The platelet is a mediator of various thrombotic, endothelial and inflammatory processes, and, as such, is pivotal in the initiation and progression of atherosclerosis. Medical therapies targeting pathways involved in platelet aggregation and activation are fundamental in our treatment of unstable and treated atherosclerotic disease; they include established and developmental drugs aimed at inhibiting thromboxane A₂ (TxA₂), the platelet adenosine diphosphate (ADP) and glycoprotein IIb/IIIa receptors, thrombin, collagen, and von Willebrand factor.^w1 Antiplatelet agents are a mainstay of the treatment of patients with acute coronary syndromes (ACS) because they have been shown to reduce the risk of death, myocardial infarction (MI), and urgent revascularisation. Some patients, however, experience adverse cardiac events, such as coronary stent thrombosis, despite treatment with single or dual antiplatelet therapy. Whether such patients are resistant to the effects of these agents, or experience cardiac events for other reasons, has been the subject of debate. The evidence for “aspirin resistance” as a clinical entity, however, is weak, and it has not been conclusively demonstrated to cause ischaemic events. With other agents, by contrast, it is possible to identify a subset of patients with low response or non-response whose risk for ischaemic events is elevated and for whom dosage adjustment or other measures may be helpful. This article aims to present concisely various aspects of antiplatelet therapy non-response and potential ways to overcome it.

PRIMARY AND SECONDARY PREVENTION OF VASCULAR EVENTS BY ASPIRIN AND CLOPIDOGREL

The role of antiplatelet therapy in the secondary prevention of vascular events was confirmed by the Antithrombotic Trialists’ Collaboration Group meta-analysis. Around 140 000 high risk patients for vascular events due to pre-existing disease or a recent vascular event from 195 trials were included, and the pooled analysis of the general antiplatelet class, with all agents combined, yielded a significant 2.5% absolute reduction in the number of major vascular events (non-fatal MI or stroke, or vascular death). Although the analysis showed that antiplatelet therapy was associated with an increase in fatal and non-fatal bleeding, this was offset by an overall positive benefit.1

Although not a direct inhibitor of the thromboxane receptor, aspirin indirectly inhibits the actions of thromboxane via its effects on the cyclooxygenase (COX) enzyme. In the aforementioned meta-analysis, aspirin alone yielded an absolute 3.1% reduction in vascular event rates versus control. Aspirin dose comparisons for <75 mg, 75–150 mg and 160–325 mg yielded reductions of 2.1%, 4.3% and 3.3%, respectively, and similar serious bleeding risks. However, results for <75 mg doses were insignificant. Therefore, daily doses from 75 mg to 150 mg exhibit the ideal risk–benefit ratio.

On the other hand the use of aspirin and other antiplatelet agents as primary prevention measures has not been firmly established, even among diabetics.. The US Physicians’ Health Study, the largest study of aspirin primary prevention, showed that aspirin (325 mg on alternate days) reduced the absolute risk of first MI in supposedly healthy men by 0.9%, but did not reduce cardiovascular mortality in subjects aged >50 years.^w2 Conversely, results from the British Doctors’ Trial of male subjects did not show any significant benefit of aspirin (500 mg/day) on mortality from stroke and MI.^w3 Subsequent studies in individuals carrying one or more cardiovascular factors applied smaller doses of aspirin (from 75 mg to 100 mg) and demonstrated similar small absolute risk reductions in first non-fatal MI risk, but not mortality.^w4–6 A meta-analysis of those trials (including the Physicians Health Study) showed that aspirin significantly reduces the risk of first MI in both men and women (absolute risk reduction of 0.7%), but not that of non-fatal stroke and vascular death alone.^w7 Similarly, aspirin has been shown to have no benefit in primary prevention of cardiovascular events or mortality in diabetic patients.2 3

A recent meta-analysis^w8 suggested that aspirin may exert different effects in men and women. These results were in accordance with the WHI (Women’s Health Initiative) aspirin as primary prevention trial.4 Aspirin was found to reduce MI risk in men and stroke risk in women. In contrast there was no significant effect on the risk of MI in women or stroke in men. Aspirin had no effect on cardiovascular mortality rates in either, but significantly increased bleeding rates in both sexes.

Clopidogrel, an orally available ADP receptor antagonist, irreversibly binds to the G protein coupled P2Y12 receptor, inhibiting platelet aggregation and response to stimuli such as TxA₂ or thrombin. Secondary prevention with clopidogrel has been established by numerous studies, and dual antiplatelet therapy has become the mainstay of treatment in the coronary stenting era.

Clopidogrel was shown in the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial5 to be marginally superior to aspirin in reduction of cardiovascular events in high risk patients and similar to aspirin in safety. CAPRIE assessed the relative efficacy and safety of clopidogrel in the secondary prevention of vascular events in 19 185 patients with a recent MI or ischaemic stroke, or with symptomatic peripheral arterial disease (PAD). Clopidogrel was associated with a borderline significant absolute reduction of 0.51% in the rate of the primary composite end point of MI, ischaemic stroke or vascular death compared with aspirin and, as such, did not lead to a change in clinical practice.

The COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction Trial)6 suggested the addition of daily clopidogrel to aspirin post-MI led to an absolute 0.9% decrease in the composite primary end point of death, reinfarction, and stroke at 28 days, without a significant increase in bleeding events.

The addition of clopidogrel to standard treatment (aspirin and fibrinolysis) for patients presenting with acute ST elevation MI (STEMI) was examined in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy Thrombolysis in Myocardial Infarction 28) trial.7 The dose of clopidogrel was 300 mg loading and 75 mg/day maintenance; this resulted in a significant absolute reduction of 6.7% in the primary end point of occluded infarct related artery at angiography, or death/recurrent MI before angiography, and 2.5% absolute reduction in the composite end point at 30 days of cardiovascular death, recurrent MI or recurrent ischaemia requiring urgent revascularisation without a significant increase in major bleeding, primarily due to a reduction in reinfarction. Again, pre-treatment with clopidogrel compared to placebo resulted in a small 2.6% reduction in cardiovascular death, MI, or stroke in these patients who subsequently underwent coronary intervention with stenting (all patients stented received open label clopidogrel).8

The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events)^w9 and CREDO (Clopidogrel for the Reduction of Events During Observation)^w10 studies examined the long term effects of clopidogrel administration as a secondary prevention measure in high risk patients. The CURE trial randomised unstable angina/non-ST segment elevation MI (NSTEMI) patients to receive clopidogrel (300 mg loading dose followed by 75 mg/day) or placebo in addition to aspirin (75–325 mg/day) for 3–12 months. Clopidogrel plus aspirin was associated with a significant 2.1% absolute reduction in the rate of the primary composite end point of MI, stroke, or cardiovascular death compared with aspirin alone. There was a significant 1.0% increase in major bleeding complications and 2.7% increase in minor bleeding with the addition of clopidogrel. At total of 2658 patients randomised to placebo or clopidogrel in the CURE study subsequently underwent in-hospital percutaneous coronary intervention (PCI), and outcome was assessed prospectively in the PCI-CURE study.^w11 Patients were treated with open label thienopyridine for 2–4 weeks after PCI and then reverted back to their study medication for a mean of 8 months. Patients in the clopidogrel arm of the study exhibited both a short and long term reduction in cardiovascular death, MI and revascularisation, without concomitant increase in major bleeding rates. The results of the CREDO trial in patients undergoing elective PCI were similar.^w10 At 12 months’ follow-up, the combined antiplatelet regimen of aspirin with clopidogrel was associated with a significant 3% absolute reduction, relative to aspirin alone, in the composite end point of death, MI, or stroke with a non-significant increase in bleeding which was confined to procedural risk (index PCI or bypass surgery).

Clopidogrel appears to be similar to the combination of aspirin and dipyridamole in the secondary prevention of ischaemic stroke,9 although the trial failed to reach the stringent non-inferiority margins. The role of dual antiplatelet therapy in secondary prevention of cerebrovascular disease is even less clear. In the MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trial,10 the addition of aspirin to clopidogrel versus clopidogrel alone in high risk patients with recent ischaemic stroke or transient ischaemic attack for secondary prevention led to a significant increase in life threatening bleeds (1.3% absolute), with a non-significant absolute 1% risk reduction in major vascular events over 18 months. However, a loading then maintenance dose of clopidogrel in addition to aspirin was more effective than aspirin alone in reducing asymptomatic embolisation at 7 days in patients with recently symptomatic carotid stenosis in the CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial.11 It has been suggested that there may be a ceiling effect in platelet inhibition in ischaemic stroke beyond which the risk of haemorrhage might increase.

Two studies have also suggested more work is required, particularly in asymptomatic patients at high risk of future cardiovascular events. There was no significant benefit of dual antiplatelet therapy with clopidogrel compared to aspirin alone in reducing the rate of MI, stroke or cardiovascular death in patients with either stable cardiovascular disease or multiple cardiovascular risk factors in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial.12 Subgroup analysis did show borderline significance of dual antiplatelet therapy in symptomatic patients, but suggested an increase in cardiovascular death and moderate to severe bleeding in asymptomatic patients.

“VARIABLE RESPONSE” DEFINITION

Failure of antiplatelet agents to prevent the conditions for which they were given (recurrent ischaemic events despite compliance and optimal dose), or failure of the agents to achieve their effect as measured in the laboratory, broadly describe antiplatelet therapy resistance. Non-response or hypo-response to antiplatelet therapy may confer a high risk of repeat cardiovascular events, in particular of coronary stent thrombosis which carries a high mortality. Studies investigating the two aspects (laboratory and clinical) of variable response have given wide ranges: 5–45%13 ^{w12 w13} of aspirin treated patients and 4–30%^{w14 w15} of those on clopidogrel have therapeutic failure, depending on the assay.

Aspirin induced inhibition of cycloxygenase is evident at doses as low as 30 mg. However, increasing aspirin dose does not result in increased response. In contrast, doses of 75–150 mg/day may be more effective at preventing ischaemic events than doses up to 10 times as high.^w16 Thus, aspirin responsiveness is not normally distributed, but appears to be an all or none phenomenon. Circumstances such as reduced bioavailability (inadequate dose or intake), alternative ways of platelet activation, cycloxygenase gene polymorphisms, drug interactions, tachyphylaxis, and increased platelet turnover (myeloproliferative disorder or major surgery) lead to inadequate platelet inhibition and increased risk of ischaemic events.

The main drawbacks of clopidogrel treatment are a wide inter-individual variability in response, a relatively long onset of action, excess acute bleeding and bleeding risk during long term prescription. The variability of response to clopidogrel, in contrast to aspirin, is not an all or none phenomenon but rather a normally distributed phenomenon, with hypo-responders/non-responders to ADP induced platelet aggregation in the lower extreme end and hyper-responders at the extreme end of response.^w17 More potent P2Y12 inhibition shifts the curve to the right with a resultant increase in the number of responders but also bleeding risk, as well as a decrease in hypo-responders and ischaemic risk. However, non-response may be more likely due to poor compliance, inadequate dose, drug interaction, variability in metabolism (due to the two step hepatic metabolism), polymorphisms in P2Y12 receptors or hepatic cytochromes, diabetes and insulin resistance, and accelerated platelet turnover.

The optimal loading and maintenance dose of clopidogrel therapy has been studied extensively. The standard 75 mg per day maintenance dose takes 3–7 days to achieve maximal platelet inhibition.14 Therefore, a loading dose is required to achieve a more rapid inhibition of platelet function and 300 mg became standard. Data now suggest that a 600 mg loading dose in the PCI setting is safe and may reduce the incidence of platelet aggregation and major adverse cardiac events at 30 days.15^–17 Higher initial loading doses of clopidogrel from 300 mg to 600 mg or 900 mg induced a stepwise more rapid and higher levels of platelet inhibition in patients with non-ST elevation MI in the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) study,17 with no difference seen in bleeding complications. A significant increase in platelet inhibition with an increase in loading dose from 300 mg to 600 mg clopidogrel was also demonstrated in stable patients undergoing coronary angiography in the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) study,16 although no significant difference was shown between the higher doses of 600 mg and 900 mg. Particularly interesting was the finding that serum concentration of inactive prodrug and active thiol and inactive carboxyl acid metabolites did not differ significantly between the 600 mg and 900 mg doses, suggesting that intestinal absorption rather than metabolism may limit additional platelet inhibition at higher doses.18

Is there any benefit of reloading patients taking a chronic maintenance dose of clopidogrel before PCI? A 600 mg loading dose of clopidogrel in 20 patients taking a 75 mg/day maintenance dose of clopidogrel led to further suppression of platelet aggregation at 6 h.19 In the RELOAD study,20 a first loading dose of either 300 mg, 600 mg or 900 mg was given to patients on a maintenance dose of 75 mg/day. There was a stepwise increase in platelet inhibition from 300 mg to 600 mg to 900 mg seen at 4 h after first loading, with lower rates of hypo-response with the higher 900 mg dose. The same incremental benefit has been suggested in the ALBION17 study in clopidogrel naïve patients. This difference is even larger in RELOAD than in ALBION. The results of RELOAD are consistent with those of the ARMYDA-4 study,15 which suggested that pre-PCI loading with 600 mg confers neither significant additional inhibition in platelet reactivity (as measured by VerifyNow and light transmission aggregometry) nor additional clinical benefit compared with no reloading in patients eligible for elective PCI who are treated long term with 75 mg clopidogrel. Other studies suggest that the dose-effect relationship still exists for doses >900 mg.21 22

There is agreement that the loading dose should be administered before PCI. What is unclear is the precise time when the loading dose must be given to achieve a desirable therapeutic effect. Evidence from the CREDO trial suggests that with a 300 mg loading dose, 6 h is the minimum time required before PCI.^w10 With the 600 mg dose, 2 h may be sufficient,23 although maximal platelet inhibition may not be achieved until 3–4 h.24 The European Society of Cardiology (ESC) guidelines are in accordance with these results.25

In the case of stable angina patients undergoing elective angiography, is it safe to administer a loading dose of clopidogrel “on the table” once the decision to intervene has been made rather than preloading the patient? A loading dose of 600 mg clopidogrel in clopidogrel naïve patients leads to similar platelet inhibition at 6 h to patients on chronic 75 mg/day clopidogrel therapy.19 The PRAGUE 8 study concluded that a high (600 mg) loading dose of clopidogrel can be given safely in the catheterisation laboratory between coronary angiography and PCI in chronic stable angina patients, while administration before elective coronary angiography increased the risk of minor bleeding complications, without a significant benefit on periprocedural infarction.26

Is the current standard of 75 mg per day clopidogrel enough? As regards maintenance dose, 150 mg has recently been shown to provide more effective platelet inhibition (as determined by ADP induced turbidometric platelet aggregation, the VerifyNow P2Y12 assay, and vasodilator activated phosphoprotein (VASP) phosphorylation) than the current standard maintenance dose of 75 mg daily.27 28 The ISAR-CHOICE study27 showed that a 150 mg maintenance dose resulted in enhanced platelet inhibition compared with a standard 75 mg maintenance dose regimen 1 month after undergoing low risk PCI. The OPTIMUS (Optimizing anti-Platelet Therapy In diabetes MellitUS) study selectively studied diabetes mellitus patients with high post-treatment platelet reactivity while in their chronic phase of treatment.28 In these patients, although a 150 mg clopidogrel maintenance dose resulted in pronounced platelet inhibition of numerous platelet function measures compared with a 75 mg dose, a considerable number of patients still remained above the therapeutic threshold of post-treatment platelet reactivity used in this study. Currently, maintenance dose increase should be considered in high risk patients for subacute stent thrombosis in whom <50% platelet aggregation is demonstrated,29 and should be considered in individuals who have acute stent thrombosis in whom no other treatable/reversible cause can be identified (for example, stent malposition). To date, no long term follow-up results of patients receiving higher maintenance doses are available yet.

LABORATORY EVALUATION

Several laboratory methods have been proposed to evaluate platelets’ resistance to antiplatelet treatment. However, all these methods have their advantages and intrinsic limitations, which are presented briefly in table 1.

WHICH FACTORS CONTRIBUTE TO HETEROGENEOUS ANTIPLATELET THERAPY RESPONSE?

Multiple mechanisms account for variable response. Some of the metabolic, genetic and cellular aspects are summarised in fig 1. Particular attention should be paid to the issues of ideal dose and compliance to antiplatelet therapy.

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Figure 1

Pathophysiology of variable response to antiplatelet therapy. ADP, adenosine diphosphate; COX-1, cycloxygenase-1; GP, glycoprotein; PLT, platelet; TxA₂, thromboxane A₂.

The active thiol metabolite of clopidogrel which inhibits the P2Y12 platelet receptor is generated by a two step hepatic metabolism. Therefore, clopidogrel responsiveness may be due to genetic variation within hepatic metabolism (P450 enzymes) or within downstream targets of the active metabolite (P2Y12, platelet glycoproteins IIb/IIIa and Ia). The metabolic activity of the P450 enzymes varies considerably among individuals. Genetic polymorphisms of the cytochrome P450 isoenzymes such as CYP3A4*1B (rs2740574), CYP3A5*3 (rs776746) and CYP2C19*2 (rs4244285) have been implicated to modulate individual response to clopidogrel.^{w18 w19} However, only the association between the CYP2C19*2 (SNP rs4244285, AA genotype) polymorphism and variable clopidogrel response has been validated in both healthy and ACS individuals.30 ^w20 The association of platelet glycoproteins and P2Y12 receptor polymorphisms with clopidogrel variable response remains to be confirmed.^w21 Drugs which interact with or are metabolised by the cytochrome P450 pathway may influence clopidogrel bioavailability, and other interacting pathways other than clopidogrel metabolism may also be indirectly involved in response variability.31

CLINICAL STUDIES OF ANTIPLATELET THERAPY RESPONSE

Various studies have assessed clopidogrel and aspirin therapy response by ex vivo platelet studies. Substantial data have already underlined the association of laboratory non-response with adverse ischaemic outcomes including stent thrombosis, peri-procedural MI and post-angioplasty ischaemic events (table 2).

The CREST (Clopidogrel Effect on Platelet REactivity in Patients With Stent Thrombosis) study32 along with studies by Ajzenberg et al,^w22 Muller et al,^w14 Barragan et al33 and Buonamici et al^w23 have underlined the association of clopidogrel non-response with subacute and late stent thrombosis applying different laboratory methods.

Periprocedural adverse events have been studied by Matetzky et al34 and Cuisset et al.^w24 These studies stratified ST elevation myocardial infarction (STEMI) and non-STEMI patients respectively who underwent primary PCI into four quartiles based on the percentage reduction in ADP induced platelet aggregation after initiation of clopidogrel therapy, and reported that patients in the highest quartile of aggregation had significantly increased likelihood for recurrent cardiovascular events.

The prognostic role of pretreatment clopidogrel non-response on post-angioplasty risk assessment was evaluated by the EXCELSIOR study.35 The EXCELSIOR study, which remains the larger prospective study examining the prognostic role of clopidogrel non-response, reported that higher preprocedural platelet ADP induced aggregation after 600 mg clopidogrel loading dose was an independent predictor of early adverse clinical outcomes.

The PREPARE Post-Stenting (Platelet Reactivity in Patients and Recurrent Events Post-Stenting)36 study and the studies of Bliden et al^w25 and Geisler et al37 examined the prognostic value of high post-treatment platelet reactivity on post-procedural ischaemic events up to 6 months in patients undergoing non-emergent PCI (stable, unstable angina and non-STEMI). Higher platelet aggregation was associated with ischaemic events, even in patients with chronic clopidogrel therapy.

Finally Lev et al38 evaluated response to clopidogrel using light aggregometry in aspirin resistant and aspirin sensitive patients undergoing elective PCI. Both aspirin and clopidogrel non-responsive patients had greater cardiac enzyme elevation than responsive patients. This result came in accordance with the results of Chen et al39 who applied the VerifyNow method. Intriguingly, in the study by Lev et al,38 aspirin resistant patients exhibited a lower response to clopidogrel than aspirin sensitive patients, and 47.4% of aspirin resistant patients were also resistant to clopidogrel.

EMERGING APPROACHES THAT BYPASS POOR ANTIPLATELET THERAPY RESPONSE

Escalating the dose of antiplatelet therapy is one approach. As regards aspirin, substantial data are not in favour of dose increase for cardiovascular disease prevention as it rather increases the risk for gastrointestinal bleeding than prevents better ischaemic events.^w26 In the case of clopidogrel dose increase may be beneficial, as was discussed above.

Another plausible approach is the administration of novel P2Y12 receptor antagonists. One irreversible (prasugrel) and two reversible antagonists have already entered phase III studies. Prasugrel is a prodrug that requires only one cytochrome P450 dependent oxidative step to generate its active metabolite. The active metabolite of prasugrel is therefore generated much faster and at higher concentrations compared with clopidogrel, resulting in improved inhibition of ADP induced platelet aggregation and fewer non-responders.^w27

Prasugrel has been compared with clopidogrel in the JUMBO-TIMI 26 (Joint Utilization of Medications to Block platelets Optimally – Thrombosis In Myocardial Infarction 26) trial.40 This phase II randomised trial compared three different dose regimens of prasugrel with a standard dose of clopidogrel in 904 patients undergoing PCI with follow-up for 30 days. There was no significant difference between the groups in terms of the rate of bleeding complications at 30 days, and no difference between the three prasugrel dose regimens. There was also a (statistically insignificant) trend towards a benefit for patients treated with prasugrel compared with those treated with clopidogrel for the composite end point of major adverse cardiovascular events at 30 days.40

The PRINCIPLE-TIMI 44 trial assessed the degree of platelet inhibition in prasugrel and clopidogrel treated patients.41 This was a randomised, double blind, phase II crossover study of prasugrel compared with high dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned PCI. In the first phase, a prasugrel 60 mg loading dose was compared with a clopidogrel 600 mg loading dose, with a primary end point of ADP induced platelet aggregation at 6 h. In the second phase, subjects received prasugrel 10 mg or clopidogrel 150 mg (after the loading dose) for 14 days and then were crossed over to the alternate treatment for an additional 14 days. Both the loading dose and the maintenance dose of prasugrel resulted in significantly greater inhibition of platelet aggregation compared with that for clopidogrel (both p<0.0001). Patients treated with prasugrel therefore had higher levels of platelet inhibition and lower rates of hypo-response.

The phase III TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) is the largest randomised head to head trial to date, reporting a significant decrease in the rate of death from all cardiovascular causes in prasugrel treated patients compared with clopidogrel.42 The primary efficacy end point (death from cardiovascular causes, non-fatal MI, or non-fatal stroke) occurred in 781 patients (12.1%) receiving clopidogrel (300 mg loading, 75 mg/day maintenance) and 643 patients (9.9%) receiving prasugrel (60 mg loading, 10 mg/day maintenance). A significant reduction in the primary end point was seen in the prasugrel group by the first prespecified time point of 3 days which persisted throughout the follow-up period, presumably related to the more rapid onset of antiplatelet activity exhibited by prasugrel. From 3 days to the end of the study, the primary end point had occurred in 6.9% of patients receiving clopidogrel and 5.6% of patients receiving prasugrel. The prasugrel group also showed a significant reduction in the secondary end point of death from cardiovascular causes, non-fatal MI, or urgent target vessel revascularisation at 30 days. Both major and life threatening bleeding was significantly higher with prasugrel treatment (2.4% and 1.4%, respectively) compared to clopidogrel treatment (1.7% and 0.9%, respectively). Despite increased bleeding risk, net clinical benefit still favours prasugrel.42

In a subanalysis of the TRITON-TIMI 38 trial it was clearly shown that intensive antiplatelet therapy with prasugrel (60 mg loading dose/10 mg maintenance dose) resulted in more than a 1% absolute decrease in stent thrombosis and a significant reduction in major adverse cardiac events in comparison with standard clopidogrel treatment irrespectively of stent type.^w28 Another analysis classified TRITON-TIMI 38 patients on the basis of pre-existing history of diabetes mellitus and further according to insulin use, and reported that subjects with diabetes mellitus tended to have a greater reduction in ischaemic events (12.2% with clopidogrel vs 17.0% with prasugrel; hazard ratio (HR) 0.70; p<0.0001) compared to non-diabetic patients (9.2% vs 10.6%; HR 0.86; p<0.02) without an observed increase in TIMI major bleeding, and therefore a greater net treatment benefit with prasugrel compared with clopidogrel.43

Cangrelor^w29 and AZD6140 (a cyclopentyltriazolopyrimidine)^w30 are novel reversible P2Y12 inhibitors given intravenously and orally, respectively. They exhibit rapid onset of action and require no metabolic activation. Interestingly, administering AZD6140 to patients already treated with clopidogrel notably suppressed platelet aggregation responses regardless of the effect of clopidogrel.^w31 Further studies investigating their safety and efficacy are in the pipeline.

CONCLUSION

Variable responses to aspirin and clopidogrel are emerging clinical entities. There are no assays of aspirin resistance that are definitively linked to clinical outcome. By contrast, there is substantial evidence that patients vary considerably in their response to clopidogrel, and that patients with low response may be at increased risk for adverse cardiac events. It has not yet been clarified whether platelet function testing should become part of therapy for patients treated with these drugs, nor which test is most reliable. Nevertheless, some patients taking these agents do not derive clinical benefit as expected. Dosage adjustment and the use of newer antiplatelet agents with less variability in patient response may help overcome resistance to antiplatelet agents.