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Current antiplatelet therapies: Benefits and limitations
Current antiplatelet therapies: Benefits and limitations Dominick J. Angiolillo, MD, PhD, FACC, FESC, Luis A. Guzman, MD, FACC, and Theodore A. Bass, MD, FACC Jacksonville, FL
Antiplatelet therapy is the current criterion standard for the treatment of patients undergoing percutaneous coronary intervention and patients who have acute coronary syndromes. Clopidogrel in combination with aspirin is the current standard of care for reducing cardiovascular events in these patients. However, patients who receive currently available antiplatelet therapy may still develop atherothrombotic events. In addition, despite the clinical benefits achieved with clopidogrel, significant clinical limitations are associated with its use. This article summarizes the current understanding of the benefits and limitations of the commonly used antiplatelet therapies. (Am Heart J 2008;156:S3-S9.)
Platelets play a pivotal role in the pathophysiology of acute coronary syndromes (ACSs) and the complications after percutaneous coronary intervention (PCI). As a result, platelet-inhibiting drugs are the cornerstone of treatment in these clinical scenarios.1 Currently, 2 oral antiplatelet therapies—the thienopyridines and aspirin—are available for the short- and long-term prevention of atherothrombotic complications in patients who have ACS or are undergoing PCI.2 The use of these agents in clinical practice has significantly improved cardiovascular outcomes. In particular, results from landmark trials have confirmed the clinical benefit of combined thienopyridine and aspirin treatment in high-risk patients.3-8 Despite the fact that dual antiplatelet therapy has resulted in significant advances in the treatment of patients with ACS and those undergoing PCI, a considerable number of patients continue to experience cardiovascular events.9 Thus, the development of antiplatelet therapies with clinical profiles superior to those of currently available agents is warranted.10,11 This article presents an overview of the benefits and limitations of current antiplatelet therapies.
From the Division of Cardiology, University of Florida College of Medicine–Jacksonville, Jacksonville, FL. Conflicts of Interest: Dominick J. Angiolillo, MD, PhD, FACC, FESC has declared the following conflicts of interest: Honoraria/Lectures: Bristol Myers Squibb (New York, NY); Sanofi-Aventis (Bridgewater, NJ); Eli Lilly and Company (Indianapolis, IN); Daiichi Sankyo, Inc (Parsipanny,NJ). Honoraria/Advisory board: Bristol Myers Squibb; SanofiAventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company (Parsipanny,NJ); Portola (San Francisco, CA); Novartis (East Hanover, NJ). Research Grants: GlaxoSmithKline (Brentford, London, United Kingdom); Otsuka (Tokyo, Japan). Luis A. Guzman, MD, FACC, has declared no conflicts of interest. Theodore A. Bass, MD, FACC has declared the following conflicts of interest: Honoraria/Lectures: Eli Lilly and Company; Daiichi Sankyo, Inc. Reprint requests: Dominick J. Angiolillo, MD, PhD, FACC, FESC, Division of Cardiology, University of Florida–Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209. E-mail: [email protected] 0002-8703/free © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.06.003
Dual antiplatelet therapy with thienopyridines and aspirin: benefits Aspirin irreversibly inhibits cyclooxygenase (COX)-1 by acetylating serine 529, thereby inhibiting the production of thromboxane A2, a promoter of platelet aggregation, and prostaglandin I2 (prostacyclin), a potent inhibitor of platelet aggregation and a powerful vasodilator, in platelets and vascular endothelial cells, respectively.12,13 Of note, in the absence of protein synthesis in platelets, thromboxane A2 inhibition persists for the lifetime of the platelet compared with vascular endothelial cells, which recover COX-1 activity shortly after exposure to aspirin. Consequently, antithrombotic, rather than prothrombotic, effects dominate in aspirin-treated patients. Accordingly, aspirin has been shown to play a key role in the secondary prevention of atherothrombotic events.12,13 Although aspirin is a cost-effective therapy, a considerable number of patients who take aspirin continue to experience atherothrombotic complications.14 This has been the reason for the continued search to identify more potent antiplatelet drugs that can be used safely, especially in high-risk patients. About a decade ago, a solution to this problem was thought to have been found with the development of the oral glycoprotein (GP) IIb/IIIa inhibitors. The GP IIb/IIIa inhibitors are very potent antiplatelet agents that inhibit the final common pathway that mediates platelet aggregation.15 Intravenous GP IIb/IIIa inhibitors have proven their efficacy to prevent periprocedural thrombotic complications; but these parenterally administered drugs are not suitable for long-term protection, resulting in the need for oral agents.15 Despite the promising rationale behind the use of oral GP IIb/IIIa inhibitors, clinical trials failed to show any benefit of these agents; and a pooled analysis from trials of oral GP IIb/IIIa antagonists showed increased mortality when these agents were given.16 The need for the blockade of alternative platelet signaling pathways thus emerged. In
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particular, the effects obtained through the combination of aspirin and a family of oral antiplatelet agents known as the thienopyridines, which inhibit platelet activation and aggregation processes through adenosine 5′-diphosphate receptor blockade, became one of the most investigated areas in cardiovascular pharmacology. Thienopyridines inhibit the adenosine 5′-diphosphate P2Y12 receptor.17 Ticlopidine is a first-generation thienopyridine that, in combination with aspirin, enhances platelet inhibition.17,18 This enhanced effect is due to the additive effects on platelet inhibition achieved with the blockade of the COX-1 and P2Y12 pathways.17,18 Dual antiplatelet therapy was first explored in the emerging clinical setting of coronary stenting. In fact, in the initial era of coronary stenting, the antithrombotic regimen of choice for the prevention of stent thrombosis was still not established; and various combinations of antiplatelet agents and anticoagulants were used with elevated complication rates. The lack of a safe and efficacious antithrombotic drug regimen for patients undergoing coronary stenting significantly limited the growth of coronary interventions. Landmark clinical trials demonstrated that, in patients undergoing coronary stenting, better clinical outcomes were achieved with the combined use of aspirin and ticlopidine than with aspirin alone or aspirin plus warfarin.19-22 These results, accompanied by a better knowledge of stent deployment technique,23 played a pivotal role in the growth of coronary stenting. However, there are 2 major limitations with the use of ticlopidine24: its safety profile (ie, ticlopidine leads to elevated rates of neutropenia, thrombocytopenia, rash, and adverse gastrointestinal effects) and its inability to induce platelet inhibition rapidly. This led researchers to pursue the development of an antiplatelet agent with the same beneficial properties of ticlopidine but without its limitations. Thus, clopidogrel, a second-generation thienopyridine, was developed. Today, clopidogrel has largely replaced ticlopidine. Clopidogrel selectively and irreversibly inhibits the P2Y12 receptor.9 It is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 system to generate an active metabolite. In particular, the thiophene ring of clopidogrel is oxidized to form an intermediate metabolite (2-oxo-clopidogrel), which is further oxidized, resulting in the opening of the thiophene ring and the formation of a carboxyl and a thiol group. The reactive thiol group of the active metabolite of clopidogrel forms a disulfide bridge to one or more cysteine residues of the P2Y12 receptor, resulting in its irreversible blockade for the life of the platelet. Thus, P2Y12 receptor blockade occurs early in the cascade of events leading to the formation of the platelet thrombus and effectively inhibits platelet activation and aggregation processes.9 In fact, platelet P2Y12 blockade prevents platelet degranulation and the release
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of prothrombotic and inflammatory mediators from the activated platelet, and also inhibits the transformation of the GP IIb/IIIa receptor to the form that binds fibrinogen and links platelets. The major benefits of clopidogrel over ticlopidine include its better safety profile24 and its ability to yield antiplatelet effects more rapidly through the administration of a loading dose.25 The fact that clopidogrel is well tolerated at high doses makes it possible to achieve antiplatelet effects within hours of administration.25 This has important clinical implications in patients with ACS and PCI, in whom thrombotic occlusions (eg, reinfarction, stent thrombosis) most commonly occur within the first 24 to 48 hours. In addition to the better safety and pharmacodynamic profiles, there is also evidence that the use of this second-generation thienopyridine leads to better clinical outcomes.26 In fact, pooled data from N10,000 patients undergoing PCI showed lower rates of major adverse cardiac events at 30 days after treatment with clopidogrel than after treatment with ticlopidine.26 Overall, the safety, pharmacodynamic, and clinical advantages of clopidogrel have led to its widespread adoption over ticlopidine as the antiplatelet agent of choice in patients undergoing PCI.27 In a head-to-head comparison with aspirin, clopidogrel has been shown to be more effective in reducing the risk for myocardial infarction (MI), ischemic stroke, and vascular death in patients at risk for ischemic events.28 In addition, long-term (up to 12 months) dual antiplatelet therapy with clopidogrel and aspirin is more effective than aspirin alone in preventing major cardiovascular events in patients with ACS, including those treated with PCI.3-5 The long-term clinical benefit associated with dual antiplatelet therapy has been observed overall in patients with non–ST-segment elevation ACS (unstable angina and non–ST-segment elevation MI) independent of coronary revascularization.3 More recently, the spectrum of clinical benefit of clopidogrel has been extended to patients with ST-segment elevation MI, including those undergoing PCI.6-8 On the other hand, results of the CHARISMA trial showed that in 15,603 high-risk but nonacute patients with clinically evident cardiovascular disease or multiple risk factors, long-term treatment (median 28 months) with clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes.29 This study actually showed dual antiplatelet therapy to be harmful in patients without documented atherothrombotic disease (n = 3,284), as these patients had higher mortality, whereas in the subgroup of patients with clinically evident atherothrombosis (n = 12,153), there was a 12% relative risk reduction in event rates with clopidogrel (P = .046).29 Most recently, a subgroup analysis of the CHARISMA trial identified patients who were enrolled with
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Table I. Clinical relevance of inadequate clopidogrel response
Stent thrombosis Muller et al33 Barragan et al34 Gurbel et al35 Ajzenberg et al36 Buonamici et al37
n
Functional parameter
Clinical relevance
105 36 120
↓ Inhibition of platelet aggregation ↑ P2Y12 reactivity ratio ↑ P2Y12 reactivity ratio, ↑ platelet aggregation, ↑ stimulated GP IIb/IIIa expression ↑ Shear-induced platelet aggregation ↑ Platelet aggregation
Stent thrombosis Stent thrombosis Stent thrombosis Stent thrombosis Stent thrombosis
↑ Platelet aggregation (4th quartile) ↑ Platelet aggregation ↑ Platelet aggregation ↑ Platelet aggregation ↑ Clopidogrel/aspirin-resistant patients ↑ Platelet aggregation ↑ Platelet aggregation (3rd and 4th quartiles) ↓ Platelet inhibition ↑ Platelet aggregation ↑ Platelet aggregation ↑ P2Y12 reactivity ratio (2nd through 5th quintiles) ↑ Platelet aggregation (4th quartile) ↑ Platelet aggregation, ↑ P2Y12 reactivity ratio ↑ P2Y12 reactivity units
Post–primary PCI ischemic events (6 m) Post-PCI ischemic events (6 m) Post-PCI myonecrosis/inflammation Post-PCI ischemic events (30 d) Post-PCI myonecrosis Post-PCI ischemic events (30 d) Post-PCI ischemic events (30 d) Post-PCI ischemic events (3 m) Post-PCI ischemic events (12 m) Post-PCI myonecrosis Post-PCI ischemic events (6 m) Ischemic events (24 m) Post-PCI ischemic events (30 d) Post-PCI ischemic events (6 m)
49 804
Post-PCI myonecrosis and ischemic events Matetzky et al38 60 Gurbel et al39 192 Gurbel et al40,41 120 Cuisset et al42 106 Lev et al43 120 Cuisset et al44 292 Hochholzer et al45 802 46 Geisler et al 379 Bliden et al47 100 Cuisset et al48 190 Bonello et al49 144 Angiolillo et al50 173 Frere et al51 195 Price et al52 380
documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease, also known as the CAPRIE-like population (n = 9,478).30 In this subgroup, there was a 17% relative risk reduction in event rates (P = .01) with clopidogrel. Of note, the greatest benefit was observed in patients with prior MI (n = 3,846), in whom there was a 23% relative risk reduction in event rates (P = .031), whereas there were no benefits seen in patients with a history of coronary artery disease but without prior MI. The findings of this study suggest that patients with a greater thrombotic burden (eg, history of plaque rupture and thrombosis) are most likely to derive benefit from an extended duration of dual antiplatelet therapy. However, studies specifically designed for these patients are warranted to test this hypothesis.
Dual antiplatelet therapy with thienopyridines and aspirin: limitations Clinical experience with clopidogrel has supported that benefits are achieved with its adjunctive use in high-risk patients, but has also led to a recognition that clopidogrel has a number of significant limitations. The major limitations of clopidogrel are attributed to its irreversible antiplatelet effects and to the broad variability of platelet inhibition achieved with this agent.9 The first limitation, which is inherent to the family of thienopyridines, is a significant increase in bleeding risk in patients requiring surgery who have not been withheld clopidogrel treatment for at least 5 to 7 days (ie, the life of the platelet). The development of an antiplatelet agent with a reversible
mechanism of action, allowing platelet function to return more rapidly to baseline status, would allow patients to undergo surgery more expeditiously without any increase in bleeding risk.9,11 The second limitation, platelet inhibition variability, may explain why the antiplatelet effects achieved with a loading dose of clopidogrel are not always rapid and why elevated platelet reactivity may persist in some patients despite the adjunctive use of this antiplatelet drug. Although the mechanisms leading to inadequate clopidogrel-induced antiplatelet effects are not fully elucidated, they may include clinical, cellular, and genetic factors.9,31 Furthermore, although the best method of assessing antiplatelet drug response has not been fully established,9,32 it is well known that enhanced platelet reactivity plays a key role in atherothrombotic complications.1,9 Currently, there is sufficient evidence to support the belief that the persistence of enhanced platelet reactivity, despite the use of clopidogrel, is a clinically relevant entity (Table I).33-52 The mechanisms leading to variability are not fully elucidated and are likely multifactorial. These include clinical, cellular, and genetic factors as summarized in Figure 1. A further limitation of clopidogrel is its inefficient conversion to the active metabolite, which may, in part, account for the variable and sometimes inadequate antiplatelet effects of clopidogrel as well as its delayed onset of action.9 The delayed onset of action of clopidogrel is indicated by the minimum of 2 to 4 hours need for achieving its maximal antiplatelet effects, a delay that may have serious consequences for an ACS patient in urgent need of catheterization.5 Approximately 85% of
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Figure 1
Proposed mechanisms leading to variability in individual responsiveness to clopidogrel. (Reprinted from the Journal of the American College of Cardiology, Vol. 49, Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al, Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives, 1505-16, 2007, with permission from Elsevier.9)
the prodrug is hydrolyzed by esterases to an inactive carboxylic acid derivative, with only about 15% metabolized by the cytochrome P450 system in the liver to generate an active metabolite.9 One way to increase the generation of the active metabolite of clopidogrel is to raise the dose of the drug, and numerous studies have focused on the impact of high loading doses of clopidogrel. Most of these studies have compared 300with 600-mg loading dose regimens and have shown that a 600-mg loading dose leads to an earlier, higher, and more sustained (up to 48 hours) inhibition of platelet function, with better response profiles.53,54 This may explain why at least 12 to 15 hours of pretreatment with a 300-mg loading dose is necessary before any clinical benefit can be observed in patients undergoing PCI.55 Using a 600-mg loading dose regimen, full antiplatelet effects are achieved after 2 hours.56 As a result, 600-mg loading doses of clopidogrel have been shown to be equally efficacious if initiated 2 to 24 hours before PCI.57 Despite the broad use of high clopidogrel doses in daily clinical practice, studies assessing high-dose regimens are few; and these regimens still have not been approved by the US Food and Drug Administration. To date, the clinical impact of a 600-mg clopidogrel loading dose has been observed in 2 small studies in patients undergoing PCI, in which pretreatment was shown to be associated
with better clinical outcomes, primarily a reduction in periprocedural MI, when compared with pretreatment with a 300-mg loading dose.44,58 The large (N ≈ 14,000) ongoing CURRENT/OASIS-7 trial has been designed to determine whether high-dose clopidogrel leads to better clinical outcomes than standard-dose clopidogrel in patients with non–ST-segment elevation ACS who are undergoing PCI.9 Patients randomized to the high dose will receive a 600-mg loading dose and then a 150-mg/d maintenance dose from days 2 through 7; patients randomized to the standard dose will receive a 300-mg loading dose and then a 75-mg/d maintenance dose from days 2 through 7. All patients will receive clopidogrel 75 mg/d from days 8 through 30. In addition, all patients will receive aspirin ≥300 mg on day 1 and then be randomized to receive low-dose (75-100 mg) or high-dose (300-325 mg) aspirin. The impact of increasing the loading dose of clopidogrel to 900 mg has been evaluated recently. Although 600- and 900-mg loading doses were associated with greater and faster platelet inhibition than was a 300-mg loading dose, there were no major differences observed between the 600- and 900-mg loading dose regimens.59,60 Thus, although clopidogrel response is dose dependent, there is a threshold, likely attributable to the absorption rate of the drug
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that does not allow enhancement of the platelet inhibitory effects beyond a certain dose.59 Importantly, despite the better degree of platelet inhibition achieved with high loading doses, a broad variability in the effects achieved still persists.53 A higher maintenance dose of clopidogrel (150 mg/d) has also been evaluated; this resulted in enhanced platelet inhibition compared with the standard 75-mg dose,61-63 but the antiplatelet effects achieved remain highly variable, and N50% of patients did not reach the suggested therapeutic targets of P2Y12 inhibition.61,64 The broad variability of antiplatelet effects achieved with clopidogrel points to the need for drugs with more favorable pharmacokinetic and pharmacodynamic profiles.9,11 Indeed, the adjunctive use of a GP IIb/IIIa inhibitor in patients with poor clopidogrel response and in whom more potent platelet inhibition is warranted (ie, high-risk patients) represents a currently available therapeutic option in the acute phase of treatment.40,65 Nevertheless, alternative treatment strategies are needed that can yield rapid and potent inhibition in the acute phase of treatment and guarantee sustained platelet inhibition without wide variability in individual response during the maintenance phase of treatment.9,11
Conclusions The thienopyridines—the first-generation ticlopidine and the second-generation clopidogrel—in combination with aspirin have established antiplatelet therapy as a cornerstone of treatment for patients with ACS and/or undergoing PCI. Thienopyridines prevent thrombotic events and improve clinical outcomes through greater antiplatelet effects than can be achieved with aspirin alone. In landmark randomized trials, ticlopidine, the first commercially available thienopyridine, reduced adverse cardiovascular events in patients undergoing coronary stenting better than aspirin alone or aspirin plus warfarin. Clopidogrel has largely replaced ticlopidine in routine clinical practice based on its superior safety profile and more rapid antiplatelet effects. In head-to-head comparisons with aspirin, clopidogrel was more effective in reducing the risk of MI, ischemic stroke, and vascular death in patients at risk for ischemic events. However, in addition to the wellestablished beneficial effects of combined clopidogrel and aspirin therapy in patients who undergo a PCI, develop ACS, or both, clinical experience with clopidogrel has revealed a number of significant limitations that compromise its utility. These include high interpatient variability in platelet inhibition, an inadequate antiplatelet response, a thienopyridine family–inherent increase in bleeding risk in certain situations (eg, in patients requiring surgery who have not stopped thienopyridine therapy for 5-7 days), and a
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delayed onset of action. The enhanced platelet reactivity that persists despite the use of clopidogrel has been shown to be a clinically relevant entity that plays a critical role in atherothrombotic events. Several novel platelet inhibitors that target the P2Y12 and protease-activated receptor–1 receptors are in advanced clinical testing and have displayed pharmacologic properties and clinical profiles that offer promise for overcoming the shortcomings of clopidogrel. The latest information on the preclinical and clinical profiles of these emerging agents will be presented in other articles in this supplement. We would like to thank MDG Development Group, LLC, for their editorial support in the preparation of this manuscript. This assistance was funded by Daiichi Sankyo, Inc, and Eli Lilly and Company. We did not receive any financial compensation for this work and had final approval of its content.
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27. Smith Jr SC, Feldman TE, Hirshfeld Jr JW, et al. ACC/AHA/ SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:e1-e121. 28. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39. 29. Bhatt DL, Fox KA, Hacke W, et al, for the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17. 30. Bhatt DL, Flather MD, Hacke W, et al, for the CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982-8. 31. Angiolillo DJ, Alfonso F. Clopidogrel-statin interaction: myth or reality? J Am Coll Cardiol 2007;50:296-8. 32. Angiolillo DJ, Alfonso F. Platelet function testing and cardiovascular outcomes: steps forward in identifying the best predictive measure. Thromb Haemost 2007;98:838-43. 33. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89: 783-7. 34. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295-302. 35. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effects on platelet reactivity in patients with stent thrombosis. Results of the CREST study. J Am Coll Cardiol 2005;46:1827-32. 36. Ajzenberg N, Aubry P, Huisse MG, et al. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study. J Am Coll Cardiol 2005;45: 1753-6. 37. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312-7. 38. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: 3171-5. 39. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46:1820-6. 40. Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153-9. 41. Gurbel PA, Bliden KP, Tantry US. The effect of clopidogrel with and without eptifibatide on tumor necrosis factor–alpha and C-reactive protein release after elective stenting: results of the CLEAR PLATELETSIb study. J Am Coll Cardiol 2006;48:2186-91. 42. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542-9.
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43. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006;47:27-33. 44. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non–ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339-45. 45. Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006;48:1742-50. 46. Geisler T, Langer H, Wydymus M, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006;27:2420-5. 47. Bliden KP, DiChiara J, Tantry US, et al. Increased risk in patients with high platelet aggregation on chronic clopidogrel therapy undergoing PCI: is the current antiplatelet therapy adequate? J Am Coll Cardiol 2007;49:657-66. 48. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007;97:282-7. 49. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilatorstimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007;5: 1630-6. 50. Angiolillo DJ, Bernardo E, Sabate M, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007;50:1541-7. 51. Frere C, Cuisset T, Quilici J, et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007;98:838-43. 52. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992-1000. 53. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004;25: 1903-10. 54. Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392-6. 55. Steinhubl SR, Berger PB, Brennan DM, et al, for the CREDO Investigators. Optimal timing for the initiation of pre-treatment with
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56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939-43. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005;111:2560-4. Kandzari DE, Berger PB, Kastrati A, et al, for the ISAR-REACT Study Investigators. Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization. J Am Coll Cardiol 2004;44:2133-6. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) study. Circulation 2005;111: 2099-106. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900- mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation 2005; 112:2946-50. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading-doses in patients with non– ST-elevation acute coronary syndromes: the ALBION trial. J Am Coll Cardiol 2006;48:931-8. Angiolillo DJ, Shoemaker SB, Desai B, et al. A randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease. Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007;115:708-16. von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007;28:1814-9. Angiolillo DJ, Bernardo E, Palazuelos J, et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Thromb Haemost 2008;99:161-8. Angiolillo DJ, Costa MA, Shoemaker S, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol 2008; 101:440-5. Dalby M, Montalescot G, Bal dit Sollier C, et al. Eptifibatide provides additional platelet inhibition in non–ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non–Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study. J Am Coll Cardiol 2004;43:162-8.
Antiplatelet therapy is the current criterion standard for the treatment of patients undergoing percutaneous coronary intervention and patients who have acute coronary syndromes. Clopidogrel in combination with aspirin is the current standard of care for reducing cardiovascular events in these patients. However, patients who receive currently available antiplatelet therapy may still develop atherothrombotic events. In addition, despite the clinical benefits achieved with clopidogrel, significant clinical limitations are associated with its use. This article summarizes the current understanding of the benefits and limitations of the commonly used antiplatelet therapies. (Am Heart J 2008;156:S3-S9.)
Platelets play a pivotal role in the pathophysiology of acute coronary syndromes (ACSs) and the complications after percutaneous coronary intervention (PCI). As a result, platelet-inhibiting drugs are the cornerstone of treatment in these clinical scenarios.1 Currently, 2 oral antiplatelet therapies—the thienopyridines and aspirin—are available for the short- and long-term prevention of atherothrombotic complications in patients who have ACS or are undergoing PCI.2 The use of these agents in clinical practice has significantly improved cardiovascular outcomes. In particular, results from landmark trials have confirmed the clinical benefit of combined thienopyridine and aspirin treatment in high-risk patients.3-8 Despite the fact that dual antiplatelet therapy has resulted in significant advances in the treatment of patients with ACS and those undergoing PCI, a considerable number of patients continue to experience cardiovascular events.9 Thus, the development of antiplatelet therapies with clinical profiles superior to those of currently available agents is warranted.10,11 This article presents an overview of the benefits and limitations of current antiplatelet therapies.
From the Division of Cardiology, University of Florida College of Medicine–Jacksonville, Jacksonville, FL. Conflicts of Interest: Dominick J. Angiolillo, MD, PhD, FACC, FESC has declared the following conflicts of interest: Honoraria/Lectures: Bristol Myers Squibb (New York, NY); Sanofi-Aventis (Bridgewater, NJ); Eli Lilly and Company (Indianapolis, IN); Daiichi Sankyo, Inc (Parsipanny,NJ). Honoraria/Advisory board: Bristol Myers Squibb; SanofiAventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company (Parsipanny,NJ); Portola (San Francisco, CA); Novartis (East Hanover, NJ). Research Grants: GlaxoSmithKline (Brentford, London, United Kingdom); Otsuka (Tokyo, Japan). Luis A. Guzman, MD, FACC, has declared no conflicts of interest. Theodore A. Bass, MD, FACC has declared the following conflicts of interest: Honoraria/Lectures: Eli Lilly and Company; Daiichi Sankyo, Inc. Reprint requests: Dominick J. Angiolillo, MD, PhD, FACC, FESC, Division of Cardiology, University of Florida–Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209. E-mail: [email protected] 0002-8703/free © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.06.003
Dual antiplatelet therapy with thienopyridines and aspirin: benefits Aspirin irreversibly inhibits cyclooxygenase (COX)-1 by acetylating serine 529, thereby inhibiting the production of thromboxane A2, a promoter of platelet aggregation, and prostaglandin I2 (prostacyclin), a potent inhibitor of platelet aggregation and a powerful vasodilator, in platelets and vascular endothelial cells, respectively.12,13 Of note, in the absence of protein synthesis in platelets, thromboxane A2 inhibition persists for the lifetime of the platelet compared with vascular endothelial cells, which recover COX-1 activity shortly after exposure to aspirin. Consequently, antithrombotic, rather than prothrombotic, effects dominate in aspirin-treated patients. Accordingly, aspirin has been shown to play a key role in the secondary prevention of atherothrombotic events.12,13 Although aspirin is a cost-effective therapy, a considerable number of patients who take aspirin continue to experience atherothrombotic complications.14 This has been the reason for the continued search to identify more potent antiplatelet drugs that can be used safely, especially in high-risk patients. About a decade ago, a solution to this problem was thought to have been found with the development of the oral glycoprotein (GP) IIb/IIIa inhibitors. The GP IIb/IIIa inhibitors are very potent antiplatelet agents that inhibit the final common pathway that mediates platelet aggregation.15 Intravenous GP IIb/IIIa inhibitors have proven their efficacy to prevent periprocedural thrombotic complications; but these parenterally administered drugs are not suitable for long-term protection, resulting in the need for oral agents.15 Despite the promising rationale behind the use of oral GP IIb/IIIa inhibitors, clinical trials failed to show any benefit of these agents; and a pooled analysis from trials of oral GP IIb/IIIa antagonists showed increased mortality when these agents were given.16 The need for the blockade of alternative platelet signaling pathways thus emerged. In
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particular, the effects obtained through the combination of aspirin and a family of oral antiplatelet agents known as the thienopyridines, which inhibit platelet activation and aggregation processes through adenosine 5′-diphosphate receptor blockade, became one of the most investigated areas in cardiovascular pharmacology. Thienopyridines inhibit the adenosine 5′-diphosphate P2Y12 receptor.17 Ticlopidine is a first-generation thienopyridine that, in combination with aspirin, enhances platelet inhibition.17,18 This enhanced effect is due to the additive effects on platelet inhibition achieved with the blockade of the COX-1 and P2Y12 pathways.17,18 Dual antiplatelet therapy was first explored in the emerging clinical setting of coronary stenting. In fact, in the initial era of coronary stenting, the antithrombotic regimen of choice for the prevention of stent thrombosis was still not established; and various combinations of antiplatelet agents and anticoagulants were used with elevated complication rates. The lack of a safe and efficacious antithrombotic drug regimen for patients undergoing coronary stenting significantly limited the growth of coronary interventions. Landmark clinical trials demonstrated that, in patients undergoing coronary stenting, better clinical outcomes were achieved with the combined use of aspirin and ticlopidine than with aspirin alone or aspirin plus warfarin.19-22 These results, accompanied by a better knowledge of stent deployment technique,23 played a pivotal role in the growth of coronary stenting. However, there are 2 major limitations with the use of ticlopidine24: its safety profile (ie, ticlopidine leads to elevated rates of neutropenia, thrombocytopenia, rash, and adverse gastrointestinal effects) and its inability to induce platelet inhibition rapidly. This led researchers to pursue the development of an antiplatelet agent with the same beneficial properties of ticlopidine but without its limitations. Thus, clopidogrel, a second-generation thienopyridine, was developed. Today, clopidogrel has largely replaced ticlopidine. Clopidogrel selectively and irreversibly inhibits the P2Y12 receptor.9 It is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 system to generate an active metabolite. In particular, the thiophene ring of clopidogrel is oxidized to form an intermediate metabolite (2-oxo-clopidogrel), which is further oxidized, resulting in the opening of the thiophene ring and the formation of a carboxyl and a thiol group. The reactive thiol group of the active metabolite of clopidogrel forms a disulfide bridge to one or more cysteine residues of the P2Y12 receptor, resulting in its irreversible blockade for the life of the platelet. Thus, P2Y12 receptor blockade occurs early in the cascade of events leading to the formation of the platelet thrombus and effectively inhibits platelet activation and aggregation processes.9 In fact, platelet P2Y12 blockade prevents platelet degranulation and the release
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of prothrombotic and inflammatory mediators from the activated platelet, and also inhibits the transformation of the GP IIb/IIIa receptor to the form that binds fibrinogen and links platelets. The major benefits of clopidogrel over ticlopidine include its better safety profile24 and its ability to yield antiplatelet effects more rapidly through the administration of a loading dose.25 The fact that clopidogrel is well tolerated at high doses makes it possible to achieve antiplatelet effects within hours of administration.25 This has important clinical implications in patients with ACS and PCI, in whom thrombotic occlusions (eg, reinfarction, stent thrombosis) most commonly occur within the first 24 to 48 hours. In addition to the better safety and pharmacodynamic profiles, there is also evidence that the use of this second-generation thienopyridine leads to better clinical outcomes.26 In fact, pooled data from N10,000 patients undergoing PCI showed lower rates of major adverse cardiac events at 30 days after treatment with clopidogrel than after treatment with ticlopidine.26 Overall, the safety, pharmacodynamic, and clinical advantages of clopidogrel have led to its widespread adoption over ticlopidine as the antiplatelet agent of choice in patients undergoing PCI.27 In a head-to-head comparison with aspirin, clopidogrel has been shown to be more effective in reducing the risk for myocardial infarction (MI), ischemic stroke, and vascular death in patients at risk for ischemic events.28 In addition, long-term (up to 12 months) dual antiplatelet therapy with clopidogrel and aspirin is more effective than aspirin alone in preventing major cardiovascular events in patients with ACS, including those treated with PCI.3-5 The long-term clinical benefit associated with dual antiplatelet therapy has been observed overall in patients with non–ST-segment elevation ACS (unstable angina and non–ST-segment elevation MI) independent of coronary revascularization.3 More recently, the spectrum of clinical benefit of clopidogrel has been extended to patients with ST-segment elevation MI, including those undergoing PCI.6-8 On the other hand, results of the CHARISMA trial showed that in 15,603 high-risk but nonacute patients with clinically evident cardiovascular disease or multiple risk factors, long-term treatment (median 28 months) with clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes.29 This study actually showed dual antiplatelet therapy to be harmful in patients without documented atherothrombotic disease (n = 3,284), as these patients had higher mortality, whereas in the subgroup of patients with clinically evident atherothrombosis (n = 12,153), there was a 12% relative risk reduction in event rates with clopidogrel (P = .046).29 Most recently, a subgroup analysis of the CHARISMA trial identified patients who were enrolled with
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Table I. Clinical relevance of inadequate clopidogrel response
Stent thrombosis Muller et al33 Barragan et al34 Gurbel et al35 Ajzenberg et al36 Buonamici et al37
n
Functional parameter
Clinical relevance
105 36 120
↓ Inhibition of platelet aggregation ↑ P2Y12 reactivity ratio ↑ P2Y12 reactivity ratio, ↑ platelet aggregation, ↑ stimulated GP IIb/IIIa expression ↑ Shear-induced platelet aggregation ↑ Platelet aggregation
Stent thrombosis Stent thrombosis Stent thrombosis Stent thrombosis Stent thrombosis
↑ Platelet aggregation (4th quartile) ↑ Platelet aggregation ↑ Platelet aggregation ↑ Platelet aggregation ↑ Clopidogrel/aspirin-resistant patients ↑ Platelet aggregation ↑ Platelet aggregation (3rd and 4th quartiles) ↓ Platelet inhibition ↑ Platelet aggregation ↑ Platelet aggregation ↑ P2Y12 reactivity ratio (2nd through 5th quintiles) ↑ Platelet aggregation (4th quartile) ↑ Platelet aggregation, ↑ P2Y12 reactivity ratio ↑ P2Y12 reactivity units
Post–primary PCI ischemic events (6 m) Post-PCI ischemic events (6 m) Post-PCI myonecrosis/inflammation Post-PCI ischemic events (30 d) Post-PCI myonecrosis Post-PCI ischemic events (30 d) Post-PCI ischemic events (30 d) Post-PCI ischemic events (3 m) Post-PCI ischemic events (12 m) Post-PCI myonecrosis Post-PCI ischemic events (6 m) Ischemic events (24 m) Post-PCI ischemic events (30 d) Post-PCI ischemic events (6 m)
49 804
Post-PCI myonecrosis and ischemic events Matetzky et al38 60 Gurbel et al39 192 Gurbel et al40,41 120 Cuisset et al42 106 Lev et al43 120 Cuisset et al44 292 Hochholzer et al45 802 46 Geisler et al 379 Bliden et al47 100 Cuisset et al48 190 Bonello et al49 144 Angiolillo et al50 173 Frere et al51 195 Price et al52 380
documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease, also known as the CAPRIE-like population (n = 9,478).30 In this subgroup, there was a 17% relative risk reduction in event rates (P = .01) with clopidogrel. Of note, the greatest benefit was observed in patients with prior MI (n = 3,846), in whom there was a 23% relative risk reduction in event rates (P = .031), whereas there were no benefits seen in patients with a history of coronary artery disease but without prior MI. The findings of this study suggest that patients with a greater thrombotic burden (eg, history of plaque rupture and thrombosis) are most likely to derive benefit from an extended duration of dual antiplatelet therapy. However, studies specifically designed for these patients are warranted to test this hypothesis.
Dual antiplatelet therapy with thienopyridines and aspirin: limitations Clinical experience with clopidogrel has supported that benefits are achieved with its adjunctive use in high-risk patients, but has also led to a recognition that clopidogrel has a number of significant limitations. The major limitations of clopidogrel are attributed to its irreversible antiplatelet effects and to the broad variability of platelet inhibition achieved with this agent.9 The first limitation, which is inherent to the family of thienopyridines, is a significant increase in bleeding risk in patients requiring surgery who have not been withheld clopidogrel treatment for at least 5 to 7 days (ie, the life of the platelet). The development of an antiplatelet agent with a reversible
mechanism of action, allowing platelet function to return more rapidly to baseline status, would allow patients to undergo surgery more expeditiously without any increase in bleeding risk.9,11 The second limitation, platelet inhibition variability, may explain why the antiplatelet effects achieved with a loading dose of clopidogrel are not always rapid and why elevated platelet reactivity may persist in some patients despite the adjunctive use of this antiplatelet drug. Although the mechanisms leading to inadequate clopidogrel-induced antiplatelet effects are not fully elucidated, they may include clinical, cellular, and genetic factors.9,31 Furthermore, although the best method of assessing antiplatelet drug response has not been fully established,9,32 it is well known that enhanced platelet reactivity plays a key role in atherothrombotic complications.1,9 Currently, there is sufficient evidence to support the belief that the persistence of enhanced platelet reactivity, despite the use of clopidogrel, is a clinically relevant entity (Table I).33-52 The mechanisms leading to variability are not fully elucidated and are likely multifactorial. These include clinical, cellular, and genetic factors as summarized in Figure 1. A further limitation of clopidogrel is its inefficient conversion to the active metabolite, which may, in part, account for the variable and sometimes inadequate antiplatelet effects of clopidogrel as well as its delayed onset of action.9 The delayed onset of action of clopidogrel is indicated by the minimum of 2 to 4 hours need for achieving its maximal antiplatelet effects, a delay that may have serious consequences for an ACS patient in urgent need of catheterization.5 Approximately 85% of
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Figure 1
Proposed mechanisms leading to variability in individual responsiveness to clopidogrel. (Reprinted from the Journal of the American College of Cardiology, Vol. 49, Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al, Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives, 1505-16, 2007, with permission from Elsevier.9)
the prodrug is hydrolyzed by esterases to an inactive carboxylic acid derivative, with only about 15% metabolized by the cytochrome P450 system in the liver to generate an active metabolite.9 One way to increase the generation of the active metabolite of clopidogrel is to raise the dose of the drug, and numerous studies have focused on the impact of high loading doses of clopidogrel. Most of these studies have compared 300with 600-mg loading dose regimens and have shown that a 600-mg loading dose leads to an earlier, higher, and more sustained (up to 48 hours) inhibition of platelet function, with better response profiles.53,54 This may explain why at least 12 to 15 hours of pretreatment with a 300-mg loading dose is necessary before any clinical benefit can be observed in patients undergoing PCI.55 Using a 600-mg loading dose regimen, full antiplatelet effects are achieved after 2 hours.56 As a result, 600-mg loading doses of clopidogrel have been shown to be equally efficacious if initiated 2 to 24 hours before PCI.57 Despite the broad use of high clopidogrel doses in daily clinical practice, studies assessing high-dose regimens are few; and these regimens still have not been approved by the US Food and Drug Administration. To date, the clinical impact of a 600-mg clopidogrel loading dose has been observed in 2 small studies in patients undergoing PCI, in which pretreatment was shown to be associated
with better clinical outcomes, primarily a reduction in periprocedural MI, when compared with pretreatment with a 300-mg loading dose.44,58 The large (N ≈ 14,000) ongoing CURRENT/OASIS-7 trial has been designed to determine whether high-dose clopidogrel leads to better clinical outcomes than standard-dose clopidogrel in patients with non–ST-segment elevation ACS who are undergoing PCI.9 Patients randomized to the high dose will receive a 600-mg loading dose and then a 150-mg/d maintenance dose from days 2 through 7; patients randomized to the standard dose will receive a 300-mg loading dose and then a 75-mg/d maintenance dose from days 2 through 7. All patients will receive clopidogrel 75 mg/d from days 8 through 30. In addition, all patients will receive aspirin ≥300 mg on day 1 and then be randomized to receive low-dose (75-100 mg) or high-dose (300-325 mg) aspirin. The impact of increasing the loading dose of clopidogrel to 900 mg has been evaluated recently. Although 600- and 900-mg loading doses were associated with greater and faster platelet inhibition than was a 300-mg loading dose, there were no major differences observed between the 600- and 900-mg loading dose regimens.59,60 Thus, although clopidogrel response is dose dependent, there is a threshold, likely attributable to the absorption rate of the drug
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that does not allow enhancement of the platelet inhibitory effects beyond a certain dose.59 Importantly, despite the better degree of platelet inhibition achieved with high loading doses, a broad variability in the effects achieved still persists.53 A higher maintenance dose of clopidogrel (150 mg/d) has also been evaluated; this resulted in enhanced platelet inhibition compared with the standard 75-mg dose,61-63 but the antiplatelet effects achieved remain highly variable, and N50% of patients did not reach the suggested therapeutic targets of P2Y12 inhibition.61,64 The broad variability of antiplatelet effects achieved with clopidogrel points to the need for drugs with more favorable pharmacokinetic and pharmacodynamic profiles.9,11 Indeed, the adjunctive use of a GP IIb/IIIa inhibitor in patients with poor clopidogrel response and in whom more potent platelet inhibition is warranted (ie, high-risk patients) represents a currently available therapeutic option in the acute phase of treatment.40,65 Nevertheless, alternative treatment strategies are needed that can yield rapid and potent inhibition in the acute phase of treatment and guarantee sustained platelet inhibition without wide variability in individual response during the maintenance phase of treatment.9,11
Conclusions The thienopyridines—the first-generation ticlopidine and the second-generation clopidogrel—in combination with aspirin have established antiplatelet therapy as a cornerstone of treatment for patients with ACS and/or undergoing PCI. Thienopyridines prevent thrombotic events and improve clinical outcomes through greater antiplatelet effects than can be achieved with aspirin alone. In landmark randomized trials, ticlopidine, the first commercially available thienopyridine, reduced adverse cardiovascular events in patients undergoing coronary stenting better than aspirin alone or aspirin plus warfarin. Clopidogrel has largely replaced ticlopidine in routine clinical practice based on its superior safety profile and more rapid antiplatelet effects. In head-to-head comparisons with aspirin, clopidogrel was more effective in reducing the risk of MI, ischemic stroke, and vascular death in patients at risk for ischemic events. However, in addition to the wellestablished beneficial effects of combined clopidogrel and aspirin therapy in patients who undergo a PCI, develop ACS, or both, clinical experience with clopidogrel has revealed a number of significant limitations that compromise its utility. These include high interpatient variability in platelet inhibition, an inadequate antiplatelet response, a thienopyridine family–inherent increase in bleeding risk in certain situations (eg, in patients requiring surgery who have not stopped thienopyridine therapy for 5-7 days), and a
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delayed onset of action. The enhanced platelet reactivity that persists despite the use of clopidogrel has been shown to be a clinically relevant entity that plays a critical role in atherothrombotic events. Several novel platelet inhibitors that target the P2Y12 and protease-activated receptor–1 receptors are in advanced clinical testing and have displayed pharmacologic properties and clinical profiles that offer promise for overcoming the shortcomings of clopidogrel. The latest information on the preclinical and clinical profiles of these emerging agents will be presented in other articles in this supplement. We would like to thank MDG Development Group, LLC, for their editorial support in the preparation of this manuscript. This assistance was funded by Daiichi Sankyo, Inc, and Eli Lilly and Company. We did not receive any financial compensation for this work and had final approval of its content.
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