Acute coronary syndromes (ACS) are a major reason for death and morbidity in the industrialised world. One of the most successful treatments for ACS has been strategies to target the platelets and inhibit their function.
Mechanisms of Platelet Activation
Thrombus formation in the arteries is dependent on platelets and their ability to attach to the injured wall despite the rapid arterial blood flow. Once attached, the platelets initiate thrombus formation by triggering both platelet aggregation and coagulation (see Figure 1).
The platelet undergoes a series of activation steps before granulation (see Figure 2). The primary step is activation by collagen, von Willebrand factor and other substances. Two important positive feedback loops are then activated: cyclo-oxygenase-1 (COX-1) generates thromboxane, and adenosine diphosphate (ADP) is released. Thromboxane activates the thromboxane receptor and ADP activates the P2Y12 and P2Y1 receptor on the platelet surface, resulting in changes in the platelet shape, with annexin expression generating thrombin, which in turn activates the coagulation system. Furthermore, the activated platelet excretes alpha and dense granulae resulting in release of growth factors, vasocontractile agents and adhesive, pro-thrombotic and inflammatory proteins. The platelets form platelet–monocyte complexes that lead to activation of inflammatory cells. The final step is activation of glycoprotein IIb/IIIa (GpIIb/IIIa) receptors, followed by platelet aggregation.1 We now have an opportunity to choose between different principles of platelet inhibition. Should we inhibit early in this cascade or later?
Aspirin for the Treatment of NSTE-ACS and STEMI
Aspirin has become the cornerstone platelet-inhibitory treatment for ACS, especially as it is such an inexpensive treatment option. After a non-ST-segment-elevation myocardial infarction (STEMI)-ACS (NSTE-ACS), aspirin reduces the risk of MI by nearly half.2 For the STEMI population, aspirin has a similar effect to thrombolytics and even reduces mortality by 20%.3 However, there are limitations. Aspirin causes bleeding complications and the net clinical benefit is not obvious in primary prevention.4 Furthermore, we have limited evidence from randomised clinical trials of long-term aspirin treatment, and yet we recommend it for lifelong treatment in all patients after an ACS.
Clopidogrel for the Treatment of NSTE-ACS and STEMI
The first indication for using ADP-receptor blockers came from the early stent era. Stenting of the blood vessel after balloon angioplasty decreased the problem with dissection and acute closure of the vessel. However, stents created a new difficulty – stent thrombosis.
The platelets recognise the metal as a foreign surface to the body and aggregate. Two factors helped to ameliorate this problem. First, the usage of intravascular ultrasound enabled percutaneous coronary intervention (PCI) operators to size the stents appropriately so that they were well positioned into the vessel wall. Second, the ADP-receptor blocker ticlodipine was used in combination with aspirin to inhibit platelet aggregation.
Ticlopidine has the disadvantage that it causes neutropenia in a small percentage of patients. It was therefore further developed into clopidogrel (Plavix®), which does not cause this side effect. Clopidogrel actually has a slightly weaker platelet-inhibitory effect compared with ticlopidine, but the better safety profile without the need to monitor neutrophil counts resulted in favour of clopidogrel.
When comparing clopidogrel with aspirin, clopidogrel was only marginally better in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study.5 However, when used as an adjunct to aspirin in patients with ACS in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, clopidogrel reduced the incidence of myocardial infarction by 20%.6 The CURE trial included patients treated both medically and invasively, and the effect was similar for both groups. The Clopidogrel for Reduction of Events During Observation (CREDO) study examined an elective PCI population and demonstrated superior long-term effects of pre-treatment and prolonged therapy compared with only one-month clopidogrel post-stenting.7 If pre-treatment was initiated at least six hours before PCI, there was a positive 28-day outcome. Later, a meta-analysis showed that pre-treatment has a major clinical effect in an NSTE-ACS population.8
Clopidogrel treatment for STEMI patients has never been tested with the now recommended direct PCI treatment strategy. However, it has been studied in the large (40,000-patient) ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), where patients were treated medically with or without thrombolysis.9
Here, clopidogrel added to aspirin reduced the incidence of myocardial infarction and mortality. A benefit for STEMI patients was also seen in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trial, in which patients were transferred after thrombolysis to PCI some days later.10 Extrapolations of these studies have led to a strategy and recommendation to give clopidogrel as soon as possible after diagnosing a STEMI, often in the ambulance; however, this upstream treatment is not based on hard evidence, but is routinely practiced.
The duration of clopidogrel treatment after ACS has been discussed, and based on the CURE study treatment for 12 months is currently recommended. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, patients with manifest atherosclerotic disease and patients with risk factors only but no established atherosclerotic disease were randomised to clopidogrel or placebo.11 The CHARISMA trial failed to show improvement in the entire population. However, a subgroup analysis of the atherosclerotic arm did show a benefit in that group, but in the risk factor group clopidogrel harmed the patients. Long-term clopidogrel should not generally be used, but as there was a benefit in patients with established vascular disease, long-term treatment could be considered as secondary prevention for selected cases and patients with drug-eluting stents.
Aspirin and Clopidogrel Resistance
‘Resistance’ is a commonly used word to describe insufficient effect of aspirin or clopidogrel. For some clinicians it means that a patient suffers from a new myocardial infarction despite aspirin treatment. For a basic researcher, true aspirin resistance is lack of inhibition of arachidonic-acid-induced platelet aggregation even when aspirin is added ex vivo. This latter resistance is highly unusual.12 However, it is common to see a weak or absent effect of aspirin for many other platelet agonists in patients on aspirin treatment. This may depend on low compliance, reduced uptake or the fact that platelet activators use other positive feedback mechanisms such as ADP release, instead of COX-1 and generation of thromboxane.
Aspirin resistance can also be defined as high urinary levels of thromboxane degradation products; however, thromboxane can be generated by cells other than the platelets, i.e. inflammatory cells. A patient with a high level of atherosclerotic inflammation will therefore continue to have high metabolite levels in urine even if the platelets are inhibited. It is therefore not surprising that these patients do not benefit from addition of clopidogrel.13 Overall, we do not have any causal treatment for aspirin resistance. Increasing the dose beyond 100mg does not give additional effect in larger meta-analyses or in the recent Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS (CURRENT/ OASIS)-7 trial; instead, it may increase bleeding complications.14 What we can do is to improve metabolic control, reduce cholesterol levels and blood pressure and get the patient to stop smoking and exercise more; however, these therapies should be implemented in all patients anyway.
Clopidogrel has a variable response and a large group of patients can be referred to as clopidogrel-resistant. The pathogenesis of clopidogrel resistance is more precisely defined biochemically than for aspirin resistance. Several studies have now shown that the inhibitory effect of clopidogrel on ADP-induced platelet aggregation is strongly correlated to the plasma level of its active metabolite.15 Clopidogrel is a prodrug that needs to be converted by cytochrome p450-enzymes (CYP) in the liver into its active metabolite, which then binds irreversibly to the ADP-receptor P2Y12. Several esterases inactivate the prodrug. Common genetic polymorphisms (20–25% of the population) in the CYP2C19 gene result in lower plasma levels of active metabolite, weaker ADP inhibition (stronger platelet aggregation) and higher incidence of stent thrombosis and myocardial infarction;16 therefore, clopidogrel resistance is a liver disease.
Poor responders to clopidogrel defined by pharmacodynamic platelet aggregation tests have been shown to have an increased risk of stent thrombosis and myocardial infarction in a large number of clinical studies.17 When using the discrimination levels of these pharmacodynamic tests to define clinically poor responders, lower levels of active metabolite in the poor responder groups were found.18 Interestingly, another important clopidogrel-resistant group, patients with diabetes, also displayed lower levels of active metabolite. The difference did not seem to rely on changes on the receptor level, as both poor responder and diabetic platelets responded normally to ADP before clopidogrel treatment. Furthermore, they responded fully to active metabolite added ex vivo.18
Some registry studies have indicated that proton pump inhibitors can cause clopidogrel resistance by interaction through liver enzymes. However, in larger randomised trials this could not be confirmed.
Increased doses of clopidogrel can improve its effect. However, the recently presented CURRENT/OASIS-7 trial could not demonstrate any significant effect of 600mg loading dose combined with 150mg maintenance dose for seven days of clopidogrel compared with 300/75mg despite a population of more than 25,000 patients (oral presentation, European Society of Cardiology [ESC] 2009). However, a subgroup analysis (performed even if the primary end-point was negative) did find higher doses in the PCI population to be beneficial. However, as the protocol used upstream clopidogrel loading and treatment, the PCI population cannot be identified beforehand. The Gauging Responsiveness With A VerifyNow Assay – Impact On Thrombosis And Safety (GRAVITAS) trial (due to end September 2009) will shed further light on this matter by randomising clopidogrel non-responders to either higher-dose or lower-dose chronic clopidogrel treatment.
Glycoprotein IIb/IIIa Inhibitors for the Treatment of NSTE-ACS and STEMI
GpIIb/IIIa inhibitors have no effect on early platelet activation steps (see Figure 2). Instead, they block the final aggregation caused by strong binding through fibrinogen between activated GpIIb/IIIa receptors. This could be a disadvantage as all early activation steps are unaffected and the platelets are still fully activated.
Most studies of GpIIb/IIIa inhibitors were performed before the clopidogrel pre-treatment era and even before stents were used; often the clinical end-point consisted mainly of procedure-related increases in cardiac markers (type 4a myocardial infarctions). It has been clearly shown that GpIIb/IIIa inhibitors are of no use in only medically treated patients. The Prospective, Randomized, Double-Blind, Placebo- Controlled Trial of the Glycoprotein IIb/IIIa Inhibition With Abciximab in Patients With ACS Undergoing Coronary Stenting After Pretreatment With a High Loading Dose of Clopidogrel (ISAR-REACT-2) study found a benefit of GpIIb/IIIa inhibitors in clopidogrel-treated NSTE-ACS patients treated with PCI, mainly by a reduction in peri-procedural non-Q-wave infarctions.19 However, the large Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY-ACS) study did not find any significant benefit of using GpIIb/IIIa inhibitors for NSTE-ACS patients.20
Evidence for GpIIb/IIIa inhibitors for STEMI also relies on studies before clopidogrel was used as pre-treatment, and in the largest study – Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) – a beneficial effect was seen only in patients treated with plain old balloon angioplasty (POBA), whereas patients treated with a stent did not benefit.21 In the presence of clopidogrel and compared with a direct thrombin inhibitor (bivalirudin) in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, GpIIb/IIIa inhibitors resulted in a small decrease in early cardiac events but caused markedly more bleeding complications. The long-term results demonstrated significant reduction in mortality in favour of bivalirudin,22 even after two years.
Furthermore, several other studies have caused a realisation that bleeding complications are dangerous and potentially fatal, even if we can handle them acutely. They cause anaemia, inflammation, blood transfusions and long hospital stays, with risk of iatrogenic complications. Furthermore, bleeding complications often result in discontinuation of antithrombotic medications, resulting in higher risk of cardiac events.
Novel Adenosine Diphosphate-receptor Blockers for the Treatment of NSTE-ACS and STEMI
The high prevalence of clopidogrel resistance has made it important to develop more efficient ADP-receptor blockers. Unfortunately, cangrelor, an interesting short-acting ADP antagonist for intravenous use, recently failed in clinical trials. However, the two oral drugs prasugrel (Effient®) and ticagrelor (Brilinta™) have succeeded in large phase III clinical trials.
Prasugrel is a thienopyridine-like clopidogrel, but instead of 85% of the prodrug being converted to an inactive metabolite, esterases convert the prodrug into an intermediate metabolite, which is then converted to active metabolite by one single CYP step. This results in a much higher and consistent level of active metabolite in the bloodstream, with a stronger and more rapid inhibition of ADP-induced platelet aggregation.16
In the Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study, including both STEMI and NSTE-ACS patients, prasugrel markedly reduced myocardial infarction and stent thrombosis compared with clopidogrel. The most important finding was the potent effect in patients with diabetes, a group known to be resistant to both aspirin and clopidogrel. Thus, for the first time there is an oral platelet inhibitor with a clear clinical effect on patients with diabetes.23
Not surprisingly, prasugrel was markedly better than clopidogrel for patients with genetic polymorphisms for low enzymatic activity in CYP2C19.16 The STEMI patients also benefited markedly with prasugrel, and here a reduction in mortality could also be seen.24 Interestingly, although the entire prasugrel-treated population suffered from increased bleeding complications, neither patients with diabetes nor STEMI patients suffered from this. Prasugrel does not seem to have any poor responders and seems to solve the problem of clopidogrel resistance. Furthermore, prasugrel reduces platelet–monocyte complex formation and annexin exposure on the platelet surface (a prerequisite for coagulation activation).25
Otherwise, bleeding complications were the major limitation for prasugrel in TRITON. They were clearly increased in the whole population, and patients with a previous transient ischaemic attack (TIA)/stroke suffered from significantly increased intracranial and fatal bleedings. Older patients (>75 years of age) and those with low weight had increased bleeding complications, resulting in a net neutral effect on the combined end-point of cardiovascular events and bleeding complications.
Ticagrelor is not a prodrug like clopidogrel and prasugrel, and thus does not require conversion in the liver for activation. Furthermore, it is a classic competitive antagonist without irreversible binding, a property that can be important for patients in need of urgent surgery or with bleeding complications, as the effects of the drug are lost much more rapidly compared with the five to seven days needed to restore platelet function for other thienopyridines.
In the phase III trial A Study of Platelet Inhibition and Patient Outcomes (PLATO), ticagrelor significantly reduced cardiovascular events compared with clopidogrel, surprisingly without significantly increasing bleeding complications.26 This is probably the reason ticagrelor also resulted in a significant reduction in total mortality, a very rare finding in antiplatelet studies.
Conclusions
Antiplatelet therapy for ACS is changing. We are moving from late blocking of platelet activation to the possibility of inhibiting platelet activation early in the cascade, thereby reducing degranulation of alpha and dense granulae and the release of growth factors, vasocontractile agents and adhesive, pro-thrombotic and inflammatory proteins. Oral platelet inhibitors are becoming more efficient with less individual variability, solving problems of clopidogrel resistance.
There is increasing awareness of the negative effects of bleeding on long-term risk and mortality. In fact, the antithrombotic drugs that have succeeded in improving the most important end-point – mortality – have achieved this not by reducing cardiovascular events, but by reducing bleeding complications. This pattern has been seen for fondaparinux in OASIS-5, for bivalirudin in HORIZONS and recently for ticagrelor in PLATO.22,26,27
At the same time, in the aforementioned studies new drugs have been tested against old therapies. When new drugs are combined, there is a lack of evidence for added benefit, especially when new drugs emerge on both the antiplatelet and anticoagulant side. The cost of novel treatments will also be a challenge. As generic antiplatelet drugs appear, such as clopidogrel, in the near future platelet-function tests will allow us to discriminate which patient groups will benefit from newer therapies and which patients will do well on old therapies, thus saving costs.