The first widely used antiplatelet agent, aspirin, continues to be standard therapy in ACS patients. The meta-analysis of the Antithrombotic Trialists’ Collaboration showed a 40% reduction in the rate of vascular events with aspirin.1
Introduction
The discovery of the thienopyridines, or ADP receptor antagonists, led to the development of more effective oral antiplatelet agents. Trials assessed dual antiplatelet therapy in high-risk patients versus aspirin alone and the significant benefits observed have resulted in dual antiplatelet therapy becoming a mainstay of treatment. As expected with more potent dual therapy, there is always a fine balance between prevention of thrombosis and bleeding risk.
There are still many challenges to overcome. Many patients, such as those with diabetes or with a previous stent thrombosis, are at high risk for further infarction, indicating the need for improvements in existing treatments. Considerable interest has also emerged regarding resistance to existing antiplatelet treatments and recent trials have shed much light on this, particularly the extent to which the variability of the effectiveness of antiplatelet agents is genetically determined. It has also been seen that some high-risk groups may not respond optimally to existing therapies.
Potential new therapeutic options are addressed in this section, including the recent introduction of prasugrel, a thienopyridine with different characteristics to clopidogrel.
Drug treatment of ACS – updated recommendations
Many international guidelines for ACS predate advances in antiplatelet treatment. The European Society of Cardiology (ESC) together with the European Association of Cardio-Thoracic Surgery (EACTS) has recently published new guidance on myocardial revascularisation.2 In the UK, NICE3 has recently updated its guidance on the early management of unstable angina and NSTEMI, which replaced previous guidance including the technology appraisal for clopidogrel. The thienopyridine prasugrel was also the subject of a NICE technology appraisal4 and was not considered further for the 2010 NICE guidance on unstable angina/NSTEMI.
Recommendations made for clopidogrel covered dosage and timing of administration. The two approaches to timing are to start treatment early (upstream) or to wait until coronary anatomy has been defined by catheterisation. The former approach has the potential to reduce early ischaemic events but also the potential for increased bleeding in patients who go on to early CABG. Also considered were the benefits of different loading doses of clopidogrel, 300 mg and 600 mg (NICE notes the higher dose is not currently licensed in the UK),3 and the benefits of clopidogrel with and without GP IIb/IIIa inhibitors on a background of aspirin therapy.
The NICE guideline recommends that once the risk of adverse cardiovascular events has been assessed, a loading dose of clopidogrel
300 mg plus aspirin should be offered to patients with a predicted six-month mortality risk >1.5% and no contra-indications.3
For particular groups of patients, NICE recommends the use of prasugrel with aspirin for patients who have diabetes or who have had a stent thrombosis on clopidogrel treatment (in addition to STEMI patients undergoing primary PCI).4
The ESC/EACTS guidelines2 recommend that (excluding patients with higher bleeding risk), prasugrel offers significant benefit over clopidogrel; that it confers a significant advantage in diabetic patients presenting with ACS; and that it should be used in patients who present with stent thrombosis while taking clopidogrel.2
In patients going on to CABG, discontinuation of clopidogrel may be considered five days before surgery if the risk of adverse events is considered low. For patients at intermediate or higher risk, it will be necessary to balance the individual risks of ischaemia and bleeding.
Length of antiplatelet therapy
NICE recommends that clopidogrel plus aspirin be continued for 12 months after the most recent episode of NSTE-ACS.3 Clinical review is advised before discontinuation of treatment: there are concerns that management facilitated by automated software programmes carry the danger of discontinuation without review. Some patients, such as those who have had a drug-eluting stent as part of complex PCI or those who have had late stent thrombosis, may be advised to remain indefinitely on dual antiplatelet treatment.
The ESC/EACTS guidelines concur that dual antiplatelet therapy should be given to all patients after ACS for one year, irrespective of revascularisation strategy. Certain patient populations, such as those at high risk of thromboembolic events, may benefit from more prolonged dual antiplatelet therapy.2
Premature discontinuation of dual antiplatelet therapy greatly increases the risk of stent thrombosis, MI and death:5 this American Science Advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent.
Concomitant therapy
Concomitant therapies, such as glycoprotein (GP) IIb/IIIa inhibitors, can be given alongside single or dual antiplatelet therapy. Some give a drug from this class routinely when the ACS patient arrives in hospital on the grounds that a treatment benefit exists whether or not the patient goes on to PCI. Other doctors discount clinical benefit upstream of PCI and wait for angiography results before considering their use.
The Boersma (2002) meta-analysis of six trials (PRISM, PRISM-PLUS, PARAGON-A, PARAGON-B, PURSUIT and GUSTO-IV ACS) compared GP IIb/IIIa inhibitors with placebo or control in NSTE-ACS patients not routinely scheduled for early revascularisation.6 The active treatment group had a significantly decreased chance of death or myocardial infarction (MI) at 30 days but also a significantly increased chance of major bleeding at 30 days. Another meta-analysis of the same six trials7 suggested that the benefit depended on the revascularisation strategy. The greatest benefit among patients not routinely scheduled for early revascularisation was seen in patients who underwent PCI during GPIIb/IIIa inhibitor infusion; the benefit was less marked in those who underwent PCI after drug discontinuation.
An analysis of the ACUITY TIMING and EARLY ACS trials published in the NICE 2010 guideline3 states that, compared with deferred use, upstream use significantly decreases the risk of MI and unplanned revascularisation at 30 days but at the expense of increased TIMI major and minor bleeding. In the ISAR-COOL trial,8 prolonged anti-thrombotic treatment (3–5 days) was compared with early intervention (<6 hours) in NSTE-ACS patients undergoing cardiac catheterisation. Those randomised to prolonged anti-thrombotic treatment had a significantly increased risk of death or non-fatal MI at 30 days.
Use of the GPIIb/IIIa inhibitors has decreased in the UK as clopidogrel has become more widely used.3 NICE felt that the evidence is less convincing for routine use of the former class of drugs in the medical management of patients with NSTE-ACS, especially with the increased use of early angiography and revascularisation. There maybe a place for IV eptifibatide or tirofiban as part of early management of patients at intermediate or higher risk of adverse cardiovascular events who are scheduled for angiography within 96 hours of hospital admission (this is a recommendation for off-label use).
Triple therapy with clopidogrel, GP IIb/IIIa inhibitors and aspirin is another area of interest although not licensed in the UK.
Maximising the consistency of antiplatelet response
Inter-individual variability of platelet inhibition with clopidogrel leads to a potential risk for recurrent atherothrombotic events.9 Other agents, such as the thienopyridine, prasugrel, appear to give a more consistent antiplatelet response.
In a review, Campo10 states that about 20% of patients who receive clopidogrel are either non-responders or poor responders. These patients have an increased risk of death, reinfarction and stent thrombosis.10 Poor/non-responsiveness is poorly defined and the literature reports variation between 5 and 56%.11 The mechanisms leading to poor responsiveness may include genetic factors (see below), accelerated platelet turnover, high baseline platelet reactivity, under-dosing and poor compliance. Switching to a different thienopyridine, re-evaluation of existing therapies and improved patient education are all potentially useful strategies in maximising the antiplatelet response.
Pharmacokinetics and response variability in antiplatelet agents
A two-way cross-over study12 found that prasugrel 60 mg results in more rapid, potent and consistent inhibition of platelet function than clopidogrel 300 mg in healthy individuals (see figure 1). In all, 68 healthy volunteers received one of the two thienopyridines orally for the initial dosing period and then crossed over to the other agent after a two-week washout period. Prasugrel 60 mg was associated with significant inhibition of platelet aggregation (IPA) in response to ADP as early as 15 minutes after treatment compared to baseline (p=0.0014); the level of IPA was significantly higher with prasugrel throughout the 24 hours after drug administration; the peak IPA was nearly twice as high with prasugrel; and there was a more consistent response between subjects in the magnitude of IPA received. The authors conclude that pharmacokinetic differences may account for the different effects of the two drugs, and that the rapid and consistent response may be of value both during urgent intervention and during long-term maintenance therapy.
Greater exposure to prasugrel’s active metabolite may result in a more favourable risk:benefit ratio. A study by Payne,9 in healthy volunteers, compared the level of platelet inhibition and the degree of response variability achieved by prasugrel (60 mg loading dose and 10 mg maintenance dose) against those achieved by clopidogrel (300 mg and 75 mg). At 30 minutes after the loading dose, prasugrel achieved greater mean inhibition of platelet aggregation (IPA) to 20 mM ADP than clopidogrel. During the maintenance phase, the mean IPA to 20 mM ADP exceeded 75% with prasugrel and was higher than that achieved with clopidogrel. The IPA was also less variable with prasugrel.
In this study, 39% of subjects could be classified as poor responders (IPA <20% at four hours or <25% at 24 hours) to clopidogrel 300 mg but all subjects responded to the loading dose of prasugrel. During the maintenance phase, all subjects taking prasugrel could be classified as responders whereas 9% were poor responders to clopidogrel. The active metabolites of prasugrel and clopidogrel are equally potent but, in vivo, a proportion of clopidogrel is hydrolysed in the intestine and/or liver to an inactive metabolite and then converted to its active metabolite by CYP enzymes. These steps limit both the rate and extent
of active metabolite formation in comparison to prasugrel.
The JUMBO-TIMI 26 trial13 was a dose-ranging study designed to assess the safety of prasugrel and clopidogrel when given at the time of PCI, in particular to establish whether the more powerful and consistent effects of prasugrel resulted in an unacceptable risk of bleeding. The study randomised 905 patients who were candidates for elective or urgent PCI. Subjects were randomised to three different loading and maintenance doses of prasugrel or to clopidogrel, with randomisation stratified by the investigators’ decision to use a GP IIb/IIIa inhibitor during PCI. All subjects received aspirin and UFH, and were monitored for 30 days. The primary end point was TIMI major plus minor non-CABG-related bleeding in the treatment groups. Bleeding rates were low: 0.7% experienced major bleeding, 1.1% minor bleeding and 2.4% minimal bleeding, with two thirds of episodes related to instrumentation. There was no significant difference between patients treated with prasugrel and those treated with clopidogrel (1.7% versus 1.2%, hazard ratio 1.42). In prasugrel-treated patients, there were numerically lower incidences of the primary efficacy composite end point (30-day major adverse cardiac events) and of the secondary end points MI, recurrent ischaemia and clinical target vessel thrombosis. The results of this trial were the foundation of the large phase III trial of prasugrel, TRITON-TIMI 38.14
Essentials of TRITON-TIMI 38
The Trial to assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel vs. Thrombolysis In Myocardial Infarction (TRITON-TIMI 38)14 was a landmark phase III trial assessing prasugrel and clopidogrel. It involved patients with ACS and scheduled PCI, and suggested that faster, greater and more consistent platelet inhibition is associated with reduced rates of ischaemic events.
The trial enrolled 13,608 patients, three quarters with moderate-to-high risk unstable angina or NSTEMI and one quarter with STEMI. Patients received a loading dose of 60 mg prasugrel or 300 mg clopidogrel, and maintenance doses of prasugrel 10 mg or clopidogrel 75 mg daily. All patients also received aspirin, and the median duration of therapy was 14.5 months. Ninety-four percent of patients received at least one intracoronary stent, and 14% of patients had multi-vessel PCI. The primary efficacy end point was a composite of rate of death from cardiovascular causes, non-fatal MI or non-fatal stroke during the follow-up period. Key safety end points were TIMI major bleeding or TIMI life-threatening bleeding not related to CABG, and TIMI major or minor bleeding.
Prasugrel demonstrated a 2.2% absolute reduction and a significant 19% relative risk reduction in the primary efficacy end point compared to clopidogrel (12.1% of clopidogrel patients vs. 9.9% of patients receiving prasugrel) (see figure 2). Rates of ischaemic events were also reduced in the prasugrel group, with a 2.3% absolute reduction and a 24% relative reduction in MI. A significant reduction in the primary end point was seen by the first pre-specified time point, three days (5.6% clopidogrel group vs. 4.7% prasugrel group, p=0.01), which persisted throughout the follow-up period. This difference was driven largely by the greater reduction in MI in the prasugrel group (9.7% in the clopidogrel group vs. 7.4% in the prasugrel group, HR 0.76, p<0.001) throughout the study. Subgroup analysis showed the need for urgent target vessel revascularisation was also reduced by 34% in the prasugrel group (3.7% vs. 2.5%, p<0.001), while stent thrombosis was reduced by 51% (2.4% vs. 1.1%, p<0.001).
All patients received aspirin. Bleeding rates were higher in patients treated with prasugrel than in patients treated with clopidogrel. Major bleeding occurred in 2.4% and 1.8%, respectively (HR 1.32, p=0.03); the rate of life-threatening bleeding was also greater with prasugrel (1.4% vs. 0.9%, p=0.01).
A pre-specified analysis of the trial which examined net clinical benefit, i.e. rates of death from any cause, non-fatal MI, non-fatal stroke and TIMI major haemorrhage showed that the net benefit significantly favoured prasugrel. However, three patient groups were identified who did not have a net clinical benefit with prasugrel treatment. Patients with a previous stroke or transient ischaemic attack had net harm from prasugrel; patients aged 75 years and above had no net benefit; and patients weighing less than 60kg had no net benefit. Patients with at least one of these three risk factors had higher rates of bleeding than those without them. The risks of intensive bleeding appear to be enhanced in these patients, and additional caution is required in their management. The summary of product characteristics should be consulted for further information.
Antiplatelet treatment and stent thrombosis
Findings from the sub-analysis of TRITON-TIMI 38 show that of 13,608 patients randomised into TRITON-TIMI 38, a total of 12,844 received a stent: 6,461 received a bare-metal stent and 5,743 had a drug-eluting stent.15 Overall, a 19% reduction in the primary end point was recorded with prasugrel compared with clopidogrel among patients who had a stent (9.7% vs. 11.9%, p=0.0001). The net clinical benefit significantly favoured prasugrel treatment (12.0% vs. 13.7%, p=0.002). There was a 51% reduction in stent thrombosis with prasugrel between day 0 and day 3; definite or probable stent thrombosis (ARC designations) were reduced by 59% within 30 days of stent placement. The analysis confirmed the adverse relationship between stent thrombosis and clinical outcomes, with 22% of such patients dying and 89% experiencing a non-fatal MI or dying. Figure 3 shows the relative risk reduction for early and late stent thrombosis in the TRITON-TIMI 38 study.
ACS in the patient with diabetes
Cardiovascular mortality risk increases continuously with blood glucose levels: elevated blood glucose, diabetes or both contribute to three million cardiovascular deaths globally a year.16 In the United States, nearly two thirds of individuals with diabetes die from cardiovascular disease.17 Diabetes confers an adverse prognosis in ACS.
The recently reported Euro Heart Survey18 on diabetes and the heart showed that abnormal glucose regulation was more common than normal glucose regulation in patients with coronary artery disease (CAD). In the study of 4,196 patients, 31% had diabetes. Looking at the subgroup of those with acute CAD without known diabetes, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group, these proportions were 37% and 14%, respectively.
In the Donahoe study,17 patients with ACS were pooled from 11 TIMI studies from 1997 to 2006, giving a cohort of 62,036 patients. Of these patients, a total of 46,577 had STEMI, 15,459 NSTEMI and 10,613 (17.1%) had diabetes. Coronary angiography data were available for 25.1% of patients. Among this subset, patients with diabetes were more likely to have multi-vessel coronary disease (62.0% vs. 48.1%, p<0.001). At 30 days, mortality was significantly higher among patients with diabetes compared to those without diabetes following either unstable angina/NSTEMI (2.1% vs. 1.1%; p<0.001) or STEMI (8.5% vs. 5.4%; p<0.001). At one year, diabetes remained a significant independent factor associated with all-cause mortality for patients presenting with unstable angina/NSTEMI (HR 1.65) and for patients presenting with STEMI (HR 1.22). By one year, the mortality of patients with diabetes presenting with unstable angina/NSTEMI approached that of patients without diabetes but with STEMI.
Platelet aggregation and activation are increased in subjects with diabetes compared to those without:19 in this study, there were also higher numbers of clopidogrel non-responders among patients with diabetes. This suggests that decreased sensitivity to antiplatelet drugs may contribute to the increased antithrombotic risk observed in diabetes. A further study by Angiolillo20 confirmed that patients with type 2 diabetes have higher platelet reactivity compared to those without, and found that high platelet reactivity was associated with atherothrombotic complications even in patients taking dual antiplatelet therapy. It was the strongest predictor of major adverse cardiac events over two-year follow-up, with a three-fold increase in event rates. The authors suggest that there is a need for tailored anti-thrombotic regimens in these high-risk patients. This is considered in more detail later.
Antiplatelet treatment for diabetes patients
A pre-specified subgroup analysis of TRITON-TIMI 38 with patients stratified by diabetes status showed that subjects with diabetes tended to have a greater net treatment benefit, with prasugrel compared to clopidogrel (figure 4).21 There was a greater reduction in ischaemic events without an observed increased in TIMI major bleeding. Of the 13,608 patients randomised into TRITON-TIMI 38, a total of 3,146 (23%) had diabetes and 776 (6%) were on insulin treatment. There were some differences between patients with diabetes and those without: those with diabetes were more likely to have unstable angina or NSTEMI, to be older, to be female, and to have a higher median body mass index (BMI). They were also more likely to have had a previous MI or CABG. Patients with diabetes were also more likely to have multivessel intervention and at least one drug-eluting stent.
Rates of thrombotic events such as MI, cerebrovascular accident and stent thrombosis were higher among patients with diabetes than among those without diabetes. After controlling for baseline demographic and treatment differences, diabetes was an independent predictor of ischaemic outcomes, including the primary end point of the trial (cardiovascular death/non-fatal MI/non-fatal stroke), MI, stent thrombosis and net clinical benefit. Prasugrel was more effective than clopidogrel in reducing events among patients with diabetes. A 14% reduction in the primary efficacy end point was seen with prasugrel treatment among patients without diabetes (p=0.02), while among those with diabetes, the primary end point was reduced by 30% (p<0.001). The NNT to prevent one primary end point event among subjects with diabetes was 21.
The reduction in the primary end point was largely driven by a lower incidence of MI (an 18% reduction in subjects without diabetes compared to a 40% reduction in subjects with diabetes). Interestingly, in this study subjects with diabetes had similar non-CABG-related TIMI major bleeding rates regardless of treatment with prasugrel or clopidogrel (2.5% and 2.6%, respectively, at 15 months). The greater effect of prasugrel compared to clopidogrel in this analysis supports the theory that greater platelet inhibition results in better outcomes among patients with diabetes. Prasugrel was more effective than clopidogrel both in patients who were taking and those who were not taking a GP IIb/IIIa inhibitor.
Results of this trial led to the licensing of prasugrel in the UK and and the NICE technology appraisal of prasugrel,4 which said that that it was appropriate to consider prasugrel for treatment of people with diabetes having PCI, since diabetes mellitus represents an important and definable risk factor for more severe cardiovascular disease and greater risk of cardiovascular events during and after PCI. It concluded that use of prasugrel for patients with diabetes undergoing PCI could be considered a cost-effective use of NHS resources and should be recommended as an option.
More recent findings on platelet reactivity
The platelet substudy of TRITON-TIMI 38 shows that prasugrel results in greater inhibition of ADP-mediated platelet function than clopidogrel in patients with ACS.22 In this substudy, 125 patients were prospectively enrolled to evaluate ADP-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) and 31 patients to evaluate ADP-stimulated platelet aggregation. VASP platelet reactivity index was lower in patients treated with prasugrel than in patients treated with clopidogrel both one to two hours after PCI and at 30 days. Maximal platelet aggregation was lower in patients treated with prasugrel than in patients treated with clopidogrel both hours after PCI and at 30 days (p<0.001). Similarly, thienopyridine hyporesponsiveness was more frequent in patients treated with clopidogrel than patients treated with prasugrel at the shorter and longer measurement times. These findings would tie in with the observations of fewer ischaemic events and more bleeding early and late following PCI in patients treated with prasugrel.
Fast inhibition of platelet aggregation is important within the setting of ACS and PCI: interestingly, it appears that slow response to clopidogrel within the first hour is a reliable marker of low response at 24 hours and high post-treatment platelet reactivity.23 This study was a post-hoc analysis of the ALBION24 study: kinetic profiles of maximal platelet aggregation (MPA) and change in MPA were studied at eight time points after clopidogrel loading in patients with NSTE-ACS. Inflammatory markers (PAC-1 and P-selectin) and VASP were also measured.
Fifty-five percent of patients were slow responders. Non-current smoking and body mass index 25kg/m2 or above were associated with lower and slower responses. High post-treatment platelet reactivity was more frequent in slow responders, and there was a dose-response relationship of clopidogrel on change in MPA. Slow responders also had a slower and lower decrease in inflammatory markers and a higher VASP index at six hours.
A maintenance dose (MD) of prasugrel 10 mg has recently been shown, in ACS patients, to result in significantly greater platelet inhibition than clopidogrel given at a higher than usual maintenance dose and after a 900 mg loading dose (LD)25 (300 mg is the licensed LD in the UK for ACS-PCI). Patients with NSTE-ACS (n=56), treated with aspirin and clopidogrel 900 mg LD, were randomised to receive a maintenance dose of either prasugrel 10 mg or clopidogrel 150 mg. After 14 days, subjects were switched to the comparator drug for a further 14 days. Prasugrel reduced maximum platelet aggregation (MPA) from the LD level (41.2% to 29.1%, p=0.003). Poor response was 0-6% for the prasugrel MD and 4-34% for the clopidogrel MD, indicating a more complete and consistent response with prasugrel.
Platelet function tests can now help the physician to identify within minutes those who are likely to be clopidogrel non-responders.
Pharmacogenetics of clopidogrel
There is some evidence that the antiplatelet effects of clopidogrel are determined by genetic factors, and that this may have a bearing on cardiovascular events.26 Clopidogrel is transformed into its active metabolite by cytochrome P-450 (CYP) enzymes; the genes encoding CYP enzymes are polymorphic.
Mega and colleagues26 compared carriers and non-carriers of a reduced-function CYP2C19 allele among 16 healthy subjects and among 1,477 subjects with acute coronary syndromes within TRITON-TIMI 38. Among the healthy subjects, carriers of at least one reduced-function allele had reduced plasma exposure to the active metabolite of clopidogrel and an absolute reduction in maximal platelet aggregation in response to clopidogrel (both p<0.001). Among TRITON-TIMI 38 subjects, carriers of this allele had a relative increase of 53% in the composite primary efficacy outcome (12.1% vs. 8.0%, p=0.01) and treble the risk of stent thrombosis (2.6% vs. 0.8%, p=0.02).
Simon and colleagues enrolled 2,208 patients presenting with an acute myocardial infarction to a nationwide French registry;27 these patients received clopidogrel and were followed up for one year. The relationship of genetic polymorphisms affecting clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19) and biological activity (P2RY12 and ITGB3) to risk of all-cause death, non-fatal stroke and myocardial infarction was examined.
The single nucleotide polymorphisms (SNPs) CYP3A5, P2RY12 and ITGB3 were not associated with risk of adverse outcome. However, patients with two variant alleles of ABCB1 had a higher rate of cardiovascular events at one year than those with the wild-type genotype (15.5% vs. 10.7%). Patients carrying any two CYP2C19 loss-of-function alleles had a higher event rate compared to those with none (21.1% versus 13.3%). The rate of cardiovascular events was 3.58 times higher among the 1,535 patients with two loss-of-function alleles who underwent PCI during hospitalisation.
Carriers of the loss-of-function mutant allele of CYP2C19 also have higher risk of stent thrombosis compared with wild-type allele carriers after PCI. Sibbing and colleagues28 followed for 30 days 2,485 consecutive patients undergoing coronary stent placement after pre-treatment with clopidogrel 600mg (an off-licence dose). The incidence of stent thrombosis was 3.8 times higher in loss-of-function allele carriers (1.5% versus 0.4%, p=0.007). The risk was highest (2.1%) among patients homozygous for the loss-of-function allele.
High on-treatment platelet reactivity (HTPR) after a clopidogrel loading dose predicts the risk of thrombotic events after PCI.29 In a prospective study of patients undergoing PCI, body mass index (p=0.01), diabetes (p=0.03) and acute coronary syndrome (p=0.02) were clinical predictors of HTPR, and the mutant *2 allele CYP2C19 polymorphism was also significantly associated. In most cases, dose adjustment with platelet reactivity monitoring improves the HTPR: BMI was the only predictor of failed dose adjustment in this study.
Genetic testing to identify carriers of this allele can now be done at the bedside before the patient is taken to the catheter lab.
Conclusion
Looking ahead, while other products are under investigation and until such time as they are licensed, reviewed by NICE and widely adopted, physicians should optimise therapy with the currently available options.
It is clear that there is no single treatment for all patients in ACS. Physicians must choose the right evidence-based treatment for patients on an individual basis. With the increasing evidence base in this area, we are now on the brink of entering a new era of personalised treatment for this common disease.
References
1. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002;324:71–86.
2. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association of Cardio-Thoracic Surgery (EACTS). Guidelines on myocardial revascularization. Eur Heart J 2010. doi:10.1093/eurheartj/ehq277.
3. The National Institute for Health and Clinical Excellence (NICE). Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. Clinical guideline CG94. London: NICE, 2010.
4. NICE. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. NICE technology appraisal TA 182 issued October 2009. Available from www.nice.org.uk
5. Grines CL, Bonow RW, Casey DE et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. Circulation 2007;115:813–18.
6. Boersma E, Harrington RA, Moliterno DJ et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized controlled trials. Lancet 2002;359:189–98.
7. Roffi M, Chew DP, Mukherjee D et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to revascularization strategy. Eur Heart J 2002;23:1441–8.
8. Neumann KJ, Kastrati A, Pogatsa-Murray G et al. Evaluation of prolonged anti-thrombotic pre-treatment (“cooling off strategy”) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA 2003;290:1593–9.
9. Payne CD, Li YG, Small DS et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007;50:555–62.
10. Campo G, Fileti L, Valgimigli M et al. Poor response to clopidogrel: current and future options for its management. J Thromb Thrombol 2010; Feb 16. Epub ahead of print.
11. Serebruany VL et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45:246–51.
12. Brandt JT, Payne CD, Wiviott SD et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007;153:66.e9–66.e16.
13. Wiviott SD, Antman EM, Winters KJ et al. Randomised comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention. Circulation 2005;111:3366–73.
14. Wiviott SD, Braunwald E, McCabe CH et al for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2007;357:2001–15.
15. Wiviott SD, Braunwald E, McCabe CH et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomized trial. Lancet 2008;371:1353–63.
16. Danaei G, Lawes CMM, Vander Hoorn S et al. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet 2006;368:1651–9.
17. Donahoe SM, Stewart GC, McCabe CH et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765–75.
18. Bartnik M, Ryden L, Ferrari R et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J 2004;25:1880–90.
19. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54:2430–5.
20. Angiolillo DJ, Bernardo E, Sabate M et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007;50:1541–7.
21. Wiviott SD, Braunwald E, Angiolillo DJ et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction 38. Doi 10.1161/circulationaha.108.791061
22. Michelson AD, Frelinger AL, Braunwald E et al; TRITON-TIMI 38 Investigators. Pharmacodynamic assessment of platelet inhibition by prasugrel versus clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009;30:1753–63.
23. Bellemain-Appaix A, Montalescot G, Silvain J et al. Slow response to clopidogrel predicts low response. J Am Coll Cardiol 2010;55:815–22.
24. Montalescot G, Sideris G, Meuleman G. A randomised comparison of high clopidogrel loading doses in patients with non-ST elevation acute coronary syndromes. J Am Coll Cardiol 2006;48:931–8.
25. Montalescot G, Sideris G, Cohen R et al. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomized, double-blind ACAPULCO study. Thromb Haemost 2010;103:213–23.
26. Mega L, Close SL, Wiviott SD et al. Cytochrome P-450 polymorphisms and response to clopidogrel. Thromb Haemost 2009;360:354–62.
27. Simon T, Verstuyft C, Mary-Krause M et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363–75.
28. Sibbing D, Stegherr J, Latz W. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009;30:916–22.
29. Bonello-Palot N, Amero S, Paganelli F et al. Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009;104:1511–15.
