European Heart Journal Supplements

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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis

Christoph Bode^* and Manfred Zehender

Department of Internal Medicine III (Cardiology), University Hospital, Hugstetter Str. 55, 79106 Freiburg, Germany

^* Corresponding author. Tel: +49 761 270 3441; fax: +49 761 270 3200. E-mail address: bode{at}mm31.ukl.uni-freiburg.de

	Abstract

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
The uptake of drug-eluting stents (DES) has been rapid since their introduction at the start of the decade, owing to their clear superiority over bare-metal stents (BMS) in reducing restenosis rates after percutaneous coronary intervention. However, with the widespread use of DES, there has been growing concern that they may also be associated with an increased risk of late stent thrombosis compared with BMS. Late stent thrombosis is a serious concern as it may lead to myocardial infarction or death. Recent analyses of clinical trials comparing the efficacy and safety of BMS and DES appear to confirm that DES may indeed be associated with a small but significant increase in the risk of late stent thrombosis and that this increased risk may continue for several years after stenting. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to be effective in reducing the risk of acute/subacute stent thrombosis. On the basis of the evidence of increased risk of late stent thrombosis, guidelines now recommend extending dual antiplatelet therapy to at least 12 months after implantation of DES, and even longer in patients at high risk of stent thrombosis. Guidelines also stress the dangers of late stent thrombosis associated with premature discontinuation of antiplatelet therapy. Reduced responsiveness to clopidogrel or to aspirin is a relatively common phenomenon and may also lead to patients being inadequately protected against late stent thrombosis. New antiplatelet agents that provide significantly greater and more consistent inhibition of platelet aggregation may have benefits in reducing the risk of late stent thrombosis and the associated burden of serious adverse cardiovascular outcomes and death.

Key Words: Late stent thrombosis • Drug-eluting stents • Antiplatelet therapy

	Introduction

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
Use of endoluminal metallic stents to maintain vessel patency following percutaneous coronary intervention (PCI) has become standard practice following clinical trials in the 1990s which consistently demonstrated reduced rates of restenosis compared with angioplasty alone.^1–3 Restenosis after PCI is a complex process involving both early and late events. Narrowing of the lumen due to elastic recoil, in which elastic fibres in the vascular wall recoil to their pre-PCI size, occurs within hours of PCI.⁴ In the longer term, angioplasty often exposes the adventitia to the lumen, activating fibroblasts and leading to cell proliferation and fibrosis of the adventitia. This late constrictive remodelling, which occurs approximately 1–6 months after PCI, reduces the luminal area and is believed to be the dominant mechanism underlying post-PCI restenosis.⁵

Stents provide a scaffold within the vessel that prevents elastic recoil and constrictive remodelling and so reduces restenosis. However, even after stenting, a substantial risk of restenosis remains. The very placement of the stent causes vessel injury, with inflammatory reactions around the stent struts triggering a cascade of events that lead to neointimal hyperplasia.⁶ The proliferation of smooth muscle and deposition of extracellular matrix often leads to significant narrowing of the lumen in the 3–6 months after PCI. Drug-eluting stents (DES), which provide a localized release of anti-proliferative agents over the course of several months, were introduced with the aim of inhibiting neointimal hyperplasia, and clinical studies have demonstrated significant reductions in restenosis compared with bare-metal stents (BMS).^7–9 However, as considered below, there have been concerns that DES may be associated with an increased risk of potentially life-threatening late stent thrombosis.¹⁰ Given that the use of DES is now widespread, it is important to optimize antiplatelet therapy to minimize the risk of thrombosis in individuals receiving stents after PCI. This article reviews the benefits of DES in reducing restenosis, the potential risks of late thrombosis, and strategies for minimizing this risk through effective antiplatelet therapy.

	Drug-eluting stents: the benefits

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
BMS were introduced in 1986 to prevent elastic recoil and constrictive remodelling after PCI, and so reduce restenosis rates. Their effectiveness in reducing restenosis has been consistently demonstrated in clinical studies. In the Benestent study, for example, bare-metal stenting reduced the risk of restenosis in the 7 months after PCI by 31% compared with balloon angioplasty alone (P = 0.02).² Results from the Stent Restenosis Study were comparable, with use of a BMS reducing the risk of restenosis by 25% over 6 months (P = 0.046).³ However, the risk of restenosis in individuals receiving BMS, while significantly reduced compared with angioplasty alone, remained high. In the Benestent and Stent Restenosis studies, restenosis rates with BMS were 22 and 32%,^2,3 respectively, and restenosis rates of 20–40% at 6 months are typical with BMS.¹¹ More recently, novel stent strut designs and the use of newer materials have reduced this rate; however, the principal problem remains.

Neointimal hyperplasia is the dominant mechanism underlying in-stent restenosis. DES that release anti-proliferative agents, such as sirolimus, paclitaxel, and zotarolimus, over the course of several weeks or months were developed to inhibit neointimal hyperplasia and so reduce the risk of in-stent restenosis compared with BMS. Clinical studies have consistently found DES to be more effective than BMS in preventing restenosis, typically lowering restenosis rates to below 10%.^7–9 Consequently, there has been a rapid uptake of DES, which have been used in nearly 6 million patients worldwide since their introduction in 2002,¹² and, in some countries, now account for more than 85% of stent usage.¹³ Studies of restenosis with the three leading anti-proliferative DES in Europe are summarized briefly in what follows.

	Sirolimus-eluting stent (Cypher®, Cordis/Guidant)

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
Sirolimus is a cytostatic agent that has immunosuppressive and potent anti-proliferative activity¹⁴ owing to its halting of the cell cycle in the G2 phase.¹⁵ The Cypher stent, consisting of the metal stent, the coating polymer, and the drug, is designed to release sirolimus for up to 30 days after implantation. The landmark RAVEL study provided the proof of concept for reduced in-stent loss in DES- vs. BMS-treated patients.¹⁶ In the SIRIUS study,⁷ the frequency of in-stent restenosis over 9 months was markedly reduced with sirolimus-eluting stents (SES) compared with BMS (3.2 vs. 35.4%, respectively; P < 0.0001), and this reduction was associated with a reduced frequency of neointimal hyperplasia. The primary endpoint of target vessel failure [a composite of death from cardiac causes, myocardial infarction (MI), and repeated percutaneous or surgical revascularization] also occurred less frequently in patients who received SES (8.6%) rather than BMS (21.0%; P < 0.0001).⁷ A 1-year follow-up of the SIRIUS study found that the reduction in frequency of restenosis with SES became greater after 9 months, with a 70–80% risk reduction compared with BMS.¹⁷ The European and Canadian SIRIUS trials confirmed the benefits of SES in patients with long lesions in small coronary vessels who are at very high risk of restenosis.^18,19

	Paclitaxel-eluting stent (Taxus®, Boston Scientific)

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
Paclitaxel is a cytotoxic agent that inhibits cell division by promoting the polymerization of tubulin and so inhibiting microtubule disassembly.²⁰ The TAXUS series of trials have clearly demonstrated the effectiveness of paclitaxel-eluting stents (PES) in reducing restenosis.^21–23 For example, in the TAXUS-II study, use of a slow-release PES reduced the 6-month incidence of angiographic restenosis to 2.3% compared with 17.9% with BMS (P < 0.0001).²² The TAXUS-IV trial demonstrated a 73% reduction (P < 0.0001) in target lesion revascularization with the use of PES rather than BMS.²⁴

The effectiveness of PES has been compared with SES in a number of studies,^25–29 as reviewed by Shafiq et al.³⁰ in 2006, and the findings regarding restenosis are summarized in Table 1. It is clear that both PES and SES are highly effective in preventing restenosis.

View this table: [in this window] [in a new window]   Table 1 Rates of restenosis in studies comparing sirolimus- and paclitaxel-eluting stents

 

	Zotarolimus-eluting stent (Endeavor®, Medtronic)

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
Zotarolimus is a synthetic analogue of sirolimus and, unlike sirolimus and paclitaxel, was developed specifically for use in DES.³¹ In the ENDEAVOR II trial,³² the rate of restenosis over 9 months was reduced from 35.0% with BMS to 13.2% with a zotarolimus-eluting stent (ZES). Target vessel failure was also significantly reduced with ZES (7.9 vs. 15.1%; P = 0.0001).³² In a comparison of ZES and SES, restenosis occurred more frequently with ZES (11.7 vs. 4.3%; P = 0.04), although rates of target vessel failure and target lesion revascularization did not differ significantly.³³

	Drug-eluting stents: the risks

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
While the benefits of DES in reducing restenosis are clear and widely recognized, there have also been concerns about their long-term safety and, specifically, that they may be associated with an increased risk of late stent thrombosis compared with BMS.^34–37 Late stent thrombosis is a rare complication of stenting and, even in studies that have indicated an increased risk with DES, the absolute risk remains low (<1.5%).^34,37 However, it is also a serious complication, resulting in MI in 60–70% of cases and mortality rates of nearly 50%,^38,39 and so any increase in the rate of late stent thrombosis is a cause for concern.

Stent thrombosis can be classified according to how soon after stenting the thrombotic event occurs (Table 2),⁴⁰ and different mechanisms appear to be involved in early and late stent thrombosis. Early stent thrombosis is most often related to mechanical factors associated with stent placement, including vessel damage and small lumen diameter and/or slow blood flow after stenting.⁴¹ In contrast, the dominant mechanism in late stent thrombosis is believed to be delayed or incomplete re-endothelialization. Inflammatory responses to the stent polymers may also play an important role.⁴⁰ By delaying re-endothelialization, the anti-proliferative activity of DES might, therefore, be a disadvantage in the context of late stent thrombosis.¹⁰ Studies at autopsy have found greater arterial healing and re-endothelialization with BMS than with DES,⁴² and these findings are supported by an angioscopic study that found incomplete neointimal coverage 3–6 months after DES implantation.⁴³

View this table: [in this window] [in a new window]   Table 2 Proposed standard definitions of coronary stent thrombosis (Academic Research Consortium)

 
The potential for late stent thrombosis owing to delayed arterial healing with DES has been investigated in a number of trials, meta-analyses, and registry reports. In the BASKET-LATE study,³⁵ 746 patients with DES or BMS were followed for up to 1 year after the discontinuation of antiplatelet treatment with clopidogrel at 6 months. Overall, rates of cardiac death or MI were similar, but in the year following discontinuation of clopidogrel these events occurred more frequently among patients with DES when compared with BMS (4.9 vs. 1.3%). Use of DES doubled the risk of late stent thrombosis and thrombosis-related clinical events compared with BMS (2.6 vs. 1.3%). As discussed subsequently, the increased risk of stent thrombosis and adverse cardiovascular outcomes with DES after clopidogrel was discontinued, suggesting that the duration of dual antiplatelet therapy may need to be extended beyond 6 months in patients with DES.

In March 2007, the New England Journal of Medicine published a series of four pooled analyses and a registry report investigating the potential for late stent thrombosis with DES,^{36,37,44–46} along with two editorials on the issue.^47,48 Analysis of data on 4958 patients from 14 randomized trials comparing SES and BMS found no difference in the overall risk of stent thrombosis, as defined according to individual study protocols.⁴⁶ However, stent thrombosis occurred more frequently with SES than BMS after 1 year from stent implantation (0.6 vs. 0.05%, P = 0.02), suggesting an increased risk of late stent thrombosis with SES. There were no significant differences between the stents in terms of the risk of death or MI, and SES reduced the combined risk of death, MI, or reintervention for major cardiac adverse events compared with BMS.

Similar findings came from a pooled analysis of four studies (n = 1748) comparing SES and BMS and five studies (n = 3513) comparing PES and BMS, with stent thrombosis again defined according to study protocols.³⁷ There was a trend towards higher rates of stent thrombosis at 4 years with DES, but the difference from BMS was not statistically significant (Figure 1). However, the rates of stent thrombosis after 1 year from implantation were significantly higher with both SES and PES. The risk of target lesion revascularization was lower with DES, and there were no significant differences in mortality or the incidence of MI.³⁷ The four studies comparing SES and BMS were also pooled in another analysis, but with reclassification of stent thrombosis using standard definitions across the studies. Use of different definitions of stent thrombosis confounds the analysis and interpretation of results across different studies. In September 2006, the Academic Research Consortium (ARC), which includes investigators, regulators, and pharmaceutical industry representatives, proposed a set of standard definitions for stent thrombosis to allow better comparison across different studies (Table 2). When cases of stent thrombosis in the four studies comparing SES and BMS were reclassified according to the ARC definitions, rates of stent thrombosis were found to be similar in the two treatment groups.⁴⁴ In another pooled analysis that applied the ARC definitions to eight randomized trials involving patients receiving SES (n = 878), PES (n = 1400), or BMS (n = 2267), the 4-year incidence of definite or probable stent thrombosis was similar with DES and BMS (SES vs. BMS: 1.5 vs. 1.7%, P = 0.70; PES vs. BMS: 1.8 vs. 1.4%, P = 0.52).⁴⁵ The incidence of definite or probable stent thrombosis from 1 year after implantation was 0.9% with SES compared with 0.4% with BMS, and 0.9% with PES compared with 0.6% for BMS.

View larger version (22K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Occurrence of stent thrombosis with (A) sirolimus-eluting stents (SES) and (B) paclitaxel-eluting stents (PES): comparison with bare-metal stents (BMS) in a pooled analysis of four double-blind trials.37

 
A report from the Swedish Coronary Angiography and Angioplasty Registry evaluated outcomes over the 3 years following implantation of either DES (n = 6033) or BMS (n = 13 738).³⁶ Overall, there was no significant difference in the primary composite endpoint of death and MI. However, a trend towards a lower risk of death and MI in the first 6 months after implantation of DES was offset by a significantly increased event rate from 6 months to 3 years after DES implantation when compared with BMS.

Finally, in a recent meta-analysis of published articles and conference presentations, as well as printed information and data on file from pharmaceutical companies, Camenzind et al.⁴⁹ concluded that SES and PES are associated with small but significant increases in late stent thrombosis. Their pooled analysis found that, compared with BMS, the risk of death and Q-wave MI over the course of follow-up was increased by 60% with SES (P = 0.03) and by 15% with PES, although this difference was not statistically significant (P = 0.46).

In September 2006, the US Food and Drug Administration (FDA) published a statement on DES concluding that ‘coronary DES remain safe and effective’ when used for approved indications and have ‘significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year.’⁵⁰ Studies that have been published since the release of this statement generally support the FDA's conclusions. However, published evidence suggests that, while the overall safety of DES is comparable with that of BMS, there may be an increased risk of late stent thrombosis and clinical thrombotic events occurring after 1 year from DES implantation for certain indications.⁴⁷ This highlights the importance of thoughtful selection of the right stent for each patient and effective antiplatelet therapy in mitigating the risk of stent thrombosis. Furthermore, it raises critical questions about the optimal timing and duration of antiplatelet use.

	Dual antiplatelet therapy with drug-eluting stents

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
The effectiveness of dual antiplatelet therapy in reducing acute and subacute stent thrombosis is clearly established. The optimal timing and duration of prophylaxis—particularly with regards to prevention of late stent thrombosis—is, however, not fully resolved.^51,52 For example, in the STent Anticoagulation Restenosis Study (STARS)⁵¹ dual antiplatelet treatment with ticlopidine and aspirin reduced the risk of angiographically evident thrombosis within 30 days of stenting by 80% compared with either aspirin (P = 0.001) or combination aspirin/warfarin therapy (P = 0.01). The effectiveness of clopidogrel in combination with aspirin has been found to be at least equivalent to that of ticlopidine.^53–55 Dual antiplatelet therapy appears to be most effective when initiated prior to stenting. In a cohort of 4160 patients in which clopidogrel treatment was initiated either 6–24 h before or immediately after stenting, the incidence of the primary composite endpoint of death, acute MI, or target vessel revascularization was significantly lower in the pre-treated group (2.8 vs. 4.7%, P = 0.002).⁵⁶ The benefits of pre-treatment appear to be reduced if less than 6 h is allowed between dosing of clopidogrel and stenting.⁵⁷ The optimal loading dose for clopidogrel continues to be a subject of debate. When administered at least 6 h before PCI, the best established evidence supports a loading dose of 300 mg clopidogrel. In practice, clopidogrel treatment is often initiated closer to, or at the time of, PCI and, in these circumstances, a higher loading dose (e.g. 600 mg) may achieve greater antiplatelet activity more rapidly than a 300 mg dose.⁵⁸ However, the safety of clopidogrel at doses above 300 mg is less clearly established and the potential for increased antithrombotic protection with a 600 mg loading dose needs to be weighed against a possible increased risk of bleeding.

The optimal duration of dual antiplatelet therapy with DES is a critical consideration given the potential for late stent thrombosis and the severity of its sequelae. The importance of continuing prophylaxis for an adequate period of time is highlighted by the finding that premature discontinuation of dual antiplatelet therapy is the strongest predictor of late stent thrombosis.³⁸ The current minimum recommended duration of dual antiplatelet therapy is 3 months with SES and 6 months with PES.^40,58 However, as considered earlier, DES have been associated with an increased risk of stent thrombosis more than 6 months after implantation, and a recent study found that the risk of late stent thrombosis continues without falling up to 3 years after stenting.⁵⁹ Furthermore, in a report of four cases of late stent thrombosis (335–442 days after stenting) with DES, all of the events occurred shortly after antiplatelet therapy was interrupted.⁶⁰

On the basis of evidence indicating that risk of thrombosis with DES extends well beyond the minimum recommended duration for dual antiplatelet therapy, treatment guidelines increasingly recommend extending prophylaxis with aspirin and clopidogrel up to at least 1 year after stenting, and possibly for even longer in patients at high risk of late stent thrombosis (Table 3).^40,58,61,62 The American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association recently joined to issue an advisory noting that dual antiplatelet therapy is often prematurely discontinued, despite the evidence that this greatly increases the risk of stent thrombosis, MI, and death, and stressing the importance of continuing prophylaxis for at least 1 year for patients receiving DES.⁶³ However, the effectiveness of extended prophylaxis in preventing late stent thrombosis is unknown and the optimal duration of dual antiplatelet therapy is not established. The assumed benefits of extended therapy also need to be balanced against the potential for increased bleeding,^64,65 and the exact duration should be tailored to the individual patient based on a careful consideration of the balance of risks owing to stent thrombosis and bleeding.⁴⁹

View this table: [in this window] [in a new window]   Table 3 Summary of recommendations for dual antiplatelet therapy after coronary stenting

 

	The need for new antiplatelet agents

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
As considered earlier, sustained antiplatelet activity is critical to minimizing the risk of stent thrombosis, and premature discontinuation of antiplatelet therapy is the strongest predictor of stent thrombosis.³⁸ Patients who continue to receive antiplatelet therapy but are non- or poor responders to the effects of the agents also appear to be at increased risk of stent thrombosis.⁶⁶ Variability in response to clopidogrel and/or aspirin appears to be a relatively common phenomenon. In a study of 105 patients with coronary artery disease undergoing elective PCI, up to 11% of the patients were non-responders to clopidogrel and 26% were semi-responders [defined as a reduction in platelet aggregation in response to 20 µmol/L adenosine diphosphate (ADP) of < 10 or 10–29%, respectively].⁶⁷ Another study found that 15% of patients who had undergone stenting responded poorly to clopidogrel (10% reduction in platelet aggregation in response to 5 µmol/L ADP) after 30 days of treatment.⁶⁸ Reported prevalence rates for aspirin non-responsiveness in patients with an array of cardiovascular diseases range from 6–45%.⁶⁹ The possible mechanisms contributing to variability in response to clopidogrel are beyond the scope of this review and are considered by Steen Husted in an accompanying paper in this supplement.⁷⁰

Evidence suggests that variability in response to clopidogrel and/or aspirin can have important clinical implications. A number of case studies of stent thrombosis associated with clopidogrel non-responsiveness, either alone or in combination with aspirin non-responsiveness, have been reported.^71–74 Variability in response to clopidogrel has also been correlated with adverse clinical outcomes in a prospective study of 60 patients undergoing primary angioplasty with stenting for acute ST-elevation MI.⁷⁵ Patients were stratified into quartiles according to their sensitivity to clopidogrel (percentage reduction of ADP-induced platelet aggregation). Of the eight recurrent cardiovascular events that occurred over the 6 months after stenting, seven occurred in the quartile with the lowest responsiveness to clopidogrel and the other event occurred in the quartile with the second lowest responsiveness (Figure 2).

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 (A) ADP-induced platelet aggregation, (B) reduction in aggregate size, and (C) incidence of recurrent major adverse cardiovascular events by quartiles of platelet activity inhibition in response to clopidogrel treatment. Adapted with permission from Matetzky et al.75

 
Results from a recent study provide further evidence that poor response to clopidogrel therapy is associated with adverse clinical outcomes. In 100 patients receiving chronic antiplatelet therapy with aspirin (75 mg daily) and clopidogrel (325 mg daily), 20 of the 23 (87%) patients who had ischaemic events within 1 year of stenting had high on-treatment platelet therapy measured by thromboelastography (TEG) before stenting [16/23 (70%) patients when measured by aggregometry]. High on-treatment platelet reactivity, measured by TEG or aggregometry, were the only variables found to correlate significantly (P < 0.001) with the risk of ischaemic events.⁷⁶

Assessment of the clinical impact of variability in response to antiplatelet agents is complicated by the limited number and small sizes of studies to date, as well as the use of different definitions of non-responsiveness. However, the correlation of poor responsiveness to clopidogrel with recurrent cardiovascular events⁷⁵ suggests that it can result in a substantial number of patients being inadequately protected from cardiovascular events owing to stent thrombosis. New treatment strategies that can overcome the variability in response sometimes associated with clopidogrel and/or aspirin have the potential to improve the care of patients by providing more consistent and reliable protection against stent thrombosis.⁷⁷

A potential strategy when faced with variability in response to clopidogrel would be to increase the clopidogrel dose. While studies investigating this have not been published, it is possible that any benefit in terms of efficacy may be offset by an increased incidence of adverse events, particularly bleeding, at higher doses. Furthermore, increasing the dose of clopidogrel may not result in enhanced efficacy, owing to limitations on the absorption and/or metabolic activation of the prodrug and competing mechanisms of metabolic inactivation and elimination. In the ISAR-CHOICE study, for example, administration of a 900 mg loading dose of clopidogrel, compared with a 600 mg loading dose, did not increase plasma concentrations of the active metabolite or enhance inhibition of platelet aggregation.⁷⁸ New antiplatelet therapies that are in development may offer even more promising approaches and include agents that—like clopidogrel—target the P2Y₁₂ receptor. Further insights into these and other antiplatelet agents are provided in the accompanying paper by Husted⁷⁰ and will be considered only briefly here. Prasugrel, like clopidogrel, is an irreversible thienopyridine P2Y₁₂ receptor antagonist and also requires conversion to an active metabolite. However, it appears that the pharmacokinetic profile of prasugrel may result in more consistent and potent inhibition of platelet aggregation, and fewer non-responders to therapy, compared with clopidogrel.⁷⁹ A phase II study in people undergoing elective or urgent PCI found a trend towards a reduced incidence of death or cardiovascular events (MI, stroke, recurrent MI, or target vessel thrombosis) with prasugrel compared with clopidogrel, but this did not achieve statistical significance.⁸⁰ The possible increase in efficacy will have to be weighed against an as yet unknown risk of bleeding.

AZD6140 and cangrelor are reversible P2Y₁₂ receptor antagonists that act directly without conversion to an active metabolite. AZD6140 belongs to the CPTP (cyclo-pentyl-triazolo-pyrimidine) class of P2Y₁₂ receptor antagonists, while cangrelor is an ATP analogue. The balance of evidence from clinical trials suggests that AZD6140 provides significantly greater and more consistent inhibition of platelet aggregation than clopidogrel, which may translate into improvements in clinical outcomes.^81,82 AZD6140 is currently in phase III development, and results from the PLATelet inhibition and patient Outcomes (PLATO) trial—a head-to-head outcomes study vs. clopidogrel enrolling 18 000 patients worldwide with acute coronary syndromes (unstable angina/non-ST-elevation MI, ST-elevation MI)—will be critical in determining the relationship between inhibition of platelet aggregation and clinical outcomes.

Other classes of antiplatelet agents under evaluation include thromboxane A₂/prostaglandin H₂ receptor antagonists (ifetroban, sulotroban, and GR 32191)^83–85 and protease-activated receptor antagonists (SCH 530348 and E5555).⁷⁰ The number and variety of agents in development suggests that the next decade may see substantial changes in the best-practice use of antiplatelet agents, and that improved options for prophylaxis with antiplatelet agents may reduce the burden of death and disease owing to late stent thrombosis. This will also allow patients to derive maximal benefit from later generation DES and self-dissolving stents.

	Summary

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
Drug-eluting stenting markedly reduces the need for revascularization compared with bare-metal stenting, but appears to be associated with an increased risk of late stent thrombosis. While late stent thrombosis remains a rare event with DES, the high mortality and other severe outcomes with which they are associated makes it critical to gain a better understanding of this risk and develop improved prophylactic strategies. Dual antiplatelet therapy with aspirin and clopidogrel is effective in reducing stent thrombosis, and guidelines recommend extending prophylaxis for at least 1 year after stenting to mitigate the risk of late stent thrombosis. However, a substantial proportion of people have a poor response to clopidogrel and/or aspirin and this may leave them at increased risk of death and adverse cardiovascular outcomes. New antiplatelet agents offering significantly greater and more consistent inhibition of platelet aggregation are currently in the late stages of development and may have benefits in reducing the risk of late stent thrombosis.

	Acknowledgements

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 
This work was supported by an unrestricted educational grant from AstraZeneca. Editorial assistance was provided by MediTech Media Ltd.

Conflict of interest: C.B. has received a lecture honoraria from Cordis, Medtronik, AstraZeneca, Sanofi–Aventis, and Essex-Pharma. M.Z. has no conflicts of interest to declare.

	References

Top Abstract Introduction Drug-eluting stents: the... Sirolimus-eluting stent... Paclitaxel-eluting stent... Zotarolimus-eluting stent... Drug-eluting stents: the risks Dual antiplatelet therapy with... The need for new... Summary Acknowledgements References

 

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