peripheral arterial disease with a 25% reduction in myocardial infarction, stroke and vascular death. The platelet ADP receptor antagonists were developed to further improve the clinical results of therapy. Ticlopidine provides an additional 10% relative risk reduction over aspirin alone in stroke prevention and coronary stent placement. However, ticlopidine is accompanied by occasional life-threatening adverse hematological events. The action of clopidogrel is similar to that of ticlopidine, and it is comparably effective. However, the side-effect profile of clopidogrel is much more favorable. Key words: ticlopidine; clopidogrel; thienopyridine; antiplatelet; atherothrombosis.
The primary role of platelets is to maintain vascular integrity through hemostasis. However, in the presence of vascular disease such as atherosclerosis, this normal process may become excessive and result in thrombosis.1 The role of platelets in the pathophysiology of arterial vascular disease has undergone extensive evaluation over the past several decades and has been confirmed as central.2 While atherosclerosis is the major underlying chronic pathology, platelet-dependent thrombosis, often initiated by acute plaque destabilization, is mainly responsible for acute clinical events including myocardial infarction, stroke and sudden death.3 Platelet adhesion, activation and aggregation are the key processes. Platelets do not adhere to normal endothelium but do adhere to disrupted endothelial surfaces. Following adhesion, platelets undergo shape change, secrete the contents of their alpha and dense granules, transform endogenous arachidonic acid into thromboxane A2,4 and undergo conformational changes in glycoprotein IIb/IIIa receptors that effect plateletto-platelet aggregation.5 * Corresponding author. Tel.: þ1-909-583-6050; Fax: þ1-909-796-2791. E-mail address: [email protected] (A.K. Jacobson). 1521-6926/$ - see front matter Published by Elsevier Ltd.
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Adenosine diphosphate (ADP) plays a major role in platelet activation. ADP originates from damaged endothelium, red blood cells and platelet dense granules. Three distinct platelet surface receptors for ADP have been identified.6 ADP binding triggers the release of platelet dense granules containing not only ADP but also serotonin, another platelet agonist, and stimulates platelet production of thromboxane A2; the result is an activation-amplification cascade. The central role of ADP makes it an inviting therapeutic target.7 Aspirin was the first effective platelet inhibitor drug to be identified. Aspirin results in an irreversible modification of the enzyme cyclo-oxygenase rendering it incapable of converting arachidonic acid into thromboxane A2. The first comprehensive evaluation of aspirin’s effectiveness in preventing vascular events came from a meta-analysis performed by the Antiplatelet Trialists’ Collaboration, published in 1984.8 The analysis included 145 randomized trials comprising 100 000 patients, including 70 000 classified as high risk. A 25% reduction in the combined endpoint of myocardial infarction, stroke and vascular death was observed. Aspirin 75– 325 mg once a day was found to be optimal with no additional benefit from higher doses, nor from any other then-existing platelet inhibitor agents including dipyridamole, sulfinpyrazone, suloctidil and combinations of aspirin with dipyridamole or sulfinpyrazone. The contribution of aspirin to the reduction of vascular morbidity is significant but is accompanied by several deficiencies. Side-effects, while generally not life-threatening, are potentially serious. Both the incidence of major hemorrhagic complications and the frequency of acid-peptic symptoms are significant and appear to be dose-related.9 – 11 Aspirin resistance may occur in up to 20% of patients. Patients may experience recurrent thrombotic events while on aspirin therapy, so-called ‘aspirin failures’.12,13 Even after adequate inhibition of cyclo-oxygenase, alternative pro-aggregatory pathways remain intact. Therefore, the development of new agents has been an appropriate and compelling goal.14
THE THIENOPYRIDINES—ADP RECEPTOR ANTAGONISTS Ticlopidine (Ticlid) Ticlopidine was the first of the new class of thienopyridine antiplatelet agents, also known as ADP receptor antagonists. It gained Food and Drug Administration (FDA) approval for clinical use in the early 1990s.15 A single oral dose of ticlopidine is absorbed rapidly, and peak plasma concentration is achieved 1 – 3 h after a 250-mg dose.16 When the drug is taken after food, the area under the curve is increased by 20%.17 Ticlopidine does not inhibit ADP-induced platelet aggregation in vitro, and hepatic biotransformation into active metabolites is required for drug action.18 Thirteen metabolites have been described, but those responsible for the antiplatelet effect have not been found. The mechanism of antiplatelet action appears to be irreversible alteration of the platelet surface P2Y12 ADP receptor, resulting in a reduction in ADP-induced platelet aggregation.19 Collagen- and thrombin-induced activation are also inhibited, probably due to blockade of amplification.20 Hepatic metabolism is delayed, and at maintenance doses, only 50% platelet aggregation inhibition is achieved at 5 days, and 60– 70% at 8 – 11 days.21 Platelet inhibitory effects are saturated at 250 mg twice daily. Metabolism is dependent on the cytochrome p450 system, and interactions with digoxin, theophylline and cimetidine have been documented.22,23 Elimination of ticlopidine is 60% renal and 23% gastrointestinal.
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Serum levels are increased in patients with renal impairment, but are apparently unassociated with an excess prolongation of the bleeding time. Ticlopidine is dosed 250 mg twice daily. Single loading doses of 500 mg have been tried but often cause abdominal cramping and discomfort.24 Serious, potentially life-threatening, hematological side-effects have prompted an FDA-mandated ‘black-box’ warning in the package insert.25 Neutropenia (absolute neutrophil count less than 1200/ml) occurs in 2.4% of treated patients, and severe neutropenia (less than 450/ml) in 0.8%. Some cases of neutropenia appear to be irreversible. Aplastic anemia occurs in about one in 4000 –8000 patients. Thrombotic thrombocytopenic purpura occurs in about one in 2000 – 4000 patients. Reactions may occur as early as a few days after treatment is started. The peak incidence is at 3 –6 weeks. Reactions are rare after 3 months’ treatment. Hematological monitoring is advised every 2 weeks for the first 3 months of treatment. Ticlopidine is also associated with an 8 –10% rise in total serum cholesterol;26 the effect on cholesterol subfractions is uniform. Gastrointestinal side-effects in stroke trials were common and curtailed treatment in 13% of patients. Rashes were noted in 5% of patients.27 Clinical trials with ticlopidine Ticlopine has been evaluated as monotherapy in patients with stroke,28 transient cerebral ischemia,29 unstable angina,30 myocardial infarction,31 intermittent claudication,32 for graft patency following coronary bypass surgery,33 and in combination with aspirin to reduce thrombotic complications following coronary stent placement.34 Major studies of ticlopidine will be reviewed. Patients with stroke precursors. The Ticlopidine Aspirin Stroke Study (TASS) compared ticlopidine with aspirin in a randomized blinded study of 3069 patients with transient ischemic attack, amaurosis fugax or minor stroke within 3 months prior to enrollment at 56 North American centers.35 Patients were randomized to ticlopidine 250 mg twice daily or aspirin 650 mg twice daily and were followed for 2 –6 years. At 3 years, the combined endpoint of non-fatal stroke and all-cause death occurred in 19% of aspirin patients and 17% of ticlopidine patients, a 12% reduction ðP ¼ 0:048Þ for ticlopidine. The reduction in fatal and non-fatal stroke was more impressive; 13% for aspirin and 10% for ticlopidine, a 21% reduction ðP ¼ 0:024Þ: Side-effects, however, curtailed ticlopidine in 20.9% of patients compared with 14.5% of patients on aspirin. The incidence of severe neutropenia was less than 1%. The authors concluded that ticlopidine was somewhat more effective than aspirin in preventing strokes but with a greater risk of side-effects. Patients with completed stroke. The Canadian American Ticlopidine Study randomized 1073 patients within 4 months of completed ischemic stroke to ticlopidine 250 mg twice daily or placebo for up to 3 years, with an average follow-up of 2 years.36 Stroke recurred in 18.6% of ticlopidine patients and 24.6% of placebo patients ðP ¼ 0:017Þ: The composite of myocardial infarction, stroke and vascular death occurred in 10.8% of ticlopidine patients and 15.3% of placebo patients, a relative reduction of 30.2%. Intracoronary stents. One major challenge of percutaneous transluminal coronary angioplasty is the high incidence of rethrombosis. Intracoronary stents offered the promise of improved long-term patency, but the early experience was an unacceptably high rate of acute and subacute stent thrombosis.37 Early antithrombotic regimens were various combinations of aspirin, dipyridamole, dextran, heparin and warfarin.38 These regimens were effective but were commonly accompanied by bleeding.
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More effective antithrombotic regimens were needed.39 The early clinical experience with ticlopidine after coronary stenting was documented in registries. As clinical experience appeared favorable, formal studies were developed. The Intracoronary Stenting and Antithrombotic Regimen trial was the first of the randomized trials and enrolled 517 patients. The anticoagulant patients experienced a 6.2% incidence of endpoints, whereas the rate was only 1.6% among patients receiving dual antiplatelet therapy, a 75% risk reduction ðP , 0:001Þ:40 Benefit in the antiplatelet arm was not seen until 3 days due to the delayed onset of action of ticlopidine. The Stent Anticoagulation Restenosis Study enrolled 1653 patients undergoing emergency or elective percutaneous coronary interventions with stent placement. Patients were randomized to three arms: ticlopidine 250 mg twice daily plus aspirin (100 – 325 mg daily), aspirin alone or aspirin 325 mg daily plus warfarin with an international normalized ratio of 3.5 –4.5.41 Therapy was continued for 30 days. The endpoint was combined death, myocardial infarction and need for revascularization. The endpoint was reached in 0.5%, 3.6% and 2.7% of patients in the three respective groups; combined aspirin and ticlopidine was the superior regimen. Bleeding complications were seen in 5.5%, 1.8% and 6.2% of patients in the respective groups. The Full Anticoagulation versus Aspirin and Ticlopidine trial also demonstrated the limitations of the slow onset of action of ticlopidine and the need for either pretreatment prior to the stent procedure or adjunctive anticoagulant therapy until ticlopidine exposure had been sufficient to inhibit platelet aggregation.42 Current FDA-approved indications for ticlopidine are to reduce the risk of thrombotic stroke with stroke precursors or completed thrombotic stroke, with the caveat that, due to hematological side-effects, treatment should be reserved for patients intolerant or allergic to aspirin or who have failed aspirin. Ticlopidine is also approved as an adjunct to aspirin in coronary stenting. Clopidogrel (Plavix) Following FDA approval of ticlopidine for clinical use in 1991, clopidogrel emerged as a promising compound structurally similar to ticlopidine, but with fewer side-effects. Clopidogrel has since been approved by the FDA for reduction of thrombotic events in recent myocardial infarction, stroke or established peripheral arterial disease, and for patients with non-ST-elevation acute coronary syndromes including percutaneous coronary interventions. Pharmacokinetics Clopidogrel differs from ticlopidine by an additional carboxymethyl side group. Clopidogrel is absorbed rapidly via the oral route. Metabolism is so extensive that clopidogrel is difficult to detect in the circulation; the major circulating compound is the inactive carboxylic acid derivative SR26334 that reaches peak plasma concentration within 1 h of ingestion.43 Elimination is 50% renal and 46% gastrointestinal. Unlike ticlopidine, clopidogrel absorption is not affected by food. Despite hepatic metabolism, little interaction with other drugs is seen.44 The mechanism of the antiplatelet effect appears to be identical to ticlopidine; permanent alteration of the platelet surface P2Y12 ADP receptor and inhibition of ADP-induced platelet activation and aggregation.45 The platelet aggregation inhibitory effect of clopidogrel 75 mg once daily is equivalent to that of ticlopidine 250 mg twice daily. Doses of 50 mg, 75 mg, 100 mg
Platelet ADP receptor antagonists 59
and 150 mg daily were not demonstrably different from each other.46 As with ticlopidine, peak antiplatelet activity on maintenance clopidogrel doses is delayed by 4 – 8 days. However, a significant advantage of clopidogrel is that loading doses of approximately 300 mg are well tolerated and result in near-maximal platelet inhibition in 2 – 5 h.47,48 The side-effect profile of clopidogrel is remarkably improved compared with ticlopidine. Severe neutropenia (absolute neutrophil count less than 450/ml) occurred in only 0.05% of patients.49,50 Thrombotic thrombocytopenic purpura was reported in only 11 patients within several weeks of treatment initiation after approximately 3 million patients had been exposed to the drug.51 Thus clopidogrel is far safer than ticlopidine, but a small risk of serious complications remains. Gastrointestinal side-effects including bloating, cramping and diarrhea occur infrequently. Bleeding is an extension of the antiplatelet effect and is significantly more common with clopidogrel plus aspirin than with aspirin alone. Limiting the dose of aspirin to 100 mg daily reduces the risk of major hemorrhage but does not compromise the efficacy of combined therapy.52 Clinical trials with clopidogrel The Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was based on the premise that atherothrombosis is a systemic condition that affects all arterial beds with a common pathophysiology.53 CAPRIE was thus unique by incorporating patients with three distinct indications into a single trial. The study was designed to compare clopidogrel 75 mg daily with aspirin 325 mg daily for prevention of vascular events in patients with stroke within 6 months, myocardial infarction within 35 days, or peripheral vascular disease. A total of 19 185 patients were followed for a mean of 1.9 years. The primary outcome was stroke, myocardial infarction or vascular death The annualized event rates were 5.32% for clopidogrel and 5.83% for aspirin, an 8.7% relative reduction favoring clopidogrel. This reduction was similar to that seen in the TASS trial when ticlopidine was compared with aspirin. Relative risks were a 7.3% reduction for the stroke group, a 3.7% increase for the myocardial infarction group, and a 23.8% reduction for the peripheral arterial disease group. The heterogeneity of effects was significant ðP ¼ 0:042Þ: Most of the benefit seen in the peripheral arterial disease group was due to a reduction in myocardial infarction. In contrast to earlier ticlopidine trials, the improved results with clopidogrel were not offset by excess side-effects. The rate of treatment discontinuation was the same in aspirin and clopidogrel groups. Side-effects occurred in 11.4% of patients, 9.3% of which were hemorrhagic events. Acute coronary syndromes. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial was designed to compare the safety and efficacy of combined aspirin-clopidogrel therapy with aspirin alone in high-risk coronary disease patients.54 The trial randomized 12 562 patients with non-ST-elevation acute coronary syndromes within 24 hour of symptom onset. All patients received aspirin (75 –325 mg daily) and were randomized to receive either clopidogrel (300 mg loading dose then 75 mg daily) or placebo for 3 – 12 months. The composite endpoint was cardiovascular death, nonfatal myocardial infarction and stroke. The endpoint occurred in 11.4% of placebo patients and in 9.3% of clopidogrel patients, a relative risk reduction of 20%.55 Major bleeding was more frequent in the clopidogrel group, and within groups, bleeding risk was aspirin dose-dependent. In patients undergoing coronary artery bypass surgery, bleeding was significantly increased if clopidogrel had not been discontinued 5 or more days before surgery. In the CURE trial, only 4% of participating centers routinely
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included glycoprotein IIb/IIIa inhibitors and early interventional procedures. Thus CURE was able to demonstrate a clear role for clopidogrel in the defined high-risk group. Evaluation in intracoronary stenting. Three randomized trials involving over 2700 patients have compared ticlopidine with clopidogrel in patients undergoing stent placement.56 – 58 The drugs were equally effective, but clopidogrel was associated with fewer side-effects. The PCI-CURE trial included 2658 patients within the CURE trial who underwent elective percutaneous coronary intervention.59 Patients received a median of 10 days of aspirin-clopidogrel or aspirin-placebo therapy prior to intervention and for 8 months following intervention. The composite endpoint was reduced by 30% (4.5% vs 6.4%, P ¼ 0:03) by 30 days in the clopidogrel-aspirin group. The value of combined treatment in emergency interventions was not clarified. In early trials of ticlopidine after coronary interventions, drug therapy was restricted to 30 days due to concern over hematological side-effects. The improved safety profile of clopidogrel has reduced the concern. The Clopidogrel for the Reduction of Events During Observation trial, similar to PCI-CURE, showed that both efficacy and safety of thienopyridine therapy could be extended to 12 months.60 Clopidogrel has also been shown to be effective in reducing the thrombotic complications of coronary vascular brachytherapy (use of ionizing radiation to prevent in-stent restenosis).61,62 Peripheral arterial disease. The relative risk reduction for the patients entering the CAPRIE trial with a diagnosis of peripheral arterial disease was 24% greater with clopidogrel than with aspirin, principally as a result of a greater reduction in the incidence of myocardial infarction. Clinical trials of ticlopidine in peripheral arterial disease showed similar benefit.63 – 66 Clopidogrel is generally regarded as the thienopyridine of choice due to its improved safety profile and once-daily dosing.67,68 Cerebrovascular disease. While a role for thienopyridines in the treatment of peripheral arterial disease is well accepted,69 a role in cerebrovascular disease remains less clear.70 Secondary vascular events in stroke patients are likely to be cerebrovascular,71 and bleeding rates in cerebrovascular patients may be higher than in cardiac populations, possibly due to age, drug interactions or the underlying ischemic injury. The CAPRIE trial showed only a non-significant relative risk reduction of 5.2% for clopidogrel compared with aspirin in stroke prevention. Interpreting the CURE trial is problematic because of the low number of strokes, under 1.5% in both groups. Perhaps the ongoing MATCH trial of combination aspirin plus clopidogrel vs aspirin alone in cerebrovascular patients will provide clarification on this important issue.72 Cost-effectiveness. One analysis of the CURE data concluded that giving clopidogrel to 1000 patients with acute coronary syndromes would prevent 15 non-fatal myocardial infarctions. Clopidogrel would also cause 10 additional major and 69 minor bleeding episodes and complicate 200 surgical decisions, during which time 978 patients would have taken the drug with no benefit, and no lives would have been saved.73 In one cost analysis of the CAPRIE trial, the estimated cost to save one life with aspirin was $8181, but it was $49 367 with clopidogrel. The cost of clopidogrel would have to fall to $0.30 per tablet to match aspirin’s cost-effectiveness per event prevented, and $0.20 to match aspirin’s cost-effectiveness per life saved.74 In a separate cost-effectiveness analysis combining data from both the CAPRIE and CURE trials, the cost of clopidogrel would have to fall by 70– 82% to become costeffective for routine use in all patients who might benefit.75 However, not all costeffectiveness analyses have been as discouraging.76
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SUMMARY Atherothrombosis is the basis for the epidemic rates of acute cerebrovascular, coronary and peripheral vascular morbidity and mortality. Antiplatelet therapy plays a central role in management. Aspirin has been the mainstay; the thienopyridines provide new opportunities for those patients who are intolerant, resistant or have failed aspirin, and for those who can derive greater benefit from combined therapy. Which patient subgroups benefit the most and cost-effectiveness concerns remain matters for further assessment. Due to its equivalence to ticlopidine, its greatly improved side-effect profile over ticlopidine, and its once-daily dosing, clopidogrel is the thienopyridine of choice.
Practice points † despite the modest efficacy of ticlopidine over aspirin, the delayed onset of action, potential for severe hematological side-effects, high incidence of gastrointestinal side-effects, and cost are all undesirable features of this particular drug † when ticlopidine must be used, blood count monitoring every 2 weeks for the first 3 months is advised † as hepatic transformation into active drug metabolites is delayed, initial maintenance doses of ticlopidine or clopidogrel will not achieve optimal antiplatelet effect for 4– 8 days. A loading dose of clopidogrel 300 mg, however, achieves steady-state platelet inhibition within 2 – 5 h and is relatively well tolerated with fewer gastrointestinal side-effects than with ticlopidine † clopidogrel is useful monotherapy in patients intolerant of aspirin, aspirin resistant or who have failed aspirin therapy † clopidogrel is useful in combination with aspirin in acute coronary syndromes and following percutaneous coronary intervention † combination therapy with clopidogrel and aspirin is associated with an aspirin dose-dependent risk of major hemorrhage; aspirin dosing at the lower end of its usual dosing range reduces the hemorrhagic risk without compromising effectiveness
Research agenda † further exploration of the heterogeneity of benefit of clopidogrel in patients presenting with initial symptoms from different vascular beds (cerebral, coronary and peripheral arterial) † refinement of the timing of clopidogrel in percutaneous coronary interventions † better clarification of the roles of the glycoprotein IIb/IIIa inhibitors and clopidogrel alone or in combination in patients undergoing percutaneous coronary interventions or coronary artery bypass surgery † clopidogrel in the primary prevention of vascular events in patients with risk factors but no manifest disease
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Seminars in Thrombosis Hemostasis 1999; 25(supplement 2): 25– 28. 47. Gurbel P, Cummings C, Bell C, et al. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial. American Heart Journal 2003; 145: 239 –247. 48. Pache J, Kastrati A, Mehilli J, et al. Clopidogrel therapy in patients undergoing coronary stenting: value of a high-loading-dose regimen. Catheterization and Cardiovascualr Intervention 2002; 55: 436 –441. 49. Besson G & Bogousslawsky J. Current and future options for the prevention and treatment of stroke. CNS Drugs 1995; 3: 351–362. 50. Schror K. Antiplatelet drugs: a comparative review. Drugs 1995; 50: 7–28. 51. Bennett CL, Connors JM & Moake JL. Clopidogrel and thrombotic thrombocytopenic purpura. The New England Journal of Medicine 2000; 343: 1193–1194. 52. Peters R, Mehta S, Fox K, 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: 1682–1687. 53. CAPRIE Steering Committee, A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
64 A. K. Jacobson 54. Mehta S & Yusuf S. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. European Heart Journal 2000; 21: 2033– 2041. 55. Yusuf S, Zhao F, Mehta S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England Journal of Medicine 2001; 345: 494–502. 56. Taniuchi M, Kurz HI & Lasala JM. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001; 104: 539 –543. 57. Bertrand ME, Rupprecht HJ & Urban P. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624 –629. 58. Muller C, Buttner HJ & Petersen J. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000; 101: 590–593. 59. Mehta S, Yusuf S, et al. Peters R.Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527 –533. 60. Steinhubl S, Berger P, Mann J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial 2002;288:2411–20.. 61. Waksman R, Bhargava B, White R, et al. Intracoronary radiation for patients with refractory in-stent restenosis: an analysis from the WRIST-Crossover Trial. Washington Radiation for In-stent Restenosis Trial. Cardiovascular Radiation Medicine 1999; 1: 317–322. 62. Waksman R, Ajani A, Pinnow E, et al. Twelve versus six months of clopidogrel to reduce major cardiac events in patients undergoing gamma-radiation therapy for in-stent restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 versus WRIST PLUS. Circulation 2002; 106: 776– 778. 63. Blanchard J, Carreras L & Kindermans M. Results of EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease. Nouv Rev Fr Hematol 1994; 35: 523–528. 64. Bergqvist D, Almgren B & Dickinson J. Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results form the Swedish Ticlopidne Multicentre Study (STIMS). European Journal of Vascular and Endovascular Surgery 1995; 10: 69 –76. 65. Lindblad B, Wakefield T, Stanely T, et al. Pharmacological prophylaxis against postoperative graft occlusion after peripheral vascular surgery: a world-wide survey. European Journal of Vascular and Endovascular Surgery 9:267–71. 66. Castelli P, Basellini A, et al. Agus G.Thrombosis prevention with ticlopidine after femoropopliteal thromboendarterectomy. International Surgery 1986; 71: 252 –255. 67. Hankey G, Sudlow C, Dunbabin D. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. In Cochrane Database Syst Rev 2000, p. CD001246. 68. Regensteiner J & Hiatt W. Current medical therapies for patients with peripheral arterial disease: a critical review. The American Journal of Medicine 2002; 112: 49–57. 69. Hiatt W. Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy. Journal of International Medicine 2002; 251: 193 –206. 70. Albers G & Amarenco P. Combination therapy with clopidogrel and aspirin: can the CURE results be extrapolated to cerebrovascular patients? Stroke 2001; 32: 2948–2949. 71. Albers G. Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients? Neurology 2000; 54: 1022–1028. 72. Hacke W. From CURE to Match: ADP receptor antagonists as the treatment of choice for high-risk atherothrombotic patients. Cerebrovascular Disease 2002; 13(supplement 1): 22– 26. 73. Khot U & Nissen S. Is CURE a cure for acute coronary syndromes? Statistical versus clinical significance. Journal of American College of Cardiology 2002; 40: 218–219. 74. Gorelick P, Born G, D’Agostino R, et al. Therapeutic benefit. Aspirin revisited in light of the introduction of clopidogrel. Stroke 1999; 30: 1716– 1721. 75. Gaspoz J, Coxson P, Goldman P, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. The New England Journal of Medicine 2002; 346: 1800–1806. 76. Sarasin F, Gaspoz J & Bounameaux H. Cost-effectiveness of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack. Archives of Internal Medicine 2000; 160: 2773–2778.
3 Platelet ADP receptor antagonists: ticlopidine and clopidogrel Alan K. Jacobson*
MD, FACC
Associate Chief of Staff/Research Research Service (151), Loma Linda VA Medical Center, 11201 Benton Street, Loma Linda, CA 92354, USA
The central role of platelets in the pathophysiology of arterial vascular disease has focused attention on the development of effective platelet inhibitor modalities to mitigate the clinical consequences of atherothrombotic disease. Aspirin has been the gold standard of therapy and is effective in cerebral, coronary and peripheral arterial disease with a 25% reduction in myocardial infarction, stroke and vascular death. The platelet ADP receptor antagonists were developed to further improve the clinical results of therapy. Ticlopidine provides an additional 10% relative risk reduction over aspirin alone in stroke prevention and coronary stent placement. However, ticlopidine is accompanied by occasional life-threatening adverse hematological events. The action of clopidogrel is similar to that of ticlopidine, and it is comparably effective. However, the side-effect profile of clopidogrel is much more favorable. Key words: ticlopidine; clopidogrel; thienopyridine; antiplatelet; atherothrombosis.
The primary role of platelets is to maintain vascular integrity through hemostasis. However, in the presence of vascular disease such as atherosclerosis, this normal process may become excessive and result in thrombosis.1 The role of platelets in the pathophysiology of arterial vascular disease has undergone extensive evaluation over the past several decades and has been confirmed as central.2 While atherosclerosis is the major underlying chronic pathology, platelet-dependent thrombosis, often initiated by acute plaque destabilization, is mainly responsible for acute clinical events including myocardial infarction, stroke and sudden death.3 Platelet adhesion, activation and aggregation are the key processes. Platelets do not adhere to normal endothelium but do adhere to disrupted endothelial surfaces. Following adhesion, platelets undergo shape change, secrete the contents of their alpha and dense granules, transform endogenous arachidonic acid into thromboxane A2,4 and undergo conformational changes in glycoprotein IIb/IIIa receptors that effect plateletto-platelet aggregation.5 * Corresponding author. Tel.: þ1-909-583-6050; Fax: þ1-909-796-2791. E-mail address: [email protected] (A.K. Jacobson). 1521-6926/$ - see front matter Published by Elsevier Ltd.
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Adenosine diphosphate (ADP) plays a major role in platelet activation. ADP originates from damaged endothelium, red blood cells and platelet dense granules. Three distinct platelet surface receptors for ADP have been identified.6 ADP binding triggers the release of platelet dense granules containing not only ADP but also serotonin, another platelet agonist, and stimulates platelet production of thromboxane A2; the result is an activation-amplification cascade. The central role of ADP makes it an inviting therapeutic target.7 Aspirin was the first effective platelet inhibitor drug to be identified. Aspirin results in an irreversible modification of the enzyme cyclo-oxygenase rendering it incapable of converting arachidonic acid into thromboxane A2. The first comprehensive evaluation of aspirin’s effectiveness in preventing vascular events came from a meta-analysis performed by the Antiplatelet Trialists’ Collaboration, published in 1984.8 The analysis included 145 randomized trials comprising 100 000 patients, including 70 000 classified as high risk. A 25% reduction in the combined endpoint of myocardial infarction, stroke and vascular death was observed. Aspirin 75– 325 mg once a day was found to be optimal with no additional benefit from higher doses, nor from any other then-existing platelet inhibitor agents including dipyridamole, sulfinpyrazone, suloctidil and combinations of aspirin with dipyridamole or sulfinpyrazone. The contribution of aspirin to the reduction of vascular morbidity is significant but is accompanied by several deficiencies. Side-effects, while generally not life-threatening, are potentially serious. Both the incidence of major hemorrhagic complications and the frequency of acid-peptic symptoms are significant and appear to be dose-related.9 – 11 Aspirin resistance may occur in up to 20% of patients. Patients may experience recurrent thrombotic events while on aspirin therapy, so-called ‘aspirin failures’.12,13 Even after adequate inhibition of cyclo-oxygenase, alternative pro-aggregatory pathways remain intact. Therefore, the development of new agents has been an appropriate and compelling goal.14
THE THIENOPYRIDINES—ADP RECEPTOR ANTAGONISTS Ticlopidine (Ticlid) Ticlopidine was the first of the new class of thienopyridine antiplatelet agents, also known as ADP receptor antagonists. It gained Food and Drug Administration (FDA) approval for clinical use in the early 1990s.15 A single oral dose of ticlopidine is absorbed rapidly, and peak plasma concentration is achieved 1 – 3 h after a 250-mg dose.16 When the drug is taken after food, the area under the curve is increased by 20%.17 Ticlopidine does not inhibit ADP-induced platelet aggregation in vitro, and hepatic biotransformation into active metabolites is required for drug action.18 Thirteen metabolites have been described, but those responsible for the antiplatelet effect have not been found. The mechanism of antiplatelet action appears to be irreversible alteration of the platelet surface P2Y12 ADP receptor, resulting in a reduction in ADP-induced platelet aggregation.19 Collagen- and thrombin-induced activation are also inhibited, probably due to blockade of amplification.20 Hepatic metabolism is delayed, and at maintenance doses, only 50% platelet aggregation inhibition is achieved at 5 days, and 60– 70% at 8 – 11 days.21 Platelet inhibitory effects are saturated at 250 mg twice daily. Metabolism is dependent on the cytochrome p450 system, and interactions with digoxin, theophylline and cimetidine have been documented.22,23 Elimination of ticlopidine is 60% renal and 23% gastrointestinal.
Platelet ADP receptor antagonists 57
Serum levels are increased in patients with renal impairment, but are apparently unassociated with an excess prolongation of the bleeding time. Ticlopidine is dosed 250 mg twice daily. Single loading doses of 500 mg have been tried but often cause abdominal cramping and discomfort.24 Serious, potentially life-threatening, hematological side-effects have prompted an FDA-mandated ‘black-box’ warning in the package insert.25 Neutropenia (absolute neutrophil count less than 1200/ml) occurs in 2.4% of treated patients, and severe neutropenia (less than 450/ml) in 0.8%. Some cases of neutropenia appear to be irreversible. Aplastic anemia occurs in about one in 4000 –8000 patients. Thrombotic thrombocytopenic purpura occurs in about one in 2000 – 4000 patients. Reactions may occur as early as a few days after treatment is started. The peak incidence is at 3 –6 weeks. Reactions are rare after 3 months’ treatment. Hematological monitoring is advised every 2 weeks for the first 3 months of treatment. Ticlopidine is also associated with an 8 –10% rise in total serum cholesterol;26 the effect on cholesterol subfractions is uniform. Gastrointestinal side-effects in stroke trials were common and curtailed treatment in 13% of patients. Rashes were noted in 5% of patients.27 Clinical trials with ticlopidine Ticlopine has been evaluated as monotherapy in patients with stroke,28 transient cerebral ischemia,29 unstable angina,30 myocardial infarction,31 intermittent claudication,32 for graft patency following coronary bypass surgery,33 and in combination with aspirin to reduce thrombotic complications following coronary stent placement.34 Major studies of ticlopidine will be reviewed. Patients with stroke precursors. The Ticlopidine Aspirin Stroke Study (TASS) compared ticlopidine with aspirin in a randomized blinded study of 3069 patients with transient ischemic attack, amaurosis fugax or minor stroke within 3 months prior to enrollment at 56 North American centers.35 Patients were randomized to ticlopidine 250 mg twice daily or aspirin 650 mg twice daily and were followed for 2 –6 years. At 3 years, the combined endpoint of non-fatal stroke and all-cause death occurred in 19% of aspirin patients and 17% of ticlopidine patients, a 12% reduction ðP ¼ 0:048Þ for ticlopidine. The reduction in fatal and non-fatal stroke was more impressive; 13% for aspirin and 10% for ticlopidine, a 21% reduction ðP ¼ 0:024Þ: Side-effects, however, curtailed ticlopidine in 20.9% of patients compared with 14.5% of patients on aspirin. The incidence of severe neutropenia was less than 1%. The authors concluded that ticlopidine was somewhat more effective than aspirin in preventing strokes but with a greater risk of side-effects. Patients with completed stroke. The Canadian American Ticlopidine Study randomized 1073 patients within 4 months of completed ischemic stroke to ticlopidine 250 mg twice daily or placebo for up to 3 years, with an average follow-up of 2 years.36 Stroke recurred in 18.6% of ticlopidine patients and 24.6% of placebo patients ðP ¼ 0:017Þ: The composite of myocardial infarction, stroke and vascular death occurred in 10.8% of ticlopidine patients and 15.3% of placebo patients, a relative reduction of 30.2%. Intracoronary stents. One major challenge of percutaneous transluminal coronary angioplasty is the high incidence of rethrombosis. Intracoronary stents offered the promise of improved long-term patency, but the early experience was an unacceptably high rate of acute and subacute stent thrombosis.37 Early antithrombotic regimens were various combinations of aspirin, dipyridamole, dextran, heparin and warfarin.38 These regimens were effective but were commonly accompanied by bleeding.
58 A. K. Jacobson
More effective antithrombotic regimens were needed.39 The early clinical experience with ticlopidine after coronary stenting was documented in registries. As clinical experience appeared favorable, formal studies were developed. The Intracoronary Stenting and Antithrombotic Regimen trial was the first of the randomized trials and enrolled 517 patients. The anticoagulant patients experienced a 6.2% incidence of endpoints, whereas the rate was only 1.6% among patients receiving dual antiplatelet therapy, a 75% risk reduction ðP , 0:001Þ:40 Benefit in the antiplatelet arm was not seen until 3 days due to the delayed onset of action of ticlopidine. The Stent Anticoagulation Restenosis Study enrolled 1653 patients undergoing emergency or elective percutaneous coronary interventions with stent placement. Patients were randomized to three arms: ticlopidine 250 mg twice daily plus aspirin (100 – 325 mg daily), aspirin alone or aspirin 325 mg daily plus warfarin with an international normalized ratio of 3.5 –4.5.41 Therapy was continued for 30 days. The endpoint was combined death, myocardial infarction and need for revascularization. The endpoint was reached in 0.5%, 3.6% and 2.7% of patients in the three respective groups; combined aspirin and ticlopidine was the superior regimen. Bleeding complications were seen in 5.5%, 1.8% and 6.2% of patients in the respective groups. The Full Anticoagulation versus Aspirin and Ticlopidine trial also demonstrated the limitations of the slow onset of action of ticlopidine and the need for either pretreatment prior to the stent procedure or adjunctive anticoagulant therapy until ticlopidine exposure had been sufficient to inhibit platelet aggregation.42 Current FDA-approved indications for ticlopidine are to reduce the risk of thrombotic stroke with stroke precursors or completed thrombotic stroke, with the caveat that, due to hematological side-effects, treatment should be reserved for patients intolerant or allergic to aspirin or who have failed aspirin. Ticlopidine is also approved as an adjunct to aspirin in coronary stenting. Clopidogrel (Plavix) Following FDA approval of ticlopidine for clinical use in 1991, clopidogrel emerged as a promising compound structurally similar to ticlopidine, but with fewer side-effects. Clopidogrel has since been approved by the FDA for reduction of thrombotic events in recent myocardial infarction, stroke or established peripheral arterial disease, and for patients with non-ST-elevation acute coronary syndromes including percutaneous coronary interventions. Pharmacokinetics Clopidogrel differs from ticlopidine by an additional carboxymethyl side group. Clopidogrel is absorbed rapidly via the oral route. Metabolism is so extensive that clopidogrel is difficult to detect in the circulation; the major circulating compound is the inactive carboxylic acid derivative SR26334 that reaches peak plasma concentration within 1 h of ingestion.43 Elimination is 50% renal and 46% gastrointestinal. Unlike ticlopidine, clopidogrel absorption is not affected by food. Despite hepatic metabolism, little interaction with other drugs is seen.44 The mechanism of the antiplatelet effect appears to be identical to ticlopidine; permanent alteration of the platelet surface P2Y12 ADP receptor and inhibition of ADP-induced platelet activation and aggregation.45 The platelet aggregation inhibitory effect of clopidogrel 75 mg once daily is equivalent to that of ticlopidine 250 mg twice daily. Doses of 50 mg, 75 mg, 100 mg
Platelet ADP receptor antagonists 59
and 150 mg daily were not demonstrably different from each other.46 As with ticlopidine, peak antiplatelet activity on maintenance clopidogrel doses is delayed by 4 – 8 days. However, a significant advantage of clopidogrel is that loading doses of approximately 300 mg are well tolerated and result in near-maximal platelet inhibition in 2 – 5 h.47,48 The side-effect profile of clopidogrel is remarkably improved compared with ticlopidine. Severe neutropenia (absolute neutrophil count less than 450/ml) occurred in only 0.05% of patients.49,50 Thrombotic thrombocytopenic purpura was reported in only 11 patients within several weeks of treatment initiation after approximately 3 million patients had been exposed to the drug.51 Thus clopidogrel is far safer than ticlopidine, but a small risk of serious complications remains. Gastrointestinal side-effects including bloating, cramping and diarrhea occur infrequently. Bleeding is an extension of the antiplatelet effect and is significantly more common with clopidogrel plus aspirin than with aspirin alone. Limiting the dose of aspirin to 100 mg daily reduces the risk of major hemorrhage but does not compromise the efficacy of combined therapy.52 Clinical trials with clopidogrel The Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was based on the premise that atherothrombosis is a systemic condition that affects all arterial beds with a common pathophysiology.53 CAPRIE was thus unique by incorporating patients with three distinct indications into a single trial. The study was designed to compare clopidogrel 75 mg daily with aspirin 325 mg daily for prevention of vascular events in patients with stroke within 6 months, myocardial infarction within 35 days, or peripheral vascular disease. A total of 19 185 patients were followed for a mean of 1.9 years. The primary outcome was stroke, myocardial infarction or vascular death The annualized event rates were 5.32% for clopidogrel and 5.83% for aspirin, an 8.7% relative reduction favoring clopidogrel. This reduction was similar to that seen in the TASS trial when ticlopidine was compared with aspirin. Relative risks were a 7.3% reduction for the stroke group, a 3.7% increase for the myocardial infarction group, and a 23.8% reduction for the peripheral arterial disease group. The heterogeneity of effects was significant ðP ¼ 0:042Þ: Most of the benefit seen in the peripheral arterial disease group was due to a reduction in myocardial infarction. In contrast to earlier ticlopidine trials, the improved results with clopidogrel were not offset by excess side-effects. The rate of treatment discontinuation was the same in aspirin and clopidogrel groups. Side-effects occurred in 11.4% of patients, 9.3% of which were hemorrhagic events. Acute coronary syndromes. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial was designed to compare the safety and efficacy of combined aspirin-clopidogrel therapy with aspirin alone in high-risk coronary disease patients.54 The trial randomized 12 562 patients with non-ST-elevation acute coronary syndromes within 24 hour of symptom onset. All patients received aspirin (75 –325 mg daily) and were randomized to receive either clopidogrel (300 mg loading dose then 75 mg daily) or placebo for 3 – 12 months. The composite endpoint was cardiovascular death, nonfatal myocardial infarction and stroke. The endpoint occurred in 11.4% of placebo patients and in 9.3% of clopidogrel patients, a relative risk reduction of 20%.55 Major bleeding was more frequent in the clopidogrel group, and within groups, bleeding risk was aspirin dose-dependent. In patients undergoing coronary artery bypass surgery, bleeding was significantly increased if clopidogrel had not been discontinued 5 or more days before surgery. In the CURE trial, only 4% of participating centers routinely
60 A. K. Jacobson
included glycoprotein IIb/IIIa inhibitors and early interventional procedures. Thus CURE was able to demonstrate a clear role for clopidogrel in the defined high-risk group. Evaluation in intracoronary stenting. Three randomized trials involving over 2700 patients have compared ticlopidine with clopidogrel in patients undergoing stent placement.56 – 58 The drugs were equally effective, but clopidogrel was associated with fewer side-effects. The PCI-CURE trial included 2658 patients within the CURE trial who underwent elective percutaneous coronary intervention.59 Patients received a median of 10 days of aspirin-clopidogrel or aspirin-placebo therapy prior to intervention and for 8 months following intervention. The composite endpoint was reduced by 30% (4.5% vs 6.4%, P ¼ 0:03) by 30 days in the clopidogrel-aspirin group. The value of combined treatment in emergency interventions was not clarified. In early trials of ticlopidine after coronary interventions, drug therapy was restricted to 30 days due to concern over hematological side-effects. The improved safety profile of clopidogrel has reduced the concern. The Clopidogrel for the Reduction of Events During Observation trial, similar to PCI-CURE, showed that both efficacy and safety of thienopyridine therapy could be extended to 12 months.60 Clopidogrel has also been shown to be effective in reducing the thrombotic complications of coronary vascular brachytherapy (use of ionizing radiation to prevent in-stent restenosis).61,62 Peripheral arterial disease. The relative risk reduction for the patients entering the CAPRIE trial with a diagnosis of peripheral arterial disease was 24% greater with clopidogrel than with aspirin, principally as a result of a greater reduction in the incidence of myocardial infarction. Clinical trials of ticlopidine in peripheral arterial disease showed similar benefit.63 – 66 Clopidogrel is generally regarded as the thienopyridine of choice due to its improved safety profile and once-daily dosing.67,68 Cerebrovascular disease. While a role for thienopyridines in the treatment of peripheral arterial disease is well accepted,69 a role in cerebrovascular disease remains less clear.70 Secondary vascular events in stroke patients are likely to be cerebrovascular,71 and bleeding rates in cerebrovascular patients may be higher than in cardiac populations, possibly due to age, drug interactions or the underlying ischemic injury. The CAPRIE trial showed only a non-significant relative risk reduction of 5.2% for clopidogrel compared with aspirin in stroke prevention. Interpreting the CURE trial is problematic because of the low number of strokes, under 1.5% in both groups. Perhaps the ongoing MATCH trial of combination aspirin plus clopidogrel vs aspirin alone in cerebrovascular patients will provide clarification on this important issue.72 Cost-effectiveness. One analysis of the CURE data concluded that giving clopidogrel to 1000 patients with acute coronary syndromes would prevent 15 non-fatal myocardial infarctions. Clopidogrel would also cause 10 additional major and 69 minor bleeding episodes and complicate 200 surgical decisions, during which time 978 patients would have taken the drug with no benefit, and no lives would have been saved.73 In one cost analysis of the CAPRIE trial, the estimated cost to save one life with aspirin was $8181, but it was $49 367 with clopidogrel. The cost of clopidogrel would have to fall to $0.30 per tablet to match aspirin’s cost-effectiveness per event prevented, and $0.20 to match aspirin’s cost-effectiveness per life saved.74 In a separate cost-effectiveness analysis combining data from both the CAPRIE and CURE trials, the cost of clopidogrel would have to fall by 70– 82% to become costeffective for routine use in all patients who might benefit.75 However, not all costeffectiveness analyses have been as discouraging.76
Platelet ADP receptor antagonists 61
SUMMARY Atherothrombosis is the basis for the epidemic rates of acute cerebrovascular, coronary and peripheral vascular morbidity and mortality. Antiplatelet therapy plays a central role in management. Aspirin has been the mainstay; the thienopyridines provide new opportunities for those patients who are intolerant, resistant or have failed aspirin, and for those who can derive greater benefit from combined therapy. Which patient subgroups benefit the most and cost-effectiveness concerns remain matters for further assessment. Due to its equivalence to ticlopidine, its greatly improved side-effect profile over ticlopidine, and its once-daily dosing, clopidogrel is the thienopyridine of choice.
Practice points † despite the modest efficacy of ticlopidine over aspirin, the delayed onset of action, potential for severe hematological side-effects, high incidence of gastrointestinal side-effects, and cost are all undesirable features of this particular drug † when ticlopidine must be used, blood count monitoring every 2 weeks for the first 3 months is advised † as hepatic transformation into active drug metabolites is delayed, initial maintenance doses of ticlopidine or clopidogrel will not achieve optimal antiplatelet effect for 4– 8 days. A loading dose of clopidogrel 300 mg, however, achieves steady-state platelet inhibition within 2 – 5 h and is relatively well tolerated with fewer gastrointestinal side-effects than with ticlopidine † clopidogrel is useful monotherapy in patients intolerant of aspirin, aspirin resistant or who have failed aspirin therapy † clopidogrel is useful in combination with aspirin in acute coronary syndromes and following percutaneous coronary intervention † combination therapy with clopidogrel and aspirin is associated with an aspirin dose-dependent risk of major hemorrhage; aspirin dosing at the lower end of its usual dosing range reduces the hemorrhagic risk without compromising effectiveness
Research agenda † further exploration of the heterogeneity of benefit of clopidogrel in patients presenting with initial symptoms from different vascular beds (cerebral, coronary and peripheral arterial) † refinement of the timing of clopidogrel in percutaneous coronary interventions † better clarification of the roles of the glycoprotein IIb/IIIa inhibitors and clopidogrel alone or in combination in patients undergoing percutaneous coronary interventions or coronary artery bypass surgery † clopidogrel in the primary prevention of vascular events in patients with risk factors but no manifest disease
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