Antiplatelet Therapy
Challenges in Oral Antiplatelet Therapy
Pat Wong and Umair Shafique
Senior Medical Writers, Touch Briefings
Abstract
The positive impact of oral antiplatelet therapy on the prevention and treatment of cardiovascular events is well-documented, especially in terms of reducing the risk of thrombotic complications in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention. The oral antiplatelet agents aspirin and clopidogrel have become the mainstay of therapy. However, a major challenge still exists in the need to determine the optimal level of platelet inhibition that is required to obtain a balance between the prevention of ischaemic events and minimisation of the risk of bleeding in various clinical settings. In addition, clopidogrel is associated with inter-individual variability of platelet response and delayed onset and offset of action, which can influence the safety and/or efficacy of the treatment. These pharmacological limitations have led to the development of new oral antiplatelets, such as prasugrel, which has recently been approved, and ticagrelor, which is in late-stage clinical development. These newer agents are associated with improved rates of onset and/or offset of action, and offer more consistent antiplatelet effects.
Keywords
Cardiovascular events, acute coronary syndrome (ACS), oral antiplatelets, challenge, unmet needs, clopidogrel, prasugrel, ticagrelor
Disclosure: Funding for the writing of this article was provided by Daiichi Sankyo. Received: 22 February 2010 Accepted: 3 March 2010 Citation: European Cardiology, 2010;6(1):53–7
Cardiovascular (CV) events are a major cause of mortality worldwide1 that are often precipitated by acute coronary syndromes (ACS). ACS result from the acute obstruction of coronary arteries and are defined as either unstable angina (UA) or myocardial infarction (MI), with or without ST-segment-elevation (STEMI and NSTEMI, respectively). Patients with moderate- to high-risk ACS are managed by an early invasive approach that includes coronary angiography followed by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). There is a high inherent risk of thrombotic complications with ACS or with the use of PCI, while MI and stroke may be serious complications of CABG surgery. Platelet aggregation and activation play key pathophysiological roles in the atherothrombotic process and the consequent development of CV events. In patients with ACS and those undergoing PCI, the risk of peri-interventional and long-term cardiac complications, including death and MI, may be reduced by utilising anticoagulant and/or antiplatelet therapies.2
The impact of oral antiplatelet medications on the prevention and treatment of CV events is well-established, with aspirin and the once- daily-administered thienopyridine clopidogrel being the cornerstones of antithrombotic therapy in patients with ACS.3,4
Both aspirin and
clopidogrel exert their beneficial antiplatelet effects by inhibiting platelet aggregation and activation. Aspirin irreversibly binds to the cyclo-oxygenase 1 (COX-1) receptor to inhibit the formation of
thromboxane A2, thereby inhibiting platelet activation and aggregation, while clopidogrel irreversibly and selectively blocks adenosine diphosphate (ADP)-dependent platelet activation and aggregation via blockade of the P2Y12 receptor.5
Dual therapy with aspirin plus clopidogrel is generally considered by cardiologists to be a gold
© T O UCH BRIEFINGS 2010
standard treatment for patients with UA/NSTEMI ACS, for those with STEMI ACS and for those undergoing PCI. This therapeutic strategy can offer up to a 20% additional reduction in death, non-fatal MI and stroke over aspirin monotherapy.6
Despite the proven efficacy of aspirin and clopidogrel in patients with ACS and those undergoing PCI, CV events remain an important cause of morbidity and mortality. The challenges of oral antiplatelet therapy in these patients are further highlighted by the results of recent clinical trials, as discussed later. Since antiplatelet agents block pathways that are important to thrombosis as well as haemostasis, their use may be associated with a high bleeding risk. A major challenge, therefore, is to find the optimal level of platelet inhibition that is needed to obtain a balance between the prevention of ischaemic events and minimisation of the risk of bleeding in various clinical settings. Determination of this ideal level will help optimise the balance between safety and efficacy. It should be noted that this challenge also gives rise to a further set of other challenges, such as the need to identify optimal dose and timing of therapy, since these factors strongly influence platelet inhibition.
Challenges with the Thienopyridine Clopidogrel
Some of the pharmacodynamic and pharmacokinetic properties of clopidogrel give rise to pharmacological limitations, including both delayed onset and offset of action and large inter-individual variability in platelet response.
Delayed Onset and Offset of Action
In the acute setting, such as in patients with STEMI or NSTEMI scheduled to undergo PCI, antiplatelet therapy needs to be given as
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