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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Unmet needs in antiplatelet therapy

Jean-Pierre Bassand*

Department of Cardiology, University Hospital Jean Minjoz, EA3920, 25000 Besançon, France

* Corresponding author. Tel: +33 381 66 85 39; fax: +33 381 66 85 82. E-mail address: jpbassan{at}univ-fcomte.fr


   Abstract
Top
 Abstract
Introduction
 Variability of response and...
 Bleeding risks
 Summary
 References
 
Despite antiplatelet therapy, patients with acute coronary syndromes (ACS) and those undergoing coronary intervention continue to experience atherothrombotic events, indicating a need for improvement in both overall patient management and antiplatelet treatments. Limitations of clopidogrel, which is widely used in dual therapy with aspirin, include slow onset of effect, low inhibition of platelet aggregation (IPA) in many patients, interindividual variability in response, and irreversible P2Y12 binding that prevents rapid offset of effect. Higher doses of clopidogrel may overcome some of these issues, and new oral agents such as the thienopyridine prasugrel and the reversible P2Y12 antagonist AZD6140 have faster onset of action and produce greater IPA. However, antiplatelet treatment must strike a balance between reduced atherothrombotic risk and bleeding risk, and it has yet to be determined whether greater platelet inhibition will produce better clinical outcome in terms of ischaemic events with an acceptable bleeding profile. Bleeding is an inherent risk of antiplatelet therapy and an independent predictor of poor prognosis in ACS patients, a factor that should be taken into account in assessing risks and benefits of antiplatelet treatment. New reversible P2Y12 antagonists offer the potential to discontinue antiplatelet therapy closer to invasive procedures compared with the thienopyridines, thus potentially reducing both procedure-related bleeding rates and duration of exposure to atherothrombotic risk prior to procedures. Ongoing large-scale Phase 3 trials will provide important information on whether the strategies of achieving higher levels of P2Y12 inhibition and using reversible inhibitors can improve antiplatelet therapy.

Key Words: AZD6140 • Acute coronary syndromes • CABG • Clopidogrel resistance


   Introduction
Top
 Abstract
 Introduction
Variability of response and...
 Bleeding risks
 Summary
 References
 
Atherothrombosis (which includes ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease) is the leading cause of death worldwide.1 Manifestations of atherothrombosis are commonly found in more than one arterial bed in individual patients, and even stable atherosclerotic disease poses substantial risk for near-term cardiovascular events. For example, data from the international prospective REACH Registry showed that among outpatients with established atherothrombotic disease (n = 53 390), the 1-year rates of cardiovascular death, myocardial infarction (MI), or stroke were 4.5% for those with coronary artery disease, 6.5% for those with cerebrovascular disease, and 5.4% for those with peripheral arterial disease (Figure 1).2


Figure 1
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  		Figure 1 One year cardiovascular event rates among REACH Registry outpatients with established coronary artery disease (n = 38 602), cerebrovascular disease (n = 18 013), or peripheral arterial disease (n = 8581), adjusted for sex and age. Data are from Steg et al.2

 
Antiplatelet agents have become a cornerstone of therapy for atherothrombosis, particularly during the early phase of treatment for acute coronary syndromes (ACS). These agents currently include aspirin, thienopyridines (ticlopidine, clopidogrel), and glycoprotein IIb/IIIa antagonists, all of which have select indications in ACS with or without ST-segment elevation (STE). Aspirin has been shown to reduce atherothrombotic risk in both the acute and the chronic settings. Dual antiplatelet therapy with aspirin plus clopidogrel (which is at least as effective as and better tolerated than ticlopidine) has become a mainstay of antiplatelet therapy in ACS and percutaneous coronary intervention (PCI), with a number of large-scale clinical trials showing effectiveness of the addition of clopidogrel to aspirin in PCI with stent placement (CLASSICS,3 CREDO,4 PCI-CLARITY,5 PCI-CURE6 trials), non-STE (NSTE) ACS (CURE trial7), and STEMI (CLARITY,8 COMMIT-CCS2 trials9).

Despite the proven benefits of antiplatelet therapy, many patients with ACS continue to experience thrombotic events. This persistent risk indicates the need for improvement in both overall ACS management and existing treatments. Much recent attention has focused on the limitations of clopidogrel as antiplatelet therapy and on the need to achieve more effective P2Y12 inhibition.


   Variability of response and ‘resistance’: limitations of clopidogrel
Top
 Abstract
 Introduction
 Variability of response and...
Bleeding risks
 Summary
 References
 
The limitations of clopidogrel include: long time-course to achieve maximal inhibition of platelet aggregation (IPA); low level of IPA; wide interindividual variability in response; excess of bleeding during long-term prescription; and the irreversible binding of the P2Y12 receptor, which prevents prompt offset of antiplatelet effect.

The limitations regarding time to onset and degree and variability of inhibition are probably related in part to the fact that clopidogrel is a prodrug that requires two-step hepatic metabolism to an active form. This can be appreciated by noting the difference in IPA with a 60 mg loading dose of the new oral thienopyridine prasugrel, which is metabolically activated in a one-step hepatic process, compared with a standard clopidogrel loading dose of 300 mg, as shown in Figure 2;10 prasugrel rapidly produces a higher peak in IPA and maintains IPA at a higher level, likely reflecting more efficient metabolism.


Figure 2
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  		Figure 2 Inhibition of platelet aggregation at 20 µM ADP in crossover study in 68 healthy subjects receiving prasugrel 60 mg or clopidogrel 300 mg. Reprinted from Am Heart J, 153, Brandt JT, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation, 66.e9–66.e16, 2007, with permission from Elsevier.10

 
The variability of response to clopidogrel, as with other drugs, is linked to multiple factors, as shown in Figure 3. It may be due to reduced bioavailability, individual factors, accelerated platelet turnover, or genetic variations linked to polymorphisms of gene coding for P2Y12 receptor or for cytochrome P3A411–13 or cytochrome P2C19.14,15 In practical terms, the variability of response is illustrated by the normal bell-shaped distribution of the percentage of platelet aggregation inhibition (at 5 µM ADP) during clopidogrel therapy in 544 patients, with mean IPA of 41.9 ± 20.8%, as shown by Serebruany et al.16 (Figure 4). Some patients might be considered as hyporesponders (those with <10% IPA) and may be exposed to an excess ischaemic risk. On the other hand, patients at the opposite end of the spectrum, with high IPA, may be exposed to an increased risk of bleeding. Use of more potent drugs may shift the bell-shaped curve to the right, so that fewer patients might be hyporesponders, altering the balance between ischaemic and bleeding risks. In the Phase 2 JUMBO-TIMI 26 trial in patients undergoing PCI, prasugrel, which was shown to lead to higher and faster IPA, was associated with a slightly higher non-significant risk of bleeding complications, but also with a slightly lower non-significant risk of ischaemic events when compared with clopidogrel, used at the standard dose (Figure 5).17 In the recently published TRITON TIMI 38 trial, which compared prasugrel and clopidogrel in 13 608 ACS patients with scheduled PCI, a significant improvement in ischaemic risk was observed, with a 20% risk reduction for death, MI, and stroke at 30 days and end of follow-up.18 However, a significant increase in the risk of bleeding (TIMI major, TIMI minor, and spontaneous bleeds) was also observed in this study with prasugrel when compared with clopidogrel. These data tend to confirm the idea that more consistent IPA may lead to improved clinical outcomes but at the expense of an increased bleeding risk.


Figure 3
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  		Figure 3 Multiple factors that could be involved in variability of clopidogrel response. Adapted with permission from Michos et al. Mayo Clin Proc 2006;81:518–526.13

 

Figure 4
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  		Figure 4 Distribution of changes in ADP-induced (5 µmol) platelet aggregation in 544 patients after receiving clopidogrel. Negative changes represent increases over baseline values. Reprinted from J Am Coll Cardiol, 45, Serebruany V, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals, 246–251, 2005, with permission from Elsevier.16

 

Figure 5
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  		Figure 5 Significant (major and minor) non–CABG-related bleeding (left) and MACE (right) at 30 days in patients undergoing percutaneous coronary intervention in the JUMBO-TIMI 26 trial who were treated with various doses of prasugrel (PRAS) or clopidogrel (CLOP) at a 300 mg loading dose followed by 75 mg/day. Data from all prasugrel patients (PRAS pool) are compared with clopidogrel. Prasugrel doses are loading dose/maintenance dose (ld/md), in mg. CTVT, clinical target vessel thrombosis; HR, hazard ratio; R/N=number of patients experiencing event/number at risk. Wiviott SD, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention. Results of the joint utilization of medications to block platelets optimally (JUMBO)-TIMI 26 trial. Circulation 2005;111:3366–3373. Reproduced with permission from Lippincott, Williams and Wilkins.17

 
There is some evidence that so-called ‘resistance’ to clopidogrel is associated with poor outcome. Variability in response to clopidogrel or other antiplatelet drugs can be measured by various platelet function tests. However, there is no simple, reliably validated test that can routinely assess the level of IPA for any antiplatelet agent used in atherothrombosis, particularly at the bedside or in the catheterization laboratory. Additionally, there is lack of consensus in defining the acceptable lower therapeutic limit of IPA. Nevertheless, an increased thrombotic risk has been associated with low response to clopidogrel.19–21 Many of the reports that have explored hyporesponsiveness and clinical outcomes were based on relatively small sample sizes and on surrogate markers, particularly biomarker release at the time of PCI. The prospective study reported by Matetzky et al.,22 performed in 60 patients with acute MI, did show that recurrent cardiovascular events were more common in those with the poorest responses to clopidogrel (Figure 6), and similar experiences have been reported by others.23–28


Figure 6
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  		Figure 6 (A) Patients with acute myocardial infarction receiving clopidogrel 300 mg followed by 75 mg/day for 3 months were stratified into quartiles (Q) according to percentage of baseline platelet aggregation on Day 6 (at 5 µM ADP). (B) Reduction in aggregate size on Day 6 by quartile. (C) Recurrent cardiovascular events at 6 months by quartile. Matetzky S, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–3175. Reproduced with permission from Lippincott, Williams and Wilkins.22

 
The problem of variable response with clopidogrel has been addressed in several studies in which higher loading doses have been administered, most frequently 600 mg and occasionally 900 mg, instead of the usual 300 mg. This strategy was explored in the ALBION trial, in which 103 patients with NSTE ACS were randomized to 300, 600, or 900 mg clopidogrel loading doses and 75 mg/day thereafter (along with aspirin and other standard therapy).29 The two higher doses produced significantly greater IPA, with dose–effect relationships being observed for onset of action, maximum plateau, 24 h area under the curve (AUC) for IPA, and rates of low IPA (<10% IPA at 6 h; Figure 7). The higher loading doses were not associated with significantly greater bleeding risk between Day 1 and hospital discharge, with no severe bleeding being observed. Moderate bleeding occurred in one (2.9%) of 35 patients in the 300 mg group, zero (0%) of 34 in the 600 mg group, and one (2.9%) of 34 in the 900 mg group; bleeding overall was observed in 11 (31.4%), 10 (29.4%), and 14 (41.2%), respectively. Follow-up at 30 days showed a numeric reduction in MACE in the higher dose groups, with events occurring in four patients in the 300 mg group, two in the 600 mg group, and zero in the 900 mg group. Similarly, in a study reported by Cuisset et al.,24 292 patients with NSTE ACS undergoing stenting received a 300 mg (n = 146) or 600 mg (n = 146) clopidogrel loading dose followed by 75 mg/day, with all patients receiving aspirin. The higher dose was associated with significantly lower platelet aggregation (50 ± 19 vs. 61 ± 16% at 10 µM ADP, P < 0.0001). No post-procedural major bleeding was reported. At 1-month follow-up, cardiovascular events had occurred in 18 patients (12%) in the 300 mg group and in seven (5%) in the 600 mg group (P = 0.02; Figure 8), with the significant difference persisting after adjustment for conventional risk factors (P = 0.035). The ongoing large-scale CURRENT/OASIS 7 trial comparing 300 and 600 mg loading doses in patients with NSTE ACS may provide firmer answers to questions regarding the risks and benefits of a larger loading dose.


Figure 7
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  		Figure 7 (A) Inhibition of platelet aggregation (IPA) at 20 µM ADP in non-ST-segment elevation patients receiving clopidogrel loading doses of 300 mg (n = 35), 600 mg (n = 34), or 900 mg (n = 34) in the ALBION trial. Reproduced with permission from Montalescot et al.28 (B) Proportions of patients with IPA <10% at 6 h at 5 and 20 µM. Reprinted from J Am Coll Cardiol, 48, Montalescot G, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes, 931–938, 2006, with permission from Elsevier.29

 

Figure 8
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  		Figure 8 Frequency of cardiovascular events, consisting of acute coronary syndrome, stent thrombosis, stroke, and cardiovascular death, among 292 patients undergoing stenting who were treated with clopidogrel loading doses of 300 mg (n = 146) or 600 mg (n = 146) followed by 75 mg/day. Reprinted from J Am Coll Cardiol, 48, Cuisset T, et al. Benefit of a 600 mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting, 1339–1345, 2006, with permission from Elsevier.24

 

   Bleeding risks
Top
 Abstract
 Introduction
 Variability of response and...
 Bleeding risks
Summary
 References
 
Major bleeding is associated with mortality and adverse cardiovascular outcomes in ACS patients. The pooled analysis of 34 146 NSTE ACS patients from the OASIS Registry (n {approx} 11 500), the OASIS-2 trial (n = 10 141; unfractionated heparin vs. hirudin), and the CURE trial (n = 12 562; clopidogrel vs. placebo) showed that after adjustment for baseline predictors and bleeding propensity, major bleeding was associated with a 5-fold greater risk of death, a 4.5-fold greater risk for MI, a 6.5-fold greater risk for stroke within 30 days, and a 1.3-fold greater risk of death between 30 days and 6 months compared with patients with no major bleeding (Table 1).30 The association of major bleeding with mortality was consistent across subgroups according to co-interventions used during hospitalization. There was a significant trend for increasing risk of death according to severity of bleeding during the first 30 days in the CURE trial and during the first 7 days in the combined CURE/OASIS-2 populations (Table 2); a similar association was observed for risk of MI and risk of stroke.


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  		Table 1 Unadjusted and adjusted hazard ratio for death, myocardial infarction, or stroke for major bleeding vs. no major bleeding among 34 146 ACS patients

 

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  		Table 2 Hazard ratio for death by severity of bleeding vs. no bleedinga

 
Dual antiplatelet therapy increases risk of bleeding compared with aspirin alone. In the CURE trial in 12 562 patients with NSTE ACS, the addition of clopidogrel 300 mg followed by 75 mg/day to aspirin treatment for 3–12 months significantly reduced the risk of cardiovascular death/MI/stroke compared with aspirin (9.3 vs. 11.4%), including a significant reduction in patients undergoing PCI (9.6 vs. 13.2%), a non-significant reduction in those undergoing CABG (14.5 vs. 16.2%), and a significant reduction in those receiving medical therapy only (8.1 vs. 10.0%).7,31 The cost in terms of bleeding complications, shown in Figure 9, included significant increases in major bleeding overall.31 In the CHARISMA trial in 15 603 patients with clinically evident cardiovascular disease or multiple risk factors, the addition of clopidogrel 75 mg/day to low-dose aspirin for a median of 28 months produced a non-significant reduction in the rate of cardiovascular death/MI/stroke (6.6 vs. 7.3%) compared with aspirin alone that included a significant reduction in the 12 153 patients with symptomatic disease.32 As shown in Table 3, patients receiving clopidogrel had a non-significant excess of severe bleeding and a significantly greater rate of moderate bleeding.


Figure 9
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  		Figure 9 (A) Bleeding rates with clopidogrel 300 mg followed by 75 mg/day vs. placebo in 12 562 patients in the CURE trial. Data are from the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.7 (B) Rates of the composite endpoint of cardiovascular death (D), myocardial infarction, or stroke (cerebrovascular accident) and life-threatening or major bleeding rates among 2072 patients undergoing CABG in the CURE trial according to whether study medication was discontinued (d/c) <5 days or ≥5 or more days before CABG. Overall, major or life-threatening bleeding occurred in 9.6% of clopidogrel patients and 7.5% of placebo patients undergoing CABG. ICH, intracranial haemorrhage. Data are from Fox et al.31

 

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  		Table 3 Relative risk for bleeding in patients with clinically evident cardiovascular disease or multiple risk factors treated with clopidogrel 75 mg/day plus low-dose aspirin vs. low-dose aspirin plus placebo for a median of 28 months in the CHARISMA trial

 
The irreversible binding of clopidogrel and other thienopyridines poses problems when rapid offset of effect is desired. Offset of effect occurs gradually with the entry of new, unbound platelets into the circulation, requiring several days without treatment until there is a sufficient population of unbound platelets to reduce or reverse the antiplatelet effect. On the basis of the data from CURE, current guidelines recommend discontinuing clopidogrel 5–7 days before elective CABG.33 This rule may be extended to all types of surgery, cardiac or non-cardiac.33,34 In practice, most patients undergoing CABG do not have clopidogrel stopped at 5 days or more before the procedure, leaving them at increased risk for bleeding complications.35 In CURE, although none of the event reductions achieved statistical significance, the preventive benefit of clopidogrel among CABG patients was greatest prior to the procedure, particularly among patients proceeding to CABG during their initial hospitalization, with little difference in event rates post-procedure (Figure 9A); however, the pre-procedure reduction was accompanied by a marked, though non-significant, excess of major bleeding in those patients discontinuing clopidogrel <5 days prior to the procedure (Figure 9B).31

As noted, it is presently unclear whether the higher degree of platelet inhibition expected from new P2Y12 antagonists in development will result in increased risk for bleeding. However, the novel reversible P2Y12 antagonists, including the oral antagonist AZD6140 and the infusional agent cangrelor, offer the potential for reducing risk associated with invasive procedures. These agents do not require metabolic activation and they non-competitively inhibit platelet aggregation by blocking ADP signalling but not its binding to the platelet receptor, allowing platelets to be functional again once plasma drug levels decrease. Both magnitude and duration of IPA are dependent on plasma drug levels, allowing more rapid offset of effect with discontinuation of administration. AZD6140 exhibits more rapid onset of effect and higher IPA than conventional doses of clopidogrel,36 and infusional cangrelor has been shown to produce rapid onset of effect, dose-related IPA, and very rapid offset of effect.37 Characteristics of these agents and the new thienopyridine prasugrel are discussed in more detail in other articles in this supplement.


   Summary
Top
 Abstract
 Introduction
 Variability of response and...
 Bleeding risks
 Summary
References
 
Persistence of thrombotic events is a reality, despite antiplatelet therapy and other preventive measures. Dual therapy with aspirin and clopidogrel is currently the mainstay of antiplatelet therapy in PCI and ACS. The low and variable levels of IPA observed with clopidogrel may compromise the antithrombotic effectiveness of dual therapy. The irreversible binding of clopidogrel and other thienopyridines is an additional practical limitation of current therapy in patients undergoing invasive procedures. It is confirmed that higher levels of IPA lead to better protection against ischaemic events, but the right balance between efficacy and safety remains to be established. However, rapid reversibility of action of antiplatelet drugs may prove to be a better strategy, particularly with respect to safety. Large-scale clinical trials of higher-dose clopidogrel, prasugrel, AZD6140, and cangrelor will provide more information on the risks and benefits associated with these strategies.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Variability of response and...
 Bleeding risks
 Summary
 References
 

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