Platelets and New Antiplatelet Drugs

REVIEW

Platelets and new antiplatelet drugs

Rosemarie A Reiter & Platelets play an important, life-saving role in hemostasis and blood clotting at sites of Bernd Jilma† vascular injury. However, unwanted platelet activation and arterial thrombus formation are †Author for correspondence implicated in the onset of myocardial infarction, stroke and other cardiovascular diseases. Medical University of Vienna, Department of Clinical Different mechanisms, such as vascular damage, the development of mural platelet thrombi Pharmacology, Währinger as a response to injury and the biochemical effects of intraplatelet substances that are Gürtel 18–20, A-1090 released in response to damage, may be involved. Thus, antiplatelet therapy has become a Vienna, Austria Tel.: +43 140 400 2981 mainstay of treatment for these conditions and the benefit of antiplatelet drugs is Fax: +43 140 400 2998 documented across a wide spectrum of clinical conditions. Aspirin has been regarded as the [email protected] prototype antiplatelet drug and is still the most widely used agent. Aspirin’s antiplatelet effect is directly due to irreversible inactivation of arachidonic metabolism and suppression of

thromboxane A2 synthesis. However, platelet activation occurs via several pathways that do not rely on amplification by released thromboxane A2. Therefore, a number of other compounds have been developed to complement the beneficial effect of aspirin. Four main classes of antiplatelet agents are currently available for clinical use: aspirin, phosphodiesterase

inhibitors, thienopyridines and the platelet glycoprotein αIIbβ3 receptor antagonists. This review discusses state-of-the-art antiplatelet therapies and recent advances, using aspirin as the reference standard.

Platelets, thrombosis & receptors. Moreover, platelet activation allows atherothrombotic vascular disease interplatelet contact and the formation of plate- Arterial thrombosis rarely occurs in the presence let aggregates. This process is mediated by the of a healthy or undamaged vascular wall of the integrin-αIIbβIIIa (GPIIb/IIIa) complex in the active involvement of endothelial cells, which pro- platelet membrane, which acts as a promiscuous vide a thromboresistant surface for flowing receptor for several ligands such as fibrinogen, blood [1]. Platelet accumulation in the arterial wall vWF and fibronectin [7]. On the surface of the is currently well accepted as a rather early and key activated platelet, the GPIIb/IIIa receptor under- event, both in initiation and perpetuation of goes a conformational change [8], allowing plate- atherosclerotic lesions. lets to bind fibrinogen and thus crosslink, which One of the early events following vascular is important for the final common pathway of injury is the adhesion of circulating platelets to stable platelet aggregation. exposed subendothelium [2]. Both superficial intimal injury, caused by endothelial denuda- Platelet adhesion tion, and deep injury, caused by plaque rupture, Inhibition of GPIb–von Willebrand expose subendothelial collagen and von Wille- factor interaction brand factor (vWF) to platelets of the circulating The initial step of thrombus formation consists blood [3]. Platelet adhesion is mediated by the of platelet adhesion to an injured vessel wall. interaction of platelet glycoprotein (GP)Ib/IX Especially under the high shear-stress conditions receptor with the subendothelial vWF under observed in stenosed coronary arteries, the Keywords: antiplatelet, aspirin, clopidogrel, high shear conditions [4] and by the platelet interaction between platelet GPIb and vWF dipyridamole GPIa/IIa receptor binding to collagen under plays a crucial role in platelet-mediated throm- glycoprotein iib/iiia, both stasis and flow [5]. This further triggers a bus formation [9]. Blocking GPIb [10–13] or vWF prevention, thrombosis network of signaling events inducing the release [14–16] with antibodies results in the inability of and local accumulation of soluble platelet ago- the platelets to attach to the exposed suben- nists (thromboxane [TX]A2, serotonin and ADP dothelium and, thus, the inhibition of the part of and thrombin) [6] and further induces activation GPIb–vWF interaction has focused considera- and aggregation of platelets by activating specific ble attention as an attractive target for the

10.2217/14750708.2.3.465 © 2005 Future Medicine Ltd ISSN 1475-0708 http://www.futuremedicine.com Therapy (2005) 2(3), 465–502 465 REVIEW – Reiter & Jilma

prevention of thrombus formation in stenosed activation and aggregation [24,25]. The binding site arteries [13,16]. Moreover, pharmacologic block- for collagen on vWF is localized to the A3 domain ade of the GPIb–vWF interaction may show a and blocking this domain from binding to colla- lower bleeding risk than GPIIb/IIIa gen by a specific antibody reduced thrombus blockade [13,17]. As shown in a baboon model, growth in vivo and prolonged skin-bleeding time the combination of a low dose of a GPIb inhibi- [26]. Thus, collagen antagonists could be potent tor with a low-dose of a GPIIb/IIIa inhibitor has antiplatelet agents, targeting platelet adhesion by a potent antithrombotic action with minimal inhibiting the collagen–platelet interaction. How- effects on the bleeding time [13]. Given the ever, as reviewed recently, these selective antago- growing awareness of the importance of inflam- nists might have potential limitations as they mation in influencing the outcomes of cardio- could have limited antithrombotic protection in vascular disease [18], GPIb inhibitors that reduce patients with arterial thrombosis [27]. Indeed, it has platelet–leukocyte interactions might have addi- been shown that most patients with acute myocar- tional therapeutic benefits. To summarize, anti- dial infarction (MI) have plaque rupture and non- GPIb and anti-vWF may be useful compounds occlusive thrombus formation up to a week before in the therapy of thrombosis and cardiovascular the clinical event [28] and, thus, collagen antago- disease. However, the clinical use of GPIb inhib- nists might be restricted to specific subsets of itors could be limited by potential pathogenic patients with vascular disease. effects on megakaryocytes [19,20] and antibody- induced thrombocytopenia [11,21] and, moreo- Platelet aggregation ver, only rare data on the use of such inhibitors Aspirin & related cyclooxygenase inhibitors in clinical trials are currently available [22]. or thromboxane antagonists Aspirin Inhibition of collagen–platelet interactions Aspirin has been regarded as the prototype Not only the interaction between platelet GPIb antiplatelet drug, with multiple dose-depend- and vWF but also the interaction between colla- ent therapeutic effects, and is still the most gen and vWF plays a crucial role under conditions widely used and studied agent. Aspirin irrevers- of high shear rates, which is typically found in the ibly inhibits arachidonate cyclooxygenase arteriolar circulation and at sites of arterial stenosis (COX) activity in platelets, thereby reducing [23]. Collagen, the most thrombogenic component the extent of TXA2 formation that occurs after of the extracellular matrix, directly binds to recep- activation of phospholipase A2 and release of tors that mediate platelet adhesion, and induces arachidonic acid (AA) (Figure 1) [29]. However, although aspirin effectively reduces plate- Table 1. Antiplatelet agents. let secretion and aggregation, it is a relatively weak platelet inhibitor [30]. Other platelet-dependent Pathways Agents prothrombotic mechanisms are less affected or not Platelet adhesion modified at all at doses that block platelet-depend- von Willebrand factor GPlb-receptor antibody, von Willebrand ent TX formation. For example, aspirin does not factor antibody inhibit shear stress-induced platelet activation and Platelet aggregation adhesion [31], does not inhibit α-granule secretion Cyclooxygenase pathway in response to ADP and other agonists, and does • Cyclooxygenase Aspirin, NO-aspirin, gingerols not inhibit fibrinogen binding [32,33]. Moreover, • Thromboxane A2 synthase Dazoxiban aspirin usage is associated with potentially life- threatening side effects such as gastric hemorrhage • Thromboxane A2 receptor Vapiprost [34]. Thus, researchers have been encouraged to • Thromboxane synthase and Ridogrel, terbogrel, picotamide investigate and develop new antiplatelet drugs that receptor are equivalent in strength to aspirin, but with • Prostacyclin Beraprost, iloprost, ebaprostanol fewer, or no, adverse events (Table 1). Phosphodiesterase Dipyridamole and cilostazol ADP P2Y12 receptor antagonists and P2Y1 Acute therapy & secondary prevention of receptor antagonists cardiovascular disease & stroke GPllb/llla Murine– human antibodies, synthetic Since the 1950s when it was recognized that aspi- peptide forms and synthetic nonpeptide rin could reduce the incidence of MI [35], multiple, forms randomized, controlled clinical trials have shown a GP: Glycoprotein; NO: Nitric oxide. clinically significant decrease in cardiovascular

466 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Figure 1. Platelet receptors and their antagonists.

Fibrinogen ADP GPIIb/IIIa antagonists

Thienopyridines

Thromboxane A2

αIIbβ3 P2Y12 Thromboxane receptor Gi

Gq Inhibition

G12/13 Activation Asprin Phospholipase C Adenylate of GP ↑ Ca2+ cyclase IIb/IIIa receptor

Arachidonic Thromboxane A2 ↓ cAMP acid

Cyclooxygenase Platelet aggregation Promotion Final common pathway 5´AMP cAMP of platelet of platelet aggregation 5´GMP cGMP aggregation and plug stabilization

Phosphodiesterase inhibitors

Thromboxane A2 is produced from arachidonic acid via cyclooxygenase and is released from the platelet to work with the thromboxane receptor. The thromboxane receptor (a G-protein coupled receptor) causes platelet aggregation via both Gq and G12/13. Aspirin irreversibly inhibits cyclooxygenase, for the lifetime of the platelets, preventing thromboxane production. Phosphodiesterase inhibitors prevent the breakdown of cAMP and cGMP. Therefore cAMP and cGMP levels are maintained inhibiting platelet aggregation. The ADP

P2Y12 receptor (a G-protein coupled receptor) is linked to adenylate cyclase via Gi. Upon stimulation the adenylate cyclase is inhibited, leading to a fall in cAMP and promotion of platelet aggregation. Thienopyridines irreversibly bind to the ADP P2Y12 receptor preventing the inhibition of adenylate cyclase, therefore maintaining cAMP levels and inhibiting platelet aggregation. The GPIIb/IIIa antagonists

prevent fibrinogen binding to the IIbß3 receptors and therefore inhibit the ‘final common pathway of platelet aggregation’. cAMP: Cyclic adenosine monophosphate; cGMP: Cyclic guanosine monophosphate. morbidity and mortality in patients at risk of randomized studies of various antiplatelet recurrent atherothrombotic events [36–39]. regimes, which demonstrated that aspirin caused a The most accurate data regarding the efficacy 25% reduction in cardiovascular outcomes (non- of aspirin comes from the Antiplatelet Trialists’ fatal MI, strokes or vascular death) in patients Collaboration (ATC), a meta-analysis of 287 with pre-existing cardiovascular disease [39]. The

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Second International Study of Infarct Survival less clear. A meta-analysis of five randomized con- (ISIS-2) has established the benefit in acute trolled trials of aspirin for primary prevention MI [36,37]. Patients (n = 17187) with acute MI demonstrated that aspirin was associated with a were randomized to one of four arms of therapy statistically significant, 32%, reduction in the risk consisting of placebo, aspirin, streptokinase or of a first MI and a significant, 15%, reduction in streptokinase plus aspirin. At the end of 5 weeks, the risk of all important vascular events, but had patients receiving aspirin therapy alone had a sig- no significant effects on nonfatal stroke or vascu- nificant (23%) reduction in vascular mortality lar death [46,47]. Interestingly, the absolute benefit and a nearly 50% reduction in the risk of nonfatal of aspirin clearly increases with the risk of cardio- reinfarction and nonfatal stroke. Administration vascular events in the treatment group [48]. Addi- of streptokinase alone was associated with a 25% tionally, aspirin increases the risk for hemorrhagic reduction in vascular deaths, and the combination strokes and major gastrointestinal bleeding [46]. of streptokinase and aspirin was significantly bet- Data regarding the use of aspirin for the primary ter than either agent alone (42% reduction in vas- prevention of strokes in high-risk patients are not cular mortality with combination therapy). encouraging [49,50]. Overall, low-dose aspirin Interestingly, the mortality benefit of combined appears to decrease the risk of MI in men with aspirin and streptokinase therapy was maintained little effect on the risk of stroke. after 10 years’ follow-up [37]. Since three of the previous five primary pre- In contrast to the secondary prevention of MI, vention trials [49–53] exclusively evaluated men, the therapeutic value of aspirin in preventing and fewer than 180 of the 2042 vascular events ischemic stroke is less clear and appears to be occurred in women, the currently published related to the cause and severity of cerebral results of the Women’s Health Study are of ischemia [40–42]. Two large, randomized trials of interest [54]. Indeed, the current recommenda- aspirin use in the setting of acute, ischemic tions for the use of aspirin in primary preven- stroke have demonstrated that the use of aspirin tion in women are based on limited direct data reduces both recurrent stroke and the combined from women [46,55,56] incidence of death or nonfatal stroke In the Women’s Health Study [54] there was a [43,44](Table 2). The relative risk reduction (RRR) nonsignificant RRR of 9% in the primary out- in fatal or nonfatal vascular events was only 10% come of first major cardiovascular events (i.e., in this setting. Accordingly, a meta-analysis MI, nonfatal stroke or death from a cardio- showed a modest 13% RRR of vascular events in vascular event). Regarding the individual end patients with cerebral ischemia of arterial points, women in the aspirin group had a 17% origin [45]. Overall, the benefit of aspirin in acute RRR (p = 0.04) in stroke, compared with the pla- stroke treatment and secondary prevention of cebo group, owing to a 24% RRR of ischemic stroke are definite but modest. stroke (p = 0.009) and a nonsignificant increase in the risk of hemorrhagic stroke. Moreover, aspi- Primary prevention of cardiovascular disease rin therapy was associated with a 22% RRR of & stroke transient ischemic attack (TIA) (p = 0.01) and a Although the beneficial effect of aspirin in the significant 19% RRR of nonfatal stroke secondary prevention of ischemic events is well (p = 0.02). However, compared with placebo, established [39], the role of primary prevention is aspirin had no significant effect on the risk of

Table 2. Trials of aspirin therapy in acute ischemic stroke [48].

End point Chinese acute stroke trial [43] International stroke trial [44] Aspirin (%) No aspirin (%) 2P Aspirin (%) No aspirin (%) 2P Death 3.3 3.9 0.04 9.0 9.4 NS Death and 5.3 5.9 0.03 11.3 12.4 <0.05 nonfatal CVA Recurrent 1.6 2.1 0.01 2.8 3.9 <0.001 CVA Hemorrhagic 1.1 0.9 NS 0.9 0.8 NS CVA Values are given as percentages with the exception of 2P values. CVA: Cerebrovascular accident. NS: Not significant.

468 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

fatal stroke, fatal or nonfatal MI or death from in patients with chronic stable angina (Table 3). cardiovascular causes. In a subgroup analysis, the Low-dose aspirin (75–150 mg) is an effective most consistent benefit of aspirin was observed antiplatelet regimen for long-term prevention of among the subgroup of women 65 years of age or serious vascular events, whereas in clinical situa- older at study entry. This subgroup showed a tions, where an immediate antithrombotic effect 26% RRR (p = 0.008) in major cardiovascular is required (such as acute MI, stroke or unstable events, a 30% RRR (p = 0.05) in ischemic stroke, angina pectoris), a loading dose of at least and a 34% RRR (p = 0.04) in MI. As expected, 150 to 325 mg is recommended [39,48,60,63–65]. For the rates of any gastrointestinal (GI) bleeding primary prevention, no clear indications currently were higher in the aspirin group than in the pla- exist, although low-dose aspirin is recommended, cebo group (4.6 vs. 3.8%, p < 0.001) but without especially in those patients believed to be at high significantly more episodes of fatal GI bleeding. risk for the development of cardiovascular disease In summary, questions remain concerning the and stroke [48,55,61,65]. optimal therapeutic dose of aspirin, and concern- In conclusion, individual trial data shows sub- ing its use in the primary prevention of vascular stantial heterogeneity in the treatment of cardio- disease. Moreover, the reasons for any sex-based vascular/cerebrovascular diseases but the reason differences in the efficacy of aspirin for primary for these differences in aspirin therapy is still prevention are unclear and require further explo- unknown. However, increased platelet-depend- rations. In patients with a relatively low risk of ent TX generation may only occur in a minority developing cardiovascular (or cerebrovascular dis- (30%) of patients with acute ischemic ease), the risk of prophylactic aspirin therapy may stroke [66,67] and a variable importance of TXA2 be outweighed by the risk of hemorrhagic compli- as a mechanism to amplify the hemostatic cation. Conversely, in high-risk patients, the bene- response to plaque destabilization in different fits of therapy may outweigh the risks of clinical settings has been suggested [62]. Thus, one hemorrhagic complications. Indeed, recent stud- may speculate that the TX-mediated amplifica- ies have suggested that the indications for aspirin tion of platelet response to acute vascular injury use should be expanded to primary prevention in plays a more important role in cardiovascular populations at high risk, including diabetes, than in cerebrovascular diseases, which might carotid stenosis, peripheral vascular disease, end- therefore explain the superior benefit of aspirin in stage renal disease [47,57,58] or polycythemia the treatment of cardiovascular diseases. vera [59]. Notwithstanding these results, it remains essential to balance the cardio/cerebrovascular risk Optimal dose of aspirin profile against the risk of potential bleeding com- The overall results of clinical trials in which differ- plications for each patient (irrespective of gender) ent doses of aspirin have been tested indicate that when prescribing aspirin [46,54,60–62]. lower doses of aspirin decrease the prevalence of GI side effects [62]. A direct comparison on the preva- Recommendations for aspirin use lence of GI toxicity among patients using 300 and Overall, aspirin remains the background template 1200 mg aspirin once daily in the UK-TIA therapy, both for acute ischemic syndromes and trial [68] showed that both subjective GI com- secondary prevention after MI, stroke or TIA and plaints and GI bleeding were more frequent at 1200 mg/day than at 300 mg/day. In the 30-mg Table 3. Summary of recommended uses for aspirin. group of the Dutch TIA [69] trial, major bleeding complications (requiring hospital attendance) were Clinical indication Recommended dose slightly less common than in the 300-mg group Acute MI, stroke, or unstable Loading dose of at least 150 mg (RRR 23%) and significantly fewer minor bleeds angina pectoris (up to 325 mg) occurred (RRR 42%). Gastric discomfort or Secondary prevention after MI, Daily therapy with 75–150 mg unspecified side effects were reported significantly nonhemorrhagic stroke, or TIA less often with 30 mg than with 300 mg of aspirin. and in patients with chronic Another study comparing clopidogrel with placebo stable angina on top of a ‘background’ of aspirin therapy (aspirin Primary prevention No clear indication at this time. Consider doses ranging from 75 to 352 mg/day were used in therapy with 75–160 mg/day in patients the Clopidogrel in Unstable angina to prevent believed to be at high risk for the Recurrent ischemic Events [CURE] trial), demon- development of cardiovascular disease. strated that bleeding risk increased with increasing MI: Myocardial infarction; TIA: Transient ischemic attack. aspirin dose, with or without clopidogrel [70]. www.futuremedicine.com 469 REVIEW – Reiter & Jilma

In contrast, the accumulated evidence from inhibit endothelial COX, such as aspirin, may clinical trials makes it clear that aspirin doses reduce the synthesis of vasodilatory PGs. from 75 to 1300 mg do not (generally) alter the Accordingly, the inhibition of COX may clinical benefit [39] (Table 4). For example, The reduce the efficacy of ACE inhibition and Acetylsalicylic Acid and Carotid Endarterectomy therefore the safety of combination therapy trial [71] reported that the risk of the composite with aspirin and ACE inhibitors has been outcome of MI, stroke, or death within questioned because both drugs affect a related three months of carotid endarterectomy was sig- PG-mediated pathway. nificantly lower among patients taking 81 or However, the results of several trials are con- 325 mg aspirin daily than in those taking 625 to troversial concerning the negative interaction of 1300 mg. CURE investigators showed that the the combined therapy of ACE inhibitors with bleeding risk increased with increasing doses of aspirin. Post hoc analysis of two large, multi- aspirin, with or without clopidogrel, but without center trials have suggested that aspirin causes any increase in efficacy [70]. Moreover, aspirin blunting, or even complete abrogation, of the doses of less than 75 mg/day have been less benefit of ACE inhibitors on mortality in widely assessed than those of 75 to 1500 mg/day patients with heart failure [77,78]. In another ret- and seemed to have a somewhat smaller effect at rospective analysis, ACE inhibitors were associ- doses lower than 75 mg/day [39] (Table 4). ated with an increased mortality in patients who Summarizing, any effective antiplatelet dose took aspirin following percutaneous coronary of aspirin is associated with an increased risk of intervention (PCI) [79]. More recently, no evi- bleeding and thus, the individual benefit:risk dence of a negative therapeutic interaction ratio determines the dose of the compound and between aspirin and ACE inhibitors was found use of the lowest effective dose of aspirin (Table 3) in stable patients with chronic heart failure is probably the most rational strategy to related to left-ventricular systolic maximize efficacy and minimize toxicity. dysfunction [80]. Similar interactions have not been found in patients with MI [81,82] and the Negative effects of aspirin on negative hemodynamic effects may be seen with angiotensin-converting enzyme inhibitors high doses of aspirin only. Indeed, several stud- Aspirin and angiotensin-converting enzyme ies have found that a negative interaction with (ACE) inhibitors are widely used in combina- ACE inhibitors is present with high doses of tion to treat a wide spectrum of cardiac disor- aspirin (i.e., 325 mg) [79,83–85], but not with low ders. There is experimental evidence showing doses (i.e., 100 mg) [80,86,87]. Although the con- that ACE inhibitors limit the development of troversy has not yet been resolved, the recom- infarct size, reduce the incidence of ischemic mendation of low-dose aspirin in patients with and reperfusion arrhythmias, and enhance the chronic heart failure seems to be justified [80,88]. recovery of contractile function of stunned myocardium [72]. The cardioprotective effects Nitric oxide-releasing aspirin of ACE inhibitors are mediated by an attenu- As aspirin can cause severe damage to the stom- ated degradation of bradykinin [73,74]. Bradyki- ach, a nitric oxide (NO)-releasing derivate nin, a potent vasodilator on its own, activates (NCX-4016) has been developed that might have vascular endothelial B2-kinin receptors, which clinical promise in the protection from athero- promote the formation of vasodilatory prostag- sclerosis without the unwanted effects on the landins (PGs) through the action of phosphol- stomach. NO protects the gastric mucosa, ipase-A2 and COX [75,76]. Thus, drugs that induces vasodilatation, and inhibits platelet

Table 4. Aspirin doses reducing vascular events in high-risk patients*. Dose of aspirin (mg/day) Number of trials Number of patients Odds reduction‡ (%) <75 3 3.655 13 ± 8 75–150 12 6.776 32 ± 6 160–325 19 26.513 26 ± 3 500–1500 34 22.451 19 ± 3 *Data from Antithrombotic Trialists Collaboration [39]. ‡Data are presented as mean ± standard deviation.

470 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

aggregation, inflammation, cellular proliferation drugs should be used for cardioprotection in the and apoptosis through both a cyclic guanosine absence of evidence from randomized controlled monophosphate (cGMP)-dependent and -inde- trials to lend support to such a practice. The only pendent mechanism [89]. In experimental animal nonaspirin NSAIDs that have been tested for their studies, NO aspirin had antiatherosclerotic and antithrombotic efficacy in randomized trials are antioxidant effects in the arterial wall of hyperc- sulfinpyrazone, indobufen, flurbiprofen and triflu- holesterol mice and inhibited restenosis after PCI sal; however, none of these drugs have been in rats [90,91]. In another rat model, NO-releasing approved as an antiplatelet drug since the overall aspirin reduced brain damage after focal cerebral results of these trials were not satisfactory [39,62]. ischemia, indicating that NO release associated Another interesting point of nonaspirin with aspirin confers neuroprotective effects NSAIDs is the fact that they may interact with the against ischemic injury [92]. cardioprotective effects of aspirin. Based on epide- Recently, a randomized, parallel-group, clini- miologic data, some people have recommended cal trial was designed to assess whether NO- avoiding ibuprofen in patients taking aspirin and releasing aspirin could have broader anti-inflam- suggested that ibuprofen reverses the cardioprotec- matory and antithrombotic effects, as well as tion offered by aspirin [99]. Indeed, results from an better gastric tolerability than aspirin [93]. A total in vivo study demonstrated an interaction between of 48 healthy subjects were randomized to aspirin and ibuprofen on platelet function, but no receive NO-releasing aspirin 800 mg twice daily, such interaction was reported with rofecoxib, NO-releasing aspirin mg twice daily plus aspirin paracetamol or diclofenac [100]. The hypothesis 325 mg, aspirin 325 mg, or placebo for 21 days. that ibuprofen may interact with the cardio- In this study, NO-releasing aspirin was equally protective effects of aspirin, at least in patients effective as aspirin in inhibiting COX activity with established cardiovascular disease, is a theory but caused less gastric damage. These beneficial that has been supported by the findings of a effects of NO-releasing aspirin, combined with recently published trial [101]. This study involved the inhibition of TXA2, are very interesting. As 7107 patients who received aspirin alone, aspirin atherogenesis and plaque rupture are points on and ibuprofen, aspirin plus diclofenac or aspirin the continuum of vascular inflammation, one plus other NSAIDs. Patients in the aspirin plus may speculate that the NO aspirin, NCX-4016, ibuprofen group had a significantly higher risk of could be superior to aspirin in the primary and all-cause mortality (p = 0.0011) and cardiovascu- secondary prevention of vascular events and in lar mortality (p = 0.0305) than those in the aspi- gastric tolerability. Furthermore, NO-releasing rin-alone group. No such increased risk was noted aspirin may offer an attractive alternative in in users of aspirin plus diclofenac or aspirin plus patients in whom COX inhibition with aspirin other NSAIDs. may be poorly tolerated. Thus, larger multi- However, as reviewed very recently [102] no center clinical trials are warranted in order to randomized, controlled trials addressing this par- establish the clinical efficacy and safety of the ticular issue exist at the moment and the data NO-releasing aspirin, NCX-4016. obtained from observational and epidemiologic studies are conflicting and limited. Nonaspirin, nonsteroidal anti-inflammatory drugs in cardiovascular disease Cyclooxygenase-2 inhibitors in Although a variety of traditional nonsteroidal anti- cardiovascular disease inflammatory drugs (NSAIDs) can inhibit TXA2- Selective COX-2 inhibitors (coxibs) differ from dependent platelet function through competitive, traditional NSAIDs in two major ways. Coxibs are reversible inhibition of COX-1 the effects of these less likely to result in NSAID-induced gastropathy, NSAIDs on cardiovascular disease are controver- and they do not inhibit platelet function [103,104]. sial. An excellent review has recently been pub- The major benefits of coxibs are the reduction in lished that addresses this problem [62]. For gastric ulcer formation and bleeding from those instance, naproxen was shown to have a protective ulcers, as reported by the VIoxx Gastrointestinal effect against acute MI [94] and to reduce the risk of Outcomes Research (VIGOR) trial [105]. Another thromboembolic cardiovascular events among benefit of the platelet-sparing coxibs is their use as patients with rheumatoid arthritis [95]. However, analgesics and anti-inflammatory agents in other population-based studies [96–98] have failed to situations in which bleeding may limit the use of detect protective effects of naproxen or other non- traditional NSAIDs, such as trauma and surgical aspirin NSAIDs, considering that none of these procedures [106,107]. Otherwise, coxibs are www.futuremedicine.com 471 REVIEW – Reiter & Jilma

supposed to have several effects that could increase Drug Administration (FDA), demonstrated an the risk of cardiovascular disease, including a increase in cardiovascular events among patients decrease in prostacyclin levels, increasing blood receiving celecoxib [401]. pressure, decreasing angiogenesis and destabilizing Summarizing, since different coxibs were found plaque [108]. to be associated with cardiovascular complica- Recently, this class of drugs has come under tions, it appears that this is a class effect. The risk scrutiny due to clinical reports of an associated of serious cardiovascular events will need to be increased risk of serious cardiovascular weighed against any potential benefits of coxibs in events [109,110]. As reported in the VIGOR trial, preventing colorectal neoplasia and in relieving there were more cardiovascular events among pain. The lesson to be learnt from this observation patients given a high dose of rofecoxib than among has been discussed very recently [119]. those patients given naproxen, a nonselective NSAID with platelet-inhibiting properties of Aspirin-related drugs unclear clinical relevance [105]. In contrast, pooled Given the presumed understanding of aspirin’s data from other randomized trials have not shown mode of antiplatelet effect, it should be possible to a significant difference in cardiovascular risk design a more specific drug to interfere with the between rofecoxib and placebo or other nonselec- COX/TX pathway. Aspirin, by nonselectively tive NSAIDs [111–113]. Indeed, most of the earlier blocking COX both in platelets and in endothelial trials of coxibs did not appear to show an increase cells, not only inhibits the TXA2 pathway of in cardiovascular events [114–116]; however, these platelet activation but, at the same time, also the trials were generally short-term studies designed to generation of vasodilating and platelet-inhibitory assess the use of this class of drug for pain relief and prostanoids, such as PGI2 (or prostacyclin), by the to evaluate associated adverse GI events. endothelial cells. This is of importance because Overall, studies have provided conflicting data there is an increased intravascular prostacyclin on the association of coxibs with cardiovascular generation in patients at advanced stages of risk but only limited long-term data have been atherosclerosis, which is paralleled by the degree available for analysis so far. However, this obser- of platelet activation [120]. Even 40-mg doses of vation has been changed since the results of aspirin are sufficient to inhibit the local produc- three long-term trials have recently been tion of antithrombotic PG generation in the published [108,117,118]. The Adenomatous Polyp blood vessels of atherosclerotic patients [121]. This PRevention On Vioxx (APPROVe) study, which appears to be a limitation to the antithrombotic was designed to determine the effect of 3 years’ efficacy of aspirin and was one of the reasons to treatment with rofecoxib on the risk of recurrent look for alternatives, specifically, more selective neoplastic polyps among patients with a history inhibitors of TX formation and action. of colorectal adenomas, showed an increased car- diovascular risk associated with the long-term Agents interfering directly with thromboxane use of rofecoxib [108]. The Coronary Artery formation &/or action Bypass Grafting (CABG) surgery study showed TX synthase inhibitors and TX receptor antago- that cardiovascular events (including MI, cardiac nists directly interfere with TX formation (syn- arrest, stoke and pulmonary embolism) were thase inhibitors) and action (receptor blockers). more frequent among the patients given TX synthase inhibitors do not reduce vascular parecoxib and valdecoxib than among those PGI2 formation but enhance it by shifting accu- given placebo (2 vs. 5%; risk ratio: 3.7; p = 0.03) mulating PG endoperoxidase into this pathway [118] . The Adenoma Prevention with Celecoxib [122]. In fact, TX synthase inhibitors and TX (APC) study reviewed all potentially serious car- receptor blockers have been demonstrated to diovascular events among 2035 patients with a exhibit potent antithrombotic effects in several history of colorectal neoplasia who were enrolled animal studies [123–129]. In general, inhibition of in a trial comparing two doses of celecoxib TX synthase appears to be more efficient than (200 and 400 mg twice daily) with placebo for the blockade of TX receptors [126,130]. To sum- the prevention of colorectal adenomas [117]. marize, all of these data suggest that the selective There was a dose-related increase in cardiovascu- inhibition of TX synthase, in particular if com- lar events for celecoxib when compared with pla- bined with the blockade of TX receptors, would cebo. Of interest, the results of a randomized, be a useful approach to antiplatelet therapy. controlled clinical trial of celecoxib with Alzhe- Picotamide, a dual TXA2 synthase inhibi- imer’s disease, reported to the US Food and tor/receptor antagonist, slowed the evolution of

472 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

early carotid lesions in a controlled study in dia- smooth muscle proliferation [143]. Thus, one may betic patients [131]. However, more well-proven speculate that this class of drugs could also have randomized controlled trials are required to fur- therapeutic potential in the treatment of cardio- ther investigate the possible benefit of picota- vascular or cerebrovascular diseases. mide in preventing the formation of arterial The PGI2 analog iloprost was, however, una- thrombus in such patients. ble to prevent reocclusions of stenosed dog coro- The Coronary Artery Restenosis Prevention nary arteries after electrical injury or On Repeated Thromboxane–antagonism (CAR- thrombolysis [144]. This could be due to receptor PORT) study compared the TX receptor antago- desensitization owing to high levels of PGI2. nist vapiprost with aspirin in patients Importantly, platelet receptors may become undergoing percutaneous transluminal coronary downregulated if there is a significant increase in angioplasty (PTCA). After a 6-month follow-up PGI2 production, for example, in unstable period, no effect on the incidence of restenosis angina and acute MI [145,146]. Moreover, only a was observed [132]. small number of larger clinical trials with PGI2- The combined TX synthase inhibitor and TX related compounds [147,148] exist and the results, receptor antagonist, ridogrel, was compared with in general, were not encouraging. In a more aspirin in patients with acute MI receiving recent study the orally active PGI2 analog, berap- streptokinase in the Ridogrel versus Aspirin rost, was compared with placebo in patients with Patient Trial (RAPT) [133]. Ridogrel was not intermittent claudication [149]. Although the superior to aspirin in enhancing the fibrinolytic incidence of critical cardiovascular events was efficacy of streptokinase, although there was a not significantly reduced in those patients lower rate of new ischemic events noted in a assigned to beraprost, there was a significant post hoc analysis. reduction in the combination of cardiovascular Moreover, terbogrel, another combined TX death and MI. Critical cardiovascular events synthase inhibitor/receptor antagonist failed to were defined as: live up to expectations in a trial of patients with • Death of cardiovascular origin, nonfatal MI or primary pulmonary hypertension [134]. Although unstable angina terbogrel was able to reduce TX metabolism by • Stroke or TIA 98% with a modest, but statistically insignificant • Critical leg ischemia, subacute critical (39%) rise in PGI2 metabolites, it was associated with severe leg pain, thus limiting its clinical ischemia, peripheral angioplasty, peripheral utility. In contrast, another study of TX synthase bypass surgery or amputation at any level inhibition in patients with primary pulmonary Nonetheless, judgements on whether PGI2 disease did not describe leg pain as a side analogs could have potential beneficial cardiopro- effect [135] and, in a recently published trial, ter- tective effects should not be made from this one bogrel was shown to be well tolerated without trial. Moreover, major problems include the obvious adverse effects in healthy receptor-mediated nature of response and the low volunteers [136]. selectivity for the platelet, which may result in In summary, despite showing considerable nonspecific effects, for example hypotension [122]. promise in preclinical studies, TX synthase To summarize, the future of these drugs as a inhibitors and TX receptor antagonists have possible potential new approach to the treatment been disappointing in clinical trials and have of vascular diseases is, indeed, questionable. not demonstrated a benefit over aspirin. There- fore, these newer drugs could provide an alter- Gingerols & related analogs native approach to antiplatelet therapy, but Gingerols, the active components of ginger (the more clinical trials are required. rhizome of Zingiber officinale, Roscoe), were shown to selectively inhibit secondary platelet Prostacyclin-related agents activation and ATP release from platelets in PGI2, known to have potent antiplatelet and human platelet-rich plasma, which is due to vasodilatatory activities [137], occurs naturally in inhibition of AA metabolism and COX the vascular endothelium and has been approved activity [150]. Gingerols and other synthetic ana- by the FDA for the management of pulmonary logs were also shown to have a strong COX-1 artery hypertension [138–140]. PGI2 relaxes vascu- inhibitory activity in rat basophilic leukemia lar smooth muscle [141,142], inhibits platelet cells [151], a cell line with COX-1 expression [152]. aggregation [141,142] and also suppresses vascular More recently, the inhibition of AA-induced www.futuremedicine.com 473 REVIEW – Reiter & Jilma

platelet activation in human blood was studied. For Effectively avoiding Second Strokes trial Gingerol and gingerol analogs dose-dependently (PRoFESS) [161]. Irrespective of the outcome of inhibited COX-1 activity and the COX-1 inhib- this study, there is one major limitation in the itory effect of these substances was more potent design of the PRoFESS study, as the two treat- than aspirin [153]. In a rat model, ginger extract ment arms will not be compared against aspirin. and other ginger preparations showed antiulcer This aspect is important since the evidence of the activity [154,155]. Thus, these substances could be superiority of aspirin/ERDP over aspirin alone useful well-tolerated platelet activation inhibi- hinges on a single trial. Moreover, in high-risk tors; however, data on these substances are rare patients with recent TIA or ischemic stroke, and additional experiments are needed to gain a clopidogrel plus aspirin was not superior to clopi- better insight into the effect of platelet inhibition dogrel alone, as demonstrated in the Manage- by gingerols. ment of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic Phosphodiesterase inhibitors stroke (MATCH) study, but was not compared Dipyridamole with aspirin alone. Thus, the results of the PRo- Both the inhibition of cyclic nucleotide FESS trial will not enable a judgement to be phosphodiesterase (PDE) (the enzyme that made on the benefits of a combination of differ- degrades cyclic adenosine monophosphate ent antiplatelet drugs as a therapeutic approach [cAMP] to 5´-AMP, resulting in the intraplatelet for patients with cerebrovascular diseases. accumulation of cAMP, a platelet inhibitor) and In conclusion, aspirin/ERDP has been FDA the blockade of the uptake of adenosine (which approved and is usually classified as a potential acts at A2 receptors for adenosine to stimulate first-line therapy in the secondary prevention of platelet adenyl cyclase and, thus, increases the ischemic stroke and TIA, especially in patients level of cAMP), have been suggested [156]. More- with lower cardiovascular comorbidity [162,163] but over, dipyridamole blocks the enzyme cGMP the current feeling is that there is not yet sufficient PDE, thereby inhibiting the breakdown of evidence to justify adoption of aspirin and dipyri- cGMP (Figure 1)[157]. Raised levels of cAMP and damole as a first-line treatment for the secondary cGMP within platelets potentiate inherent prevention of stroke. Thus, aspirin should be the mechanisms, resulting in vasodilatation and first-line antiplatelet therapy in the secondary pre- inhibition of aggregation [158]. vention of stroke and TIA [39,164,165] (Table 3) until prospective, randomized clinical trials have shown Dipyridamole in cerebrovascular disease a sustained benefit of aspirin/ERDP or clopidog- Dipyridamole appears to have similar efficacy to rel plus aspirin over the gold-standard treatment low-dose aspirin in preventing stroke [159]. In with aspirin. patients with cerebrovascular disease, the Euro- pean Stroke Prevention Study (ESPS)-2 demon- Dipyridamole & coronary artery steal strated that the combination of low-dose aspirin Perfusion imaging during coronary vasodilata- (50 mg daily) and extended-release dipyridamole tion with either adenosine or dipyridamole is (ERDP) (400 mg daily) was superior in prevent- widely used for the diagnosis of coronary artery ing nonfatal stroke than either drug alone [159]. disease (CAD) [166–168]. Dipyridamole, admin- However, comparing dipyridamole plus aspirin istered intravenously, represents a well-estab- with aspirin alone was associated with only a lished medication that induces dilatation of nonsignificant reduction in serious vascular coronary arteries by inhibiting the degradation events [39,160]. Indeed, the apparent reduction in of adenosine. nonfatal stroke was derived mainly from the Vasodilatation in nonischemic regions can ESPS-2 study but this result was not supported divert blood from already underperfused by the findings for nonfatal stroke in other stud- regions to parallel-perfused regions where the ies or by the overall findings for nonfatal MI or vasodilator reserve has not been exhausted vascular death [39]. Finally, headaches limited the (coronary steal) [169]. Coronary steal has been use of aspirin/ERDP as they occurred in 37% of well described in canine studies of CAD after treated patients in the ESPS-2 study and resulted intravenous dipyridamole [170]. Moreover, in a high rate of noncompliance. myocardial ischemia due to coronary steal is Currently, aspirin/ERDP is being compared generally believed to be manifested clinically with clopidogrel in the largest ever secondary by ST segment depression following coronary stroke-prevention trial: the Prevention Regimen vasodilatation [171,172].

474 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Indeed, there are some reports concerning proliferation was greater in the cilostazol than in patients who developed angina pectoris manifested the ticlopidine group [192]. Moreover, a meta-anal- by ischemic electrocardiographic changes and per- ysis of five clinical studies comparing cilostazol fusion defects, which occurred after dipyridamole (plus aspirin) with ticlopidine (plus aspirin) administration [173–175]. Moreover, a significant showed no difference regarding the effectiveness difference on coronary angiography between and safety for a 1-month period when used as an patients with dipyridamole-induced angina pec- adjunctive therapy after coronary stenting [193]. toris and those without angina pectoris was found Despite the obvious beneficial effect of cilosta- in the presence of collaterals (p < 0.05) [173]. zol in these clinical settings, there may be con- Therefore, it has been suggested that angina pec- cerns regarding the study designs of these trials. toris during dipyridamole stress test is due to Indeed, these trials were single-center studies ischemia, which is not related to the severity of with a relatively small number of patients [186–192] CAD but is probably owing to coronary steal to and some of them were not randomized [190] or the collateralized territory in patients without double blinded [188,192]. Thus, large-scale, multi- transmural MI. Thus, dipyridamole-induced center, randomized trials are needed to confirm angina pectoris could be predictive for collaterals the efficacy of cilostazol in other patients groups and may indicate viability in patients with MI [173]. of different ethnicity. Overall, since dipyridamole has a vasodilatatory In animal studies, cilostazol was shown to effect, it should be used with caution in patients decrease ischemic brain infarction [194–196]. In a with severe CAD (e.g., unstable angina and MI) recently published study of guinea pig and and chest pain may be aggravated in patients human cerebral arteries, it has been suggested underlying CAD who are receiving dipyridamole. that cilostazol is still effective under conditions with possible dysfunctional NO-cGMP path- Cilostazol way, such as in ischemic stroke or cerebral vasos- Cilostazol, a potent inhibitor of platelet aggrega- pasm [197]. Thus, it is of interest whether this tion [176] with vasodilating properties, inhibits drug could also have therapeutic potential in cAMP-selective PDE-III [177], thereby increasing patients with cerebrovascular disorders. the intracellular level of cAMP. Cilostazol revers- In a previous report [185], it could be demon- ibly inhibits platelet aggregation induced by a strated that cilostazol prevented the progression variety of stimuli, including thrombin, ADP, col- of carotid intima thickness in patients with lagen, AA, epinephrine and shear stress [178]. Type II diabetes mellitus. The group without Cilostazol has also been shown to be a potent cilostazol had a significant increase in infarct-like antiplatelet agent with antiproliferative proper- lesions which was positively correlated with the ties [179], that increases peripheral blood flow [180] intima media thickness. The intima media thick- and ameliorates insulin resistance [181,182]. Thus, ness of the carotid artery is used as a surrogate of it has been suggested that cilostazol could pre- definite atherosclerosis with a high risk of vascu- vent both thrombosis and restenosis after coro- lar events [198–200]. The results of a secondary nary stenting when coadministered with prevention study using cilostazol 200 mg/day aspirin [183,184] but it could also be effective in showed a reduction of stroke by 43.3% com- the primary prevention of ischemic stroke in pared with the placebo group [201]. However, subjects with Type II diabetes mellitus [185]. cilostazol was compared with placebo without Several reports have demonstrated that cilosta- administering a standard antiplatelet therapy. zol can prevent subacute thrombosis after stent Indeed, as this was a secondary prevention study implantation and may reduce restenosis after coro- of patients (n = 1052) who suffered from cere- nary interventions [186–189]. As reported [190], after bral infarction 1 to 6 months prior to enrolment, coronary angioplasty, the restenosis rate was signif- this appears inadequate. As the place of aspirin in icantly lower in groups with cilostazol than in the secondary prevention of stroke/TIA has been groups with aspirin or ticlopidine. Moreover, established to the satisfaction of most cilostazol has been shown to have an outstanding authors [39,164,165,202], the design of this study has effect on the prevention of acute or subacute to be criticised. Moreover, the antithrombotic thrombotic complication after coronary stenting, effects of cilostazol after stent implantation may equal to ticlopidine [191]. A very recent study dem- be somewhat overstated, particularly with drug- onstrated that ticlopidine showed significantly less eluting stents. Indeed, patients receiving cilosta- subacute thrombosis after stenting compared with zol had more acute/subacute stent thrombosis cilostazol but the inhibition of neointimal compared with those receiving clopidogrel. www.futuremedicine.com 475 REVIEW – Reiter & Jilma

Taken together, cilostazol has been routinely Agents interfering with ADP-mediated used as an antithrombotic agent for the treatment platelet reactions of peripheral arterial occlusive disease in Japan Thienopyridines (ticlopidine & clopidogrel) and some Asian countries for more than 15 years ADP is an important platelet agonist, which [203,204] and a new indication for stroke preven- activates platelets by binding to purinergic tion has been recently approved in Japan [204]. In receptors on the platelet surface. There are contrast, cilostazol has been available for the three recognized subtypes of P2 receptors on treatment of intermittent claudication in the platelet membranes, namely P2X1, Y1 and USA since 1999 and in the UK since 2000 [204] Y12 [208–210]. The latter is the target of the but is not generally considered an antithrombotic antiplatelet thienopyridines, ticlopidine and agent in Western countries, perhaps due to the clopidogrel [211,212]. Both drugs selectively bulk of its antithrombotic preclinical and clinical inhibit ADP-induced platelet aggregation with development being conducted in Japan. no direct effects on AA metabolism (Figure 1) [213]. While not studied as extensively Phosphodiesterase inhibitors in perspective as aspirin, several clinical trials have confirmed NSP-513 is a novel selective PDE-III inhibitor the ability of thienopyridines to reduce cardio- on PDE isozyme activities and in vitro platelet vascular events in patients with several different aggregation and in vivo thrombus formation types of cardiovascular disease (Table 5) [214,215]. were investigated as reported recently [205]. Moreover, ticlopidine has been established as an NSP-513 selectively inhibited human platelet alternative to aspirin in the prevention of recur- PDE-III isozyme in vitro. In a mouse pulmonary rent cerebral ischemia and stroke [216] but its thromboembolism model, orally administered use has been limited due to potentially detri- NSP-513 showed in vivo antithrombotic effects mental side effects, including fatal severe neu- that were 320- to 470-times more potent than tropenia and thrombotic thrombocytopenic those of cilostazol. In a rat carotid arterial throm- purpura [217] as well as aplastic anemia [218]. As a bosis model, intraduodenally administered result, it has been replaced by clopidogrel NSP-513, cilostazol and aspirin reduced throm- [62,214,219]. Indeed, clopidogrel has become a bus formation by 75, 66 and 48%, respectively. mainstay in antiplatelet therapy [99,220,221] and In contrast, intravenously administered dipyrid- several studies have been preformed using this amole did not significantly prevent thrombus drug (Table 5). formation and therefore NSP-513 is suggested to have the potential to prevent, not only in vitro Clinical studies of patients with vascular diseases, platelet aggregation, but also in vivo thrombus particularly patients with cardiovascular diseases formation. Of interest, this study shows that the The Clopidogrel versus Aspirin in Patients at antiplatelet and antithrombotic activities of Risk of Ischemic Events (CAPRIE) trial, involv- NSP-513 are greater than those of cilostazol, ing 19185 subjects, was the first randomized, dipyridamole or aspirin, thus, may have thera- double-blinded, international trial to evaluate the peutic potential in the treatment of arterial efficacy of aspirin 325 mg once daily versus clopi- thrombotic disorders. dogrel 75 mg once daily in patients with recent KW-7, a new inhibitor of cyclic nucleotide ischemic stroke or MI, or established peripheral PDE, was shown to inhibit cAMP- and cGMP- disease [214]. An intent-to-treat analysis of all ran- PDE activities as well as AA-stimulated TXA2 domized patients showed a modest 8.7% RRR production [206]. This was associated with an (p = 0.043) in the primary outcome of stroke, MI increase in PGD2 levels, indicating that KW-7 is or vascular death. Interestingly, in a subgroup also an inhibitor of TX synthase. In a very recent analysis, patients with peripheral arterial disease study, it was demonstrated that cilostazol and derived the greatest benefit from the drug dipyridamole synergistically inhibited platelet (RRR: 23.8%; p = 0.0028) whereas a nonsignifi- aggregation in vitro and ex vivo, compared with cant 7.3% RRR in patients with stroke and a treatment with either drug alone [207]. Although nonsignificant 3.7% risk increase in the primary the dual inhibition of KW-7 on PDE and TX outcome of patients with MI was obtained. Over- synthase and the combination of cilostazol and all, the safety and tolerability of clopidogrel and dipyridamole might provide an attractive target in aspirin were similar and, therefore, clopidogrel developing new antiplatelet drugs, only few data was established as an alternative antiplatelet to exist and no data on the use of such inhibitors in aspirin for secondary prevention across a wide clinical trials are currently available. spectrum of patients with vascular disease.

476 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Table 5. Clinical studies of dual antiplatelet therapy with clopidogrel Trial Patients Subjects Treatment Primary end point Result Ref. (n)

CLASSICS Patients 1020 Clopidogrel loading dose Major peripheral or 50% RRR in the occurrence [219] after 300 mg + 325 mg aspirin, bleeding complications, of primary endpoint in favor coronary followed by clopidogrel neutropenia, of clopidogrel stenting 75 mg/day + aspirin thrombocytopenia or (p = 0.005) 325 mg/day vs. early discontinuation of clopidogrel 75 mg/day study drug as the result + aspirin 325 mg/day of noncardiac adverse vs. ticlopidine 250 mg event during the study twice daily + aspirin treatment period 325 mg/day CREDO Patients 2116 Clopidogrel loading dose 1-year incidence of the Following PCI, long-term [224] undergoing 300 mg (Group A) or composite of death, MI clopidogrel therapy PCI placebo (Group B) before or stoke in the intent- significantly reduced the PCI plus aspirin to-treat population and risk of ischemic events 325 mg/day 28-day incidence of the (27% RRR; p = 0.02) (Group A + Group B), composite of death, MI, A loading dose of followed by or urgent target-vessel clopidogrel given before Group A: clopidogrel revascularization in the PCI did not reduce 75 mg/day + aspirin per-protocol population ischemic events at 28 days 325 mg/day for 12 (18.5% RRR; p = 0.23). months However, a subgroup of vs. Group B: clopidogrel patients receiving 75mg/day for 28 days; clopidogrel >6 h before from day 29 through 12 PCI experienced a 38.6% months placebo + aspirin RRR (p = 0.051) compared 325 mg/day for 12 with no reduction in months patients receiving clopidogrel less than 6 h before PCI. CURE Unstable 12562 Clopidogrel loading dose Composite of 20% RRR in ischemic events [222] angina or 300 mg, followed by cardiovascular death, in favour of clopidogrel non-ST clopidogrel 75mg/day MI or stroke and the (p < 0.001) segment + aspirin 325 mg/day, composite of There were significantly elevation vs. placebo loading dose, cardiovascular death, more patients with major MI followed by placebo MI, stroke or refractory bleeding in the clopidogrel + aspirin 325 mg/day ischemia group than in the placebo group (3.7 vs 2.7%, 1.38 RRR; p < 0.001) but there were not significantly more patients with episodes of life-threatening bleeding (2.1 vs 1.8%; p = 0.13) or hemorrhagic strokes.

CREDO: Clopidogrel for Reduction of Events During Observation trial; CURE: Clopidogrel in Unstable angina to prevent Recurrent Events trial; MATCH: Management of Atherothrombosis with clopidogrel in high-risk patients with recent Transient isCHemic attacks or ischemic stroke trial; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PCI-CURE: Percutaneous coronary intervention – Clopidogrel in Unstable angina to prevent Recurrent Events trial; RRR: Relative risk reduction.

www.futuremedicine.com 477 REVIEW – Reiter & Jilma

Table 5. Clinical studies of dual antiplatelet therapy with clopidogrel (Cont.). Trial Patients Subjects Treatment Primary end point Result Ref. (n)

PCI-CURE Subset of 2658 Clopidogrel loading dose Composite of 30% RRR in ischemic events [70] CURE 300 mg, followed by cardiovascular death, from PCI to 30 days in favor undergoing clopidogrel 75 mg/day + MI or urgent target- of clopidogrel (p = 0.03). PCI aspirin 325 mg/day vessel revascularization Overall (including ischemic vs placebo loading dose, within 30 days of PCI events before and after PCI) followed by placebo + there was a 31% RRR in aspirin 325 mg/day cardiovascular death or MI After PCI, patients (p = 0.002) received either clopidogrel or ticlopidine + aspirin for 2 to 4 weeks, after which administration of the randomly assigned study medication was started until the end of the scheduled follow-up MATCH Recent 7599 Clopidogrel 75 mg/day First reoccurrence of There was a nonsignificant [225] ischemic + aspirin 75 mg/day ischemic stroke, MI, 6.4% RRR in the primary stroke or vs clopidogrel 75 mg/day vascular death or endpoint when adding transient + placebo rehospitalisation for an aspirin to clopidogrel ischemic acute ischemic event (p = 0.244). attack with Adding aspirin to at least one clopidogrel was associated additional with increased life-threating vascular bleedings (absolute risk risk factor increase 1.26%; p < 0.0001) and increased major bleeding (absolute risk increase 1.36%; p < 0.0001). No difference between groups was recorded in mortality. CREDO: Clopidogrel for Reduction of Events During Observation trial; CURE: Clopidogrel in Unstable angina to prevent Recurrent Events trial; MATCH: Management of Atherothrombosis with clopidogrel in high-risk patients with recent Transient isCHemic attacks or ischemic stroke trial; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PCI-CURE: Percutaneous coronary intervention – Clopidogrel in Unstable angina to prevent Recurrent Events trial; RRR: Relative risk reduction.

Moreover, CLASSICS demonstrated the supe- There was a RRR of 20% in (9.3% patients in rior efficacy and safety of clopidogrel plus aspirin the clopidogrel group vs. 11.4% in the placebo compared with ticlopidine plus aspirin in group; p < 0.001) in the composite primary out- patients undergoing coronary stenting [219]. This come of death from cardiovascular causes, non- was the first randomized trial of clopidogrel in fatal MI or stroke. The rates of bleeding were coronary stenting and the first study to evaluate higher in the clopidogrel group than in the pla- clopidogrel–aspirin combination therapy and a cebo group (3.7 vs. 2.7%; p = 0.001), but there loading dose of clopidogrel. were not significantly more episodes of life- The CURE trial investigated the effect of threatening bleeding. The PCI-CURE, a sub- clopidogrel combined with aspirin in the treat- study of CURE, showed that the benefit of ment of patients with acute coronary syndromes clopidogrel over placebo was also seen in patients (ACSs) that included unstable angina and MI receiving PCI [70]. Overall, there was a 31% without ST-segment elevation [222]. A total of reduction in cardiovascular death or MI 12562 patients presenting within 24 h after the (p = 0.002). Moreover, a meta-analysis of ten onset of symptoms received clopidogrel (300 mg studies, comparing clopidogrel plus aspirin ver- immediately, followed by 75 mg once daily) or sus ticlopidine plus aspirin after coronary stent- placebo in addition to aspirin for 3 to 12 months. ing demonstrated that clopidogrel, in addition to

478 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

better tolerability and fewer side effects, is at The results of this study are of interest, as the RRR least as effective as ticlopidine in reducing in a subgroup analysis for stroke alone was not sig- 30-day major adverse cardiac events [223]. Thus, nificant in the CAPRIE study [214]. However, the clopidogrel plus aspirin should replace ticlo- CAPRIE study was not designed to specifically pidine plus aspirin as the standard antiplatelet address patients who had cerebrovascular disease. regimen after stent deployment. Indeed, the The MATCH trial showed a nonsignificant combination of aspirin and clopidogrel has RRR of 6.4% (16% patients in the clopidogrel become standard treatment up to 12 months and aspirin arm vs. 17% patients in the clopi- after coronary stent implantation [99]. dogrel-only arm; p = 0.244) in the composite The CREDO trial was designed to evaluate primary outcome of ischemic stroke, MI, vascu- the benefit of clopidogrel pretreatment and lar death, or rehospitalization for an acute long-term therapy to a more stable population ischemic event. The 6.4% RRR in favor of aspi- undergoing coronary stenting [224]. Patients rin plus clopidogrel in the intent-to-treat-analy- receiving 1 year instead of 1 month of clopidog- sis among all randomized patients is in the range rel showed a significant 27% RRR in the com- that was reported about the stroke subgroup posite of death, MI or stroke. Clopidogrel population (7.3%) in the CAPRIE study [214]. pretreatment did not significantly reduce the The rates of life-threatening bleeding were combined risk of death, MI or urgent target ves- higher in the clopidogrel plus aspirin arm versus sel revascularization at 28 days. However, in a the clopidogrel-only arm (3 vs. 1%; p < 0.0001) subgroup analysis, patients who received a load- but in both treatment arms, no hemorrhagic ing dose of 300 mg at least 6 h before PCI expe- transformation of ischemic stroke was reported rienced a 38.6% RRR (p = 0.051) for this end as life-threatening bleeding and no significant point compared with no reduction with treat- difference was recorded in the incidence of ment less than 6 h before percutaneous inter- fatal bleeding. However, several cardiology vention. Risk of major bleeding at 1 year trials [70,222,224] have demonstrated a clear benefit increased, but not significantly. of the combination of clopidogrel and aspirin To summarize, the findings of these rand- over aspirin alone for the prevention of vascular omized controlled trials have shown the sustained end points in patients with coronary heart dis- benefit of clopidogrel in addition to standard ease. Moreover, the increase in bleeding risk with treatment including aspirin, especially in patients the combination was smaller than in MATCH. with coronary manifestation of atherothrombo- The differences between the MATCH trial sis. The overall safety profile of clopidogrel is at and the cardiology trials could be due to differ- least as good as that of medium-dose aspirin and ent designs. Whereas in the cardiology trials is superior to that of ticlopidine. clopidogrel was added to treatment, in the MATCH trial aspirin was added to clopidog- Clinical studies addressed to patients with rel. Consequently, the MATCH trial provided cerebrovascular diseases or heart failure a measure of the benefit-to-risk ratio of aspirin Data from the MATCH trial have recently been in addition to clopidogrel, not for clopidogrel published [225]. The trial, involving added to aspirin as in the cardiology trials. One 7599 patients, was a first randomized, double- major limitation of this study is that clopidog- blinded trial that was designed to assess whether rel was used as the standard therapy for the addition of aspirin 75 mg once daily to clopi- patients with cerebrovascular diseases although dogrel 75 mg once daily could have a greater aspirin presently is considered the treatment of benefit than clopidogrel alone in reducing the choice for secondary prevention of disorders risk of recurrent ischemic vascular events in associated with arterial thrombosis [39,164,165]. high-risk patients after TIA or ischemic stroke. Indeed, a meta-analysis of more than 287 clin- Patients were included if they had an ischemic ical trials showed that, overall, aspirin reduces stroke or TIA in the previous 3 months and had the risk of stroke, MI and vascular death by one or more of five additional risk factors: approximately 23% in patients with various • Previous ischemic stroke cardiovascular and cerebrovascular diseases [39]. •Previous MI Thus, recommendations for clopidogrel are usually made to patients who are intolerant of • Angina pectoris aspirin, who have had a recurrent ischemic • Diabetes mellitus event while on aspirin, or who are at vascular • Symptomic peripheral arterial disease high risk [39,65,99,162,163,202,220]. www.futuremedicine.com 479 REVIEW – Reiter & Jilma

In summary, the outcome of the MATCH prior ischemic events [230–232]. Clopidogrel, in trial indicates that the combination therapy of combination with aspirin, has been demon- aspirin plus clopidogrel is not superior to clopi- strated to be more efficacious than aspirin alone dogrel alone, and that the addition of aspirin to in patients presenting with ACS, with a favorable clopidogrel results in significantly higher bleed- safety profile [222,224,233]. ing rates. As a consequence, the combination of As most of the trials were addressed to patients aspirin and clopidogrel for cerebrovascular pre- with cardiovascular diseases, numerous trials vention should only be given within controlled have now been initiated to study the benefits of studies. Indeed, the design of the PRoFESS trial combining aspirin and clopidogrel for other indi- has been changed [402] following the announce- cations such as stroke or atrial ment of the results of the MATCH trial and this fibrillation (Table 6). One of these interesting trial is no longer utilizing a combination of studies is the Clopidogrel for High Atherothrom- clopidogrel plus aspirin as the comparator – it is botic Risk and Ischemic Stabilization, Manage- now clopidogrel alone. Unfortunately, whether ment, and Avoidance (CHARISMA) study clopidogrel is superior to aspirin in the treatment (Table 6) which was designed to evaluate the effi- of cerebrovascular diseases cannot be concluded cacy and safety of clopidogrel plus aspirin versus from the MATCH trial and therefore no recom- placebo plus aspirin in patients with established mendation can yet be given for the primary use coronary, cerebral or peripheral arterial disease or of clopidogrel in these patients. Additional infor- in patients with multiple risk factors for athero- mation could be obtained by a further study thrombosis who have not yet suffered from an comparing clopidogrel versus aspirin addressed ischemic event [234]. The results of this study will especially to patients with cerebrovascular dis- be of interest since it is unknown whether dual eases. Indeed, this is of interest as several contro- antiplatelet therapy is superior to aspirin mono- versial recommendations and guidelines therapy for high-risk primary and secondary pre- concerning the use of antiplatelet drugs in vention. This large-scale trial of patients at a high patients with TIA or stroke have been risk for atherothrombotic events will allow deter- published [162–165,202,226–228] but there are no mination of the value of the strategy of adding data available regarding how these recommenda- clopidogrel to the current standard of care, tions translate into clinical practice and which including low-dose aspirin, for a wide spectrum affect the choice of antiplatelet drugs in patients of patients with atherothrombosis. with a recent ischemic cerebrovascular event. The Warfarin and Antiplatelet Therapy in Clopidogrel: a better antiplatelet drug for the Chronic Heart failure (WATCH) trial was prevention of gastrointestinal bleeding? designed to determine the optimal antiplate- An overview of randomized trials of aspirin let/thrombotic agent for heart failure. Patients therapy found that GI toxicity (both major and were randomized to open-label warfarin (target minor) was dose related, with daily doses international normalized ratio [INR]: 2.5–3.0) between 30 and 1300 mg [235]. Even when or double-blind antiplatelet therapy with aspirin administered at very low doses (30–50 mg/day), 162 or clopidogrel 75 mg. Unfortunately, the aspirin can cause serious GI bleeding [69,159]. Pro- trial had to be terminated after a study period of ton-pump inhibitors reduce the risk of aspirin- 18 months due to poor enrolment, with a result- induced ulcera-bleeding [236,237] and thus, con- ing reduction of its power to achieve its original current therapy with these drugs has become a objectives [229]. standard treatment for patients at risk for ulcera bleeding who are taking aspirin [238,239]. Thienopyridines in perspective An alternative strategy is to replace aspirin Thienopyridines have become a mainstay in with another antiplatelet drug that does not antiplatelet therapy. Ticlopidine is currently used induce GI ulcera. Clopidogrel has been shown as a reserve drug due to its unfavourable side- to be potentially superior to aspirin in patients effect profile (neutropenia and thrombocyto- with atherothrombotic disease [214]. Moreover, penic purpura) and has been replaced by clopi- administration of clopidogrel resulted in a dogrel. Clopidogrel has been shown to be slightly lower rate of GI bleeding when com- superior to aspirin in patients with atherothrom- pared with aspirin (0.5 vs. 0.7%) [214] and did botic disease [214]. The benefit of clopidogrel not induce gastric damage in healthy volun- appears particularly pronounced in patients teers [240]. Thus, clopidogrel has recently been with diabetes, prior revascularization, and recommended for patients unable to take

480 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Table 6. Ongoing trials with clopidogrel. Trial Patients Number of Study design subjects ACTIVE A Atrial fibrillation 7500 Patients with a contraindication to warfarin or who refuse anticoagulant therapy will be randomized to receive either clopidogrel 75 mg/day + aspirin 75–100 mg/day or aspirin 75–100 mg/day ACTIVE W Atrial fibrillation 6500 Patients eligible for anticoagulants will be randomized to receive either clopidogrel 75 mg/day + aspirin 75–100 mg/day or adjusted dose vitamin K antagonist (INR 2.0–3.0) ARCH Aortic arch atheroma 1500 Patients will be randomized to receive either warfarin (INR 2.0–3.0) or aspirin 75–325 mg/day + clopidogrel 75 mg/day CAMPER Peripheral arterial 2000 Unknown intervention CASPAR Peripheral arterial bypass 1460 Unknown surgery CCS- Acute ST-segment 45000 Clopidogrel 75 mg/day + aspirin versus aspirin alone 2/COMMIT elevation MI CHARISMA Secondary and high-risk 15603 Two treatment groups will be randomized to receive either clopidogrel primary prevention 75 mg/day or placebo, in combination with aspirin 75–162 mg/day CLARITY Acute ST-segment 3000 Clopidogrel 75mg/day + aspirin vs aspirin alone elevation MI FASTER Acute TIA and minor 7500 All patients will be on aspirin. Patients will be randomized to ischemic stroke within 12 clopidogrel (300 mg loading dose + 75 mg/day) or placebo, and to hours of onset simvastatin (40 mg/day) or placebo PRoFESS Secondary prevention of 15500 Patients will be randomized to either of two antiplatelet combination stroke regimens: aspirin/ERDP (25 mg aspirin/200 mg extended-release dipyridamole) or clopidogrel 75 mg/d, and randomized to treatment with telmisartan 80 mg or placebo SPS3 Secondary prevention of 2500 Patients will be randomized to receive either aspirin 325 mg/day or a stroke, major vascular combination of aspirin 325 mg/day + clopidogrel 75 mg/day. events and cognitive Hypertensive S3 patients will be randomized to receive decline among patients antihypertensive therapy with a target systolic blood pressure of either with small subcortical <150 mmHg or stroke <130 mmHg. ACTIVE: Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events A trial; ARCH: Aortic arch Related Cerebral Hazard; CAMPER: Clopidogrel and Aspirin in the Management of Peripheral Endovascular Revascularization; CASPAR: Clopidogrel and Aspirin in bypass Surgery for Peripheral ARterial disease; CCS2/COMMIT: Second Chinese Cardiac Study/ClOpidogrel and Metoprolol Myocardial Infarction Trial; CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CLARITY: CLopidogrel as Adjunctive ReperfusIon TherapY; FASTER: Fast Assessment of Stroke and TIA to prevent Early Recurrence study INR: International normalized ratio; MI: Myocardial infarction: PRoFESS: Prevention Regimen For Effectively avoiding Second Strokes trial; SPS3: Secondary Prevention of Stroke 3 trial; TIA: Transient ischemic attack.

aspirin owing to previous GI intolerance which clopidogrel (75 mg/day) was compared [65,220]. However, although one study found a with aspirin (80 mg/day) plus esomeprazole lower incidence of GI bleeding among patients (20 mg twice daily) in high-risk patients who receiving clopidogrel than in those receiving had a history of aspirin-induced upper GI bleed- aspirin, a relatively high dose of aspirin ing, have been reported [241]. Over a 1-year fol- (325 mg/day) was used for the secondary pre- low-up period, the incidence of recurrent ulcera vention of cardiovascular/cerebrovascular bleeding was significantly higher in patients tak- events in this study [214]. ing clopidogrel when compared with those tak- Interestingly, until very recently, there has ing aspirin plus esomeprazole (8.6 vs. 0.7%). been no prospective trial available to assess Among patients with a history of aspirin- whether clopidogrel is an alternative to aspirin induced ulcera bleeding, aspirin plus esomepra- plus a proton-pump inhibitor for patients at risk zole was definitely superior to clopidogrel for the for ulcera. Currently, the results of a study in prevention of recurrent GI bleeding.

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At present the current recommendation for the European Society of Cardiology (ESC) in patients who already have had a GI complication August 2004, evaluated 904 patients. Subjects while taking aspirin is to replace aspirin with received aspirin 325 mg daily and were assigned clopidogrel [39,65,99,220]. However, although there to either clopidogrel (300-mg loading dose and are several potential limitations of the recently 75 mg maintenance doses for 1 month) or one published study [241,242], the observation of this of three prasugrel loading- and maintenance- study clearly do not support the current recom- dose regimens [403]. There was no significant mendation that clopidogrel should be used for difference in bleeding between combined patients who already have had GI complications prasugrel groups and clopidogrel (1.7% prasug- while taking aspirin. rel vs. 1.2% clopidogrel; p = 0.77). Death, MI, stroke, clinical target vessel thrombosis and Development of new drugs interfering with severe recurrent ischemia nonsignificantly ADP-mediated platelet reaction favored prasugrel (7.2% prasugrel vs. 9.4% The development of new ADP-receptor antago- clopidogrel; p = 0.31) without a dose–response nists possessing high potency and platelet selec- effect [252]. Despite limitations, predominantly tivity provides a new pharmacologic approach due to the exploratory nature of the trial, the for modulating platelet reactivity with the results are interesting and promising and clini- potential to prevent arterial thrombosis. cally significant differences in efficacy have to A more recent and related P2Y12 receptor be established in the future by the Triton antagonists, AR-C69931MX [243], is found to be a TIMI-38 trial. Patients will be followed on highly potent and selective antagonist at the maintenance therapy for 12 months. In this P2Y12 receptor that, unlike clopidogrel, is active trial, 13.000 patients with ACS will be enroled in vitro [243–245]. AR-C69931MX reversibly inhib- and randomized to either prasugrel or standard its aggregation, granule secretion, P-selectin doses of clopidogrel. The primary end point expression and procoagulant activity induced by will be the composite of cardiovascular death, agonists other than ADP, including U46619, MI, and stroke. The secondary end point will thrombin receptor-activating peptide and colla- include bleeding, recurrent ischemia and urgent gen [244,246]. In a canine model, AR-C69931MX target-vessel revascularization [403]. administered as an intravenous infusion Since it is known that P2Y1-null mice display (4.0 µg/kg/min) was shown to prevent occlusive strong resistance to the thromboembolism arterial thrombus formation in vivo in response to induced by intravenous injection of ADP, a mix- a deep arterial lesion in the canine carotid artery ture of collagen and adrenalin [253,254] and [247]. The first Phase II study of intravenous AR- thromboplastin [255] the P2Y1 receptor represents C69931MX in patients with ACS showed that it a potential pharmacological target for anti- was well tolerated as adjunctive therapy, including thrombotic drugs. Indeed, the administration of heparin and aspirin, with effective inhibition of the reversible P2Y1 receptor antagonist ADP-induced platelet aggregation, rapid onset of MRS2179 to mice was shown to strongly inhibit action and a plasma half-life of only several min- ADP-induced aggregation [253,255,256]. As both utes [245]. Moreover, it was demonstrated that, in P2Y1 and Y12 antagonists alone can potently both healthy volunteers and patients with ACS, inhibit ADP-induced platelet activation [257,258] AR-C69931MX inhibited ADP-induced platelet it was of interest to investigate whether there is a aggregation, P-selectin expression and platelet- synergistic effect of these antagonists. In a leukocyte conjugate formation in vitro and recently published study a synergistic effect in vivo, whereas aspirin had no effect on any of regarding inhibition of ADP-induced platelet these responses [248]. activation was obtained with the combination of Another novel thienopyridine P2Y12 receptor the P2Y12 antagonist AR-C69931MX and the antagonist is CS-747 [249]. CS-747 inactivates P2Y1 antagonist MRS2179 [259]. Moreover, a the P2Y12 receptor through its active metabo- strong synergistic effect in inhibition of lite, by the same mechanism such as clopidogrel thrombin-induced platelet activation with com- [249–251]. Currently, CS-747 (prasugrel) is being bination of AR-C69931MX and the thrombin investigated for the treatment of patients with inhibitor melagatran could also be shown. ACS who undergo PCI. The Phase IIb Joint Whether the synergistic effect in vitro also results Utilization of Medications to Block platelets in an improved antithrombotic effect in vivo Optimally – Thrombolysis In Myocardial Inf- with or without an increased risk of bleeding arction (JUMBO-TIMI) 26 trial, presented at should be established in further studies.

482 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Another promising target of ADP-receptor therapy with GPIIb/IIIa antagonists has recently antagonists could be the P2X1 receptor. An excel- been published [266]. Recommendations for the lent review has recently been published focusing use of GPIIb/IIIa antagonists in patients with on the role of P2X1 receptors in platelet activa- cardiovascular diseases are available from tion [210]. Indeed, results from functional evidenced-based guidelines [99,221,220]. genomic studies showed that P2X1 receptors sig- nificantly increased the risk of thrombosis PIIb/IIIa antagonists in cardiovascular disease whereas knockout of P2X1 receptors led to a Intravenous GPIIb/IIIa antagonists for PCI in high-risk reduced risk of thrombosis [260]. Moreover, it has patients and in patients with ACS without been suggested from both knock-in and -out persistent ST-segment elevation studies, that this receptor appears to contribute to As previously reported, there is outstanding evi- platelet activation under condition of high shear dence supporting the utility of intravenous rates such as found in the arterial circulation [210]. GPIIb/IIIa inhibition, mainly for abciximab, as an To summarize, the ATP analogs of the AR-C adjunct to aspirin and heparin in high-risk series, which are potent competitive ADP-recep- patients undergoing PCI and in patients with tor antagonists, have proved to be efficient plate- ACS without persistent ST-segment elevation let drugs in animal models and some of them are before revascularization [266]. Indeed, the use of in Phase II clinical trials for the treatment of GPIIb/IIIa antagonists has been validated in dedi- ACS. Moreover, in addition to the clopidogrel or cated trials for patients undergoing PCI with or the AR-C compound-sensitive P2Y12 receptor, without stenting [267–271]. However, a recent clini- the P2Y1 and X1 receptor are promising potential cal trial was designed to evaluate the possible addi- targets for new antithrombotic drugs. tional benefit of the GPIIb/IIIa antagonist abciximab in 2159 patients at low-to-intermedi- GPIIb/IIIa receptor antagonists ate risk undergoing PCI pretreated with 600 mg It is well established that the expression of of clopidogrel [272]. The trial showed no addi- GPIIb/IIIa on the platelet surface is the final tional benefit of abciximab in the composite pri- common pathway of platelet aggregation [261]. mary outcome of death, MI or target-vessel These receptors recognise an arginine-glycine- revascularization within the first 30 days in those aspartic-acid sequence contained in adhesive patients. Moreover, the role in the purely medical molecules such as fibrinogen and von Wille- management of patients with ACS without brand factor (vWF). When platelets get acti- persistent ST-segment elevation is less certain [266]. vated, GPIIb/IIIa is converted into a functional receptor, binding these proteins and allowing Intravenous GPIIb/IIIa antagonists for platelets to aggregate and form a hemostatic plug primary percutaneous transluminal coronary [8]. Thus, this receptor has become the target of angioplasty (with or without stenting) in acute novel antiplatelet drugs [262]. Murine mono- myocardial infarction clonal antibodies were the first antagonists of the On the basis of trials investigating the possible GPIIb/IIIa receptor to be developed [263]. Plate- benefit of intravenous GPIIb/IIIa antagonists for let aggregation is highly inhibited by the block- primary PTCA in acute MI it is suggested that ade of 80% of the surface GPIIb/IIIa receptors there is no definite indication for these drugs as an [264]. Three classes of GPIIb/IIIa antagonists adjunct to primary PTCA, as this treatment have been developed [265]: modality was demonstrated to have variable • Murine–human chimeric antibodies, such as effects [266]. Indeed, there had been debate in this abciximab field since the results of the four largest trials [273–276] did not support the benefit of abcix- • Synergistic peptide forms, such as eptifibatide imab at the primary end point timing of • Synthetic nonpeptide forms, such as tirofiban 6 months. Moreover, the study designs and meth- and lamifiban odology were quite variable in the clinical setting The development of this new class of drugs that of these trials. Finally, the data on tirofiban and blocks fibrinogen binding to the GPIIb/IIIa eptifibatide in primary PCI are far more limited receptors (Figure 1) has raised the possibility that than for abciximab [99,277]. Thus, given the size these potent agents may reduce thrombotic com- and limitations of the available data set, the rou- plications in ACS or after PCI. A large number tine administration of GPIIb/IIIa antagonists of trials have been carried out so far and an excel- with PCI (with or without stenting) in patients lent review on the current status of antiplatelet with MI is still a matter of debate [266,278]. www.futuremedicine.com 483 REVIEW – Reiter & Jilma

However, a meta-analysis of pooled data from coronary patency with favorable trends for clini- the previous four trials [277] and of the more cal outcomes. The early administration of recent Abciximab and Carbostent Evaluation GPIIb/IIIa antagonists was associated with a (ACE) trial (Table 7) [279] showed an overall 46% 28% relative reduction of mortality from 4.7 to reduction in death, reinfarction and target vessel 3.4%, which was not significant but consistent revascularization; a 34% reduction in death or with similar trends for reinfarction and the reinfarction; and a 26% reduction in death at 30 composite ischemic end point. days [277]. In all of the trials except the Controlled To summarize, although there has been con- Abciximab and Device Investigation to Lower troversy in the routine administration of Late Angioplasty Complications trial (CADIL- GPIIb/IIIa antagonists with PCI [277,278], it is LAC), there was support for abciximab treatment now recommended that treatment with abcixi- benefit for reduction of death or reinfarction at mab is started as early as possible in patients 6 months’ follow-up, and in both Abciximab undergoing primary PCI (with or without stent- before Direct angioplasty and stenting in Myocar- ing) [277,281] and treatment with tirofiban or epti- dial Infarction Regarding Acute and Long-term fibatide may be considered before primary PCI follow-up (ADMIRAL) and ACE the differences (with or without stenting) [99]. Moreover, the were statistically significant (Table 7). meta-analysis by Topol and colleagues [277] clearly Moreover, concerning the effects of early ver- indicates that catheter-based reperfusion with sus delayed administration of GPIIb/IIIa antago- adjunctive abciximab should be considered the nists in patients with ST-segment elevation MI preferred reperfusion therapy for acute MI and undergoing PCI a meta-analysis of 6 randomized do not justify a different level of recommendation trials [283] showed that the early administration for the use of GPIIb/IIIa inhibitors in acute MI of abciximab or tirofiban appeared to improve according to whether or not a stent is implanted.

Table 7. Clinical studies with intravenous GPIIb/IIIa antagonists for PTCA in acute MI Trial Patients Subjects Treatment Primary end point Result Ref. (n)

RAPPORT Acute MI within 483 Abciximab 0.25 mg/kg Composite of death No difference in primary [273] 12 h and ST- bolus followed by a from any cause, 6-month endpoint, segment elevation 12-h infusion of nonfatal reinfarction, although abciximab in two contiguous 0.125 µg/kg/min + and any TVR within significantly reduced leads or a new stenting vs. placebo + 6 months, or death, reinfarction or complete left stenting composite of death, urgent TVR at all time bundle-branch reinfarction, and points measured. Major block pattern, urgent TVR at 7 and bleeding was significantly referred for 30 days. higher with abciximab coronary than with placebo (16.6 angioplasty vs. 9.5%; p = 0.02) ISAR-2 Patients 401 Abciximab 0.25 mg/kg Composite of death, The primary 30-day end [274] undergoing bolus followed by 12-h reinfarction, and TVR point was reached in stenting within 48 infusion of 10 µg/min + at 30 days 5.0% of the abciximab h after onsets of reduced-dose heparin + group and in 10.5% of symptoms of acute stenting vs. standard the control group MI and ST- dose heparin+ stenting (p = 0.038). During 1-year segment elevation follow-up, there was no in two or more additional benefit from a contiguous leads reduction in TVR nor did abciximab reduce angiographic restenosis.

ACE: Abciximab and Carbostent Evaluation trial; ACS: Acute coronary syndromes; ADMIRAL: Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up trial; CADILLAC: Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial; ECG: Electrocardiography; ISAR: Intracoronary Stenting and Angiographic Results trial; MI: Myocardial infarction; PTCA: Percutaneous transluminal coronary angioplasty; RAPPORT: ReoPro And Primary PTCA Organization and Randomized Trial; TVR: Target vessel revascularization.

484 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Table 7. Clinical studies with intravenous GPIIb/IIIa antagonists for PTCA in acute MI (Cont.). Trial Patients Subjects Treatment Primary end point Result Ref. (n) ADMIRAL Patients 300 Abciximab 0.25 mg/kg Composite of death, Significant difference in [275] undergoing bolus, followed by a reinfarction, or primary 30-day endpoint stenting within 12-h infusion of urgent TVR at (6% for abciximab and 12 h after onset of 0.125 µg/kg/min + 30 days 14,6% for placebo; stenting vs. placebo + p = 0.01) which remained stenting significant through 6-month follow up (7.4 vs. 15.9%; p=0.02) One major bleeding event occurred in the abciximab group compared to none in the placebo group The primary 6-month endpoint occurred in 20.0% after PTCA, 16.5% after PTCA + abciximab, 11.5 % after stenting, and 10.2% after stenting + abciximab (p < 0.001) CADILLAC symptoms of acute 2082 Abciximab + PTCA vs. Composite of death, No differences among the [276] MI and ST-segment PTCA alone vs. reinfarction, groups in the rates of elevation in abciximab + multiLink disabling stroke, and death, stroke or two contiguous stent vs. multiLink stent ischemia-driven reinfarction, although leads alone revascularization of abciximab did reduce Symptoms of MI the target vessel at rates of repeated >30min within 6months revascularization during 12 h and lytic the first week postinitial eligible ECG procedure. The primary 30-day endpoint occurred in 10.5% after stenting, and 4.5% after abciximab + stenting (p = 0.023) ACE Symptoms of MI 400 Abciximab 0.25 mg/kg Composite of death At 6 months, the [279] >30 min bolus, followed by a from any cause, cumulative difference in associated with ST- 12-h infusion of reinfarction, TVR, mortality between the segment elevation 0.125 µg/kg/min + and stroke at 30 days groups increased (4.5 vs. in two or more stenting vs. stenting 8%), and the incidence of contiguous leads alone the composite of within 6 h or 6-month death and between 6 and reinfarction was lower in 24 h if there was the abciximab group than evidence of in the stent only group continuing (5.5% and 13.5%,p = ischemia. Patients 0.006). Six-month repeat with cardiogenic TVR and restenosis rates shock due to were similar between the predominant two groups. ventricular failure were also included ACE: Abciximab and Carbostent Evaluation trial; ACS: Acute coronary syndromes; ADMIRAL: Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up trial; CADILLAC: Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial; ECG: Electrocardiography; ISAR: Intracoronary Stenting and Angiographic Results trial; MI: Myocardial infarction; PTCA: Percutaneous transluminal coronary angioplasty; RAPPORT: ReoPro And Primary PTCA Organization and Randomized Trial; TVR: Target vessel revascularization.

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IIntravenous GPIIb/IIIa antagonists as adjuncts to SM-20302 [288,289], ME3277 [290,291], murine lytic therapy in acute myocardial infarction 7E3 F(ab´)(2) [292,293] and SDZ–GPI 562 [294] The use of GPIIb/IIIa antagonists as adjuncts to have been reported to preserve microvascular lytic therapy in acute MI is not recommended patency in different animal models of acute [266] as the results of the large GUSTO V study ischemic stroke and they may have neuroprotec- were disappointing with no difference in mortal- tive properties. More recently, FK419, a novel ity rates [282]. Indeed, the clinical efficacy of nonpeptide GPIIb/IIIa antagonist dose-depend- GPIIb/IIIa antagonists has been equivocal in ently shortened the time to first reperfusion and terms of mortality in patients with ST-elevated the total middle cerebral artery occlusion time MI, although a subgroup analysis of the ADMI- and reduced ischemic brain damage in a guinea- RAL trial has suggested that the early adminis- pig model [295]. Thus, GPIIb/IIIa antagonists tration of abciximab may provide further benefit may be suitable as a single therapeutic or as an [280]. A meta-analysis of 16 randomized, control- adjunct therapeutic to thrombolysis with led trials demonstrated that the parenteral alteplase for the treatment of stroke, although GPIIb/IIIa antagonists significantly reduced bleeding risk will be a major concern. mortality at 48 to 96 h but mortality benefits of Results of pilot trials in the setting of acute 30 days and 6 months were not statistically sig- ischemic stroke with the three GPIIb/IIIa nificant [284]. However, the meta-analysis showed antagonists abciximab, tirofiban, and eptifi- that GPIIb/IIIa antagonists provided a consist- batide are promising [288,296–299]. To evaluate ent and sustained therapeutic benefit on death, the safety of abciximab in acute ischemic stroke MI, and revascularization in patients with a randomized, double-blind, placebo-control- ischemic heart disease. led, dose-escalation trial was conducted in patients presenting within 24 h following Limitations of intravenous GPIIb/IIIa antagonists ischemic stroke onset [300] who were rand- Although GPIIb/IIIa antagonists have been omized to receive either an escalating dose of shown to be beneficial, the drugs have a narrow abciximab or placebo. There were no identified therapeutic window with regard to potential cases of fatal or nonfatal major intracranial complications such as increased bleeding risk or hemorrhage within either 5 days or 3 months thrombocytopenia particularly for abciximab [265]. of randomization. Asymptomatic parenchymal However, across all clinical trials, the rate of life- hemorrhages were detected on poststudy agent threatening bleeding and intracranial haemor- computed tomography in 7% of patients rhage was less than 0.2% and the most common treated with abciximab and 5% of the placebo- bleeding site was the vascular access site [286]. treated patients. Overall, abciximab is consid- Critical thrombocytopenia, eventually leading to ered safe when administered up to 24 h after uncontrolled bleeding, has been estimated in stroke onset. Analysis of the pooled abciximab 0.4 to 1.6% patients treated with abciximab and data provided some preliminary evidence that severe thrombocytopenia does even occur in this agent might improve outcome after stroke, healthy volunteers [287]. In trials with other since the proportion of patients with minimal GPIIb/IIIa antagonists, the incidence of throm- residual disability at 90 days was higher in the bocytopenia is generally lower than 1% [287]. abciximab group. Overall, intravenous GPIIb/IIIa antagonists have The currently ongoing Safety of Tirofiban in become a mainstay in the treatment of patients acute Ischemic Stroke (SaTIS) trial, in which undergoing PCI and in these patients with ACS patients receive either tirofiban or placebo, will undergoing revascularization [266]. help to further evaluate the safety and efficacy of GPIIb/IIIa antagonists in the treatment of GPIIb/IIIa antagonists in cerebrovascular disease acute stroke [301]. Moreover, GPIIb/IIIa antago- Compared with coronary arterial diseases, only nists in combination with reduced doses of few trials have evaluated the efficacy and tolera- thrombolytic agents may have the potential for bility of platelet GPIIb/IIIa antagonists in improving safety and efficacy compared with patients with cerebrovascular diseases. On the standard recombinant tissue plasminogen acti- basis of experience in ACS, parenteral vator [298]. However, GPIIb/IIIa antagonists GPIIb/IIIa antagonists may have potential appli- cannot be recommended for general use in cations in the treatment of acute ischemic stroke patients with cerebrovascular disease before and as adjunctive therapy to carotid angioplasty. prospective randomized placebo-controlled Indeed, the administration of agents such as clinical trials are completed.

486 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

Table 8. Clinical studies with oral GPIIb/IIIa antagonists. Trial Patients Subjects Treatment Primary end Result Ref. (n) point

OPUS-TIMI 16 ACS within 10302 Orbofiban 50 mg Death, MI, Trial terminated prematurely [302] 72 h; history of twice daily vs. recurrent due to an unexpected increase cardiovascular orbofiban 50 mg ischemia, urgent in 30-day mortality in the disease, positive twice daily for revascularisatio orbofiban group cardiac markers 30 days, followed by or stroke Major or severe bleeding was or ECG changes, 30 mg twice daily higher with orbofiban; it peripheral or vs. placebo occurred in 2.0%, 3.7% and cerebrovascular 4.5% of patients disease, or DM SYMPHONY ACS after 9233 Aspirin 80 mg twice Death, MI, and No difference between aspirin [303] stabilisation daily vs. low-dose severe recurrent group (9.8%), low- (10.1%), or sibrafiban twice daily ischemia at high-dose sibrafiban (10.1%). vs. high-dose 90 days Sibrafiban was associated with sibrafiban twice daily increased major bleeding SYMPHONY-2 ACS after 6671 Aspirin 80mg twice Death, MI and No difference between aspirin [304] stabilisation daily vs. low-dose severe recurrent (9.3%), low-dose sibrafiban sibrafiban plus ischemia plus aspirin (9.2%) or high-dose aspirin 80 mg twice sibrafiban (10.5%) daily vs. high-dose Aspirin with low-dose sibrafiban twice daily sibrafiban caused more bleeding than aspirin alone. There was a trend toward increased mortality in this group and a significant increase in the high-dose arm EXCITE Patients 7232 Xemilofiban 20 mg Death, MI and No difference between placebo [305] undergoing PCI or placebo before recurrent (13.5%), 10 mg (13.9%) or PCI, followed by revascularization 20 mg xemilofiban (12.7%) at Xemilofiban 10 mg at 30 and 182 days. Significant increase in three-times daily vs,. 182 days major bleeding in the xemilofiban 20 mg xemilofiban group three-times daily vs. placebo BRAVO Recent ACS, 9200 Lotrafiban 30 mg + Death, MI, Stopped at interim analysis [306] stroke, TIA, or aspirin twice daily vs. stroke, recurrent because lotrafibran had a peripheral lotrafiban 50 mg+ ischemia higher mortality than placebo vascular disease aspirin twice daily requiring (2.7 vs. 2.0%). Lotrafiban was vs. placebo hospitalization associated with a higher and urgent mortality, more major bleeding, revascularization and a greater risk of serious thrombocytopenia ACS: Acute coronary syndromes; BRAVO: Blockade of the glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial; DM: Diabetes mellitus; ECG: Electrocardiography; EXCITE: Evaluation of oral Xemilofiban in ControllIng Thrombotic Events; MI: Myocardial infarction; OPUS-TIMI: Orbofiban in Patients with Unstable coronary Syndromes – Thrombolysis In Myocardial Infarction; PCI: Percutaneous coronary intervention; SYMPHONY: Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart Events post–acute CorONary sYndromes trial; TIA: Transient ischemic attack.

Oral antagonists of GPIIb/IIIa receptors of patients with ischemic heart disease treated To further test the clinical efficacy of GPIIb/IIIa with oral GPIIb/IIIa antagonists (Table 8) [302–306]. antagonists, oral agents of this interesting class In contrast to the favorable results of the intrave- of drugs have been developed but only led to nous GPIIb/IIIa antagonists, the long-term use of disappointing clinical results. oral GPIIb/IIIa antagonists showed no benefit in To date, five large Phase III trials including reducing major adverse cardiac events, and signifi- 45,523 patients investigated the clinical outcomes cantly increased mortality in these patients. www.futuremedicine.com 487 REVIEW – Reiter & Jilma

Indeed, a meta-analysis of trials with oral An excellent review on antiplatelet therapy GPIIb/IIIa antagonists demonstrated a 31% provides some possible explanations for this ‘dark increase in mortality rate [307]. Despite the lack of side’ of GPIIb/IIIa antagonists [312]. In general, clinical benefit, excess bleeding complications the disappointing results of the oral agents were associated with the oral GPIIb/IIIa antago- sibrafiban, orbofiban and xemilofiban may be nists in these trials and, as a consequence, new oral due to suboptimal levels of platelet inhibition, drugs of this class were synthesized and tested in leading to paradoxical agonist-induced platelet dose–response and safety studies. activation and/or vascular inflammation [312–315]. The safety and tolerability of roxifiban, a sec- Indeed, it could be possible that the short half-life ond-generation oral nonpeptide platelet of oral GPIIb/IIIa antagonists function as antago- GPIIb/IIIa receptor antagonist, was tested in nists at peak concentrations (causing bleeding) 98 patients with a history of chronic stable but at lower concentrations they might act as par- angina pectoris [308]. Roxifiban-induced inhibi- tial agonists via a mechanism known as ‘platelet tion of platelet aggregation was dose dependent escape’ [316,317]. Thus, these agents may cause and sustained throughout the study period: bleeding at peak levels and promote thrombosis higher drug dosages correlated with higher levels at trough levels in the same patient. Indeed, pre- of platelet inhibition and a higher incidence of vious studies have demonstrated that chronic minor bleeding events. No serious adverse inhibition of platelets with oral GPIIb/IIIa antag- events were observed at any dosage. However, onists might be associated with platelet receptor the Roxifiban Oral Compound Kinetics Evalua- activation, continued procoagulant activity or tion Trials (ROCKET)-I trial demonstrated enhanced platelet–neutrophil interaction that, despite achieving sustained inhibition of [318–321]. Apart from that, even intravenous platelet aggregation, therapy with roxifiban was GPIIb/IIIa antagonists such as tirofiban have lim- associated with over expression or phasic ited efficacy under conditions of platelet activa- changes of major platelet receptors in patients tion, high vWF release, high shear stress and with CAD [309]. Another second-generation oral physiological calcium concentrations [322]. platelet GPIIb/IIIa receptor antagonist is the In a more recent study, it has been demonstrated prodrug UR-3216. UR-3216 maintains a high that the oral GPIIb/IIIa antagonist roxifiban signif- level of inhibition of platelet aggregation and, icantly decreased ADP- and collagen-induced due to a small peak-to-trough ratio, severe platelet aggregation, although platelet receptors bleeding is avoided [310]. Moreover, UR-3216 such as GPIIb/IIIa, P-selectin, and plate- induces no prothrombotic activity in human let/endothelial cell-adhesion molecule (PECAM)- platelets, distinctly different from orbofiban and 1 were paradoxically activated, monotherapy with other small molecule antagonists [311]. Although aspirin resulted in a mild, but consistent, inhibi- UR-3216 may be a promising orally-active tion of these receptors. Moreover, oral GPIIb/IIIa GPIIb/IIIa antagonist, hardly any data on this antagonists may have proinflammatory potency at drug are available. subtherapeutic levels, which could be an important To summarize, oral GPIIb/IIIa antagonists are factor in the toxicity of these agents [312]. not effective in reducing ischemic events when Overall, various factors have been proposed to used on a long-term basis after ACS and, cur- explain their failure, such as: rently, it seems unlikely that second-generation • Low affinity for the receptor oral platelet GPIIb/IIIa receptor antagonists will • Large peak-to-trough ratio be brought into Phase III testing. • Low bioavailability Dark side of GPIIb/IIIa antagonists & • Partial agonist activity future directions • Proaggregatory effect Paradoxical platelet activation after treatment • The fact that oral GPIIb/IIIa antagonists don’t with oral GPIIb/IIIa antagonists may be seem to entice the clinical market responsible for and explain the increased rate of mortality and high incidence of acute Monitoring of platelet function thrombotic events in patients with CAD. Although the role of antiplatelet drugs in the Moreover, the inability to maintain stable sus- treatment of vascular disease is well established, tained platelet inhibition for chronic regimes there remains concern about aspirin contributes substantially to the withdrawal of resistance [323], the less well known clopidogrel this class of drugs. resistance [324], and nonresponsiveness to other

488 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

antiplatelet drugs such as GPIIb/IIIa antagonists stenting were resistant to clopidogrel (mean [366,325]. Thus, the monitoring of antiplatelet ther- ADP-induced platelet aggregation on day 6 of apy is becoming increasingly important and many treatment: 103 ± 8% of baseline) and, therefore, instruments have been, or will be, utilized as point- might be at an increased risk for recurrent cardio- of-care instruments for monitoring antiplatelet vascular events [332]. Otherwise, from a secondary therapy or for the assessment of bleeding risk [326]. post-hoc analysis it has been demonstrated that A single dose of 160 mg completely abolishes pretreatment platelet activity and clinical charac- platelet TXA2 production [324] and the same teristics were not associated with responsiveness effect can be progressively achieved with the to clopidogrel [333]. In this study, platelet func- chronic administration of daily doses of 30 to tion before and after clopidogrel therapy was 50 mg [29]; however, variable platelet responses to analyzed in all 544 individuals by conventional aspirin have been described. Indeed, based on aggregometry. Hypo- (4.8%) and hyper- measurements of platelet aggregation in response responders (4.3%) to clopidogrel, as determined to arachidonate and ADP, 5 and 24% of by change in ADP-induced platelet aggregation, patients, respectively with stable cardiovascular did not significantly differ in clinical characteris- disease who were receiving 325 mg aspirin once tics from those whose responses were within the daily were defined as being ‘resistant’ and ‘sem- standard range. Moreover, platelet activity before iresponders’ [327]. The aspirin-resistant group the administration of clopidogrel, which was had an increased risk of death, MI, or cerebro- defined by baseline platelet aggregation response vascular accident during almost 2 years’ follow- to ADP, did not appear to be associated with the up. Another study using different techniques to response to clopidogrel. measure platelet aggregation, showed that 57% Measurement of platelet function by the rapid of a group of 88 patients with documented heart platelet function assay (Ultegra) has been found failure who had been treated with aspirin. to predict therapeutic response to GPIIb/IIIa 325 mg/day for over a month, showed ‘aspirin antagonists in patients with PCI [334]. Moreover, nonresponsiveness’ [328]. there have been several examples of the applica- The ADP receptor blocker clopidogrel reduces tion of the FDA-approved platelet function ana- the incidence of recurrent ischemic events in lyzer 100 (PFA-100) in therapeutic monitoring patients with ACS [220] and after coronary stent- [335]. In patients suffering from peripheral arterial ing [222]. Platelet inhibition with clopidogrel is occlusive disease poor responders to clopidogrel evident within two hours of an initial dose and (detected by the PFA-100) had an increased like- the maximal effect with an initial dose has been lihood of experiencing restenosis after percutane- noted to occur at 400 mg (40% platelet inhibi- ous angioplasty [336]. Patients with ST-elevated tion). In healthy volunteers ADP-induced plate- MI had significantly enhanced platelet function let aggregation was inhibited within 2 days when measured under high shear rates with the (platelet inhibition by ∼30%), and reached a PFA-100 [337] and standard doses of GPIIb/IIIa maximal inhibition (60% platelet inhibition) antagonists, particularly tirofiban, had a limited within 4 to 7 days of continued dosing impact on high shear-induced platelet formation (50–100 mg/day) of clopidogrel [156]. However, at physiologic Ca2+ concentration [322]. Moreover, clopidogrel ‘nonresponsiveness’ has been reported since GPIIb/IIIa antagonists have been shown to to be present in as few as 5% to as many as 56% dose dependently inhibit platelet of patients who are undergoing coronary stent- aggregation [322,338] one may speculate that the ing. Previous studies [329–331] labeled patients as inefficacy of these antiplatelet drugs could be due nonresponders based on the arbitrary definitions to insufficient therapeutic dosing. Indeed, as sug- of the change in ADP-induced platelet aggrega- gested by the Enhanced Suppression of the Plate- tion before and after the start of clopidogrel ther- let IIb/IIIa Receptor with Integrilin Therapy apy. Indeed, a significant number of (ESPRIT) trial [271], both medically treated cardiovascular events continue to occur [23,222]. In patients and patients undergoing PCI may bene- a more recent study, the antiplatelet effect of fit from higher dosages of GPIIb/IIIa antagonists. clopidogrel was studied prospectively in 60 con- However, the use and benefit of the monitoring secutive patients who underwent PCI with stent- of antiplatelet drugs in clinical settings are cur- ing for acute MI to determine whether variability rently controversially discussed [324] and further in response to clopidogrel affects clinical out- well-designed studies are needed to demonstrate comes. This study demonstrated that up to 25% its utility in different populations of patients with of patients undergoing primary PCI with vascular disease. www.futuremedicine.com 489 REVIEW – Reiter & Jilma

Potential antidotes • Administer a DDAVP infusion When bleeding occurs under treatment with • Transfuse platelet concentrates in case of antiplatelet agents, evaluation of platelet func- major or life-threatening bleeding or urgent tion may also help to guide further decision need for normalization of platelet function in making. In the acute event, platelet concentrates case of surgery. (PC) or desmopressin (DDAVP) may be helpful. Concerning the use of PC the pharmaco- Expert opinion & outlook kinetics of GPIIb/IIIa inhibitors is of impor- An ideal antiplatelet agent should specifically block tant practical implication [265]. The plasma thrombogenic platelet-dependent mechanisms in levels of unbound abciximab drop very rapidly vascular diseases without interfering with normal after administration. The rapid disappearance platelet functions that are required in hemostasis of free abciximab in plasma is an important and wound healing. Additionally, these agents consideration for reversing the therapeutic should be free of any major adverse events. effect. In the acute situation, the transfusion of Although, several antiplatelet strategies have platelets results in an immediate and partial already been developed or are under preclinical or normalization of platelet function, since the clinical investigation (Table 1) none of the available amount of unbound plasma abciximab availa- antiplatelet drugs meet all of these criteria. ble to inhibit transfused platelets is very small. Aspirin has been, and will be, the standard ref- In contrast to abciximab, the plasma concen- erence compound for long-term oral treatment of tration of eptifibatide molecules at peak dosing platelet hyper-reactivity, most notably in the sec- is very high relative to the number of ondary prevention of cardiovascular diseases [39]. GPIIb/IIIa molecules. As a result, newly trans- However, aspirin is neither selective for platelets fused platelets would probably be rapidly nor a potent antiplatelet compound. As platelet inhibited. Tirofiban is intermediate between activation occurs via several pathways that do not abciximab and eptifibatide in its peak molecu- rely on amplification by released TXA2, adding a lar concentration relative to the number of second antiplatelet drug to aspirin might have GPIIb/IIIa molecules. Thus, platelet transfu- additional benefits in some clinical circumstances, sions are possibly far more effective after abcix- but more research into this strategy is required. imab administration than following tirofiban The combination of modified-released dipyri- or eptifibatide infusion. damole and low-dose aspirin therapy has been DDAVP has been shown to accelerate approved by the FDA but recommendations for normalization of in vitro platelet dysfunction this class of antiplatelet drugs are induced by GPIIb/IIIa antagonists [238]. Com- controversial [162–165,202]. The reduction in non- bined use of platelet concentrates and DDAVP fatal stroke was derived merely from one large has been shown to additively enhance recovery trial [159], but this result was not supported by of normal platelet function after infusion of the findings for nonfatal stroke in other studies GPIIb/IIIa antagonists [338]. Thus, based on our or by the overall findings for nonfatal MI or vas- previous reports [338,339] and based on the poten- cular death [39]. Although dipyridamoles are con- tial necessity to administer large numbers of PC sidered to have some benefit in cerebrovascular [340] in case of bleeding induced by GPIIb/IIIa disease they have not been proven as an effective inhibitors cautious recommendations may be agent in cardiovascular disease. given: DDAVP should be used whenever bleed- Thienopyridines such as clopidogrel have been ing is suspected to stem from aspirin or shown to be beneficial in the treatment of vascular GPIIb/IIIa inhibitors. As long as there are no disease. Moreover, thienopyridines are the thera- clinical trials in bleeding patients, the authors peutic alternative in aspirin tolerance or resist- cautiously recommend the following course of ance. In combination with low-dose aspirin, action: clopidogrel has been shown to be more efficacious • Stop the GPIIb/IIIa infusion than aspirin alone, especially in patients with ACS [222,224,234] and several studies are currently • Obtain a platelet count and monitor activated planned or ongoing (Table 6). Newer ADP recep- partial thromboplastin (aPTT) or anti-FXa tor antagonists will probably become part of activity levels when anticoagulants are used clinical practice in the next few years. concomitantly Currently, the intravenous GPIIb/IIIa antago- • If possible, measure the degree of platelet nists are the most potent inhibitors of platelet inhibition with a rapid bedside test aggregation. Their use is restricted to patients

490 Therapy (2005) 2(3) Platelets and new antiplatelet drugs – REVIEW

undergoing PCI and to patients with ACS before To summarize, there is a better understanding of revascularization but the role of GPIIb/IIIa the molecular events regulating thrombogenesis antagonists in the nonintervential management and ongoing investigations are exploring the value of ACS is more controversial [266]. Oral of novel antiplatelet agents in various preclinical or GPIIb/IIIa antagonists have failed to be benefi- clinical trials. Future developments might probably cial in the treatment of vascular disease and it include combined-mode agents targeting one or seems unlikely that there will be any further more steps in the thrombotic process to optimize development of these drugs. the efficacy and safety of antiplatelet therapy.

Highlights

• Aspirin: multiple, randomized, controlled clinical trials have shown a clinically significant decrease in cardiovascular morbidity and mortality in patients at risk of recurrent atherothrombotic events. Although the beneficial effect of aspirin in secondary prevention of ischemic events is well established, the role of primary prevention is less clear, particularly in women. • Dipyridamole: the combination of modified-released dipyridamole and low-dose aspirin therapy has been approved by the US Food and Drug Administration; however, recommendations for this class of antiplatelet drugs are controversial. • Thienopyridines: clopidogrel has been shown to be more efficacious than aspirin alone especially in patients with acute coronary syndrome and several studies are currently planned or ongoing. Clopidogrel should not be used when aspirin causes gastrointestinal (GI) intolerance, because aspirin plus esomeprazole was definitely superior to clopidogrel for the prevention of recurrent GI bleeding among patients with a history of aspirin-induced ulcer bleeding. • GP IIb/IIIa antagonists: a large number of trials have been carried out with GPIIb/IIIa antagonists and several studies have shown the benefit of GP IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndrome (ACS) before revascularisation. In contrast, the oral GPIIb/IIIa antagonists have failed to be beneficial in the treatment of vascular disease and it seems unlikely that there will be any further development of these drugs. • Monitoring of platelet function: with the increasing number of anti-platelet drugs, the monitoring of antiplatelet therapy is becoming increasingly important and many devices have been or will be studied as point-of-care instruments for monitoring antiplatelet therapy or assessing bleeding risk • Potential antidotes: when bleeding occurs under treatment with antiplatelet agents evaluation of platelet function may help to guide further decision making. Combined use of platelet concentrates and desmopressin has been shown to additively enhance recovery of normal platelet function after infusion of GPIIb/IIIa antagonists, thus, in the acute event or desmopressin and/or platelet concentrates may be helpful.

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