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New antiplatelet agents : ready for clinical application?

An article from the e-journal of the ESC Council for Cardiology Practice

New antiplatelet agents have been developed for patients at high risk of thrombosis. Their benefits in terms of mortality and major cardiovascular events have been demonstrated, but some concerns remain regarding the possible increase in bleeding. At present, they should be indicated only in selected patients.

Cardiovascular Pharmacology and Pharmacotherapy


1. Background

Coronary heart disease is a common cardiovascular disease, affecting millions of patients all over the world, and continues to be the leading cause of death in industrialised countries (1). Atherothrombosis is the main pathophysiologic mechanism leading to acute coronary syndromes (ACS): non ST-elevation myocardial infarction (NSTEMI), unstable angina (UA) and ST-elevation myocardial infarction (STEMI).

Platelet activation is one of the essential mechanisms in the genesis and onset of atherothrombotic complications. Some established mechanisms interplay in the pathogenesis of thrombosis in coronary disease: endothelial injury, platelet activation, synthesis and activation of soluble coagulation proteins, and abnormal blood flow-shear stress.

Antiplatelet therapy is a first-line medical treatment for patients with any clinical manifestation of coronary disease. As percutaneous coronary interventions (PCI) increase in number and complexity, more patients must be treated with antiplatelet therapy for cardiovascular diseases in which arterial thrombosis plays a major role, including double or even triple antiplatelet regimens after stent implantation.

Current anti-platelet therapy is highly effective in preventing atherothrombotic complications. Nevertheless, a significant number of patients continue to experience recurrent complications despite being properly treated, due to some reasons: pharmacokinetics and interactions of drugs, genetic background and increased thrombus formation. This has lead to big research efforts to provide new antiplatelet drugs which better preventive properties without increased bleeding risk.

2. Drawbacks of current antiplatelet therapy

The main mechanisms of action of current oral anti-platelet drugs are depicted in Figure 1. Aspirin is indicated for life for virtually all manifestations –both acute and chronic- of coronary disease; clopidogrel is indicated temporally to prevent thrombus formation after ICP and/or stent implantation, as a substitute to aspirin when contraindicated or not tolerated and after ACS Figure 2).

Monitoring antiplatelet efficacy

There is a considerable variation in response to antiplatelet therapy among patients. This has led to the use of a variety of platelet function tests to monitor the effects of antiplatelet drugs in cardiovascular diseases, in an attempt to tailor type and dosing of antiplatelet therapy for an optimal prevention or treatment of thrombosis while minimizing bleeding complications.

Aspirin resistance

Up to 8% of patients receiving 81 mg-dose of aspirin have significantly less platelet inhibition than those receiving higher dose. Nevertheless, patients taking > 100 mg-dose aspirin may improve their response.

In those patients showing high platelet reactivity despite 100 mg-dose aspirin, 325 mg-dose should be considered. Other drugs with similar antiplatelet effects such as triflusal may be an option for these patients.

Thienopiridine resistance

Patients with poor responsiveness to clopidogrel are at high risk of thromboembolic complications, especially in the setting of ACS and stent implantation. There are no practice guidelines recommending platelet functional tests in order to adjust antiplatelet therapy with thienopiridines.

Several options have been proposed. Firstly, to increase loading and maintenance doses up to 600 mg and 75-mg twice daily associated with high-dose aspirin (300-325 mg), as the CURRENT study has demonstrated (2). A comparison study showed no increased bleeding risk. A second option would be to change from clopidogrel to ticlopidine (with different hepatic metabolism), although the safety profile of this agent is not as good as that of clopidogrel. Recent development of new antiplatelet drugs such as prasugrel or ticagrelor adds new therapeutic options for these patients, and will soon become part of daily practice.

3. New antiplatelet agents

3.1. Prasugrel vs Clopidogrel

The new antiplatelet agent prasugrel is an ADP-P2Y12 receptor inhibitor that has a faster (3) and more consistent inhibitory effect of platelet aggregation and was shown to reduce cardiovascular mortality in the setting of ACS undergoing PCI.

In the TRITON-TIMI 38 trial 13,608 patients already taking aspirin were randomised to receive clopidogrel (300 mg-loading dose and then 75 mg-maintenance) or prasugrel (60 mg-loading dose followed by 10 mg-maintenance) following ACS and planned PCI (4).

After a median of 12 months follow-up, patients taking prasugrel had a 19% reduction of the composite endpoint of cardiovascular death, myocardial infarction, or stroke. There was also a significant increase in major non-CABG bleeding risk (32%), which persisted over the duration of treatment. Subgroups with increased risk of bleeding were patients with prior stroke, age over 75 and body weight under 60 kg. In this population, prasugrel is discouraged despite its increased in efficacy.

There is an ongoing clinical trial called TRILOGY-ACS investigating clopidogrel vs prasugrel in patients following an ACS medically managed.

3.2. Ticagrelor vs Clopidogrel

Ticagrelor is a new non-thienopyridinic antiplatelet drug with some pharmacokynetic advantages over prasugrel and clopidogrel (mainly because is not a pro-drug and does not need hepatic transformation into an active metabolite and its reversible platelet inhibition). The main clinical trial with this drug has been the PLATO study, in which 18,624 patients with NSTEMI (moderate-to-high-risk) or STEMI undergoing PCI were randomized to receive clopidogrel (300 mg loading dose then 75 mg maintenance) or ticagrelor (180 mg loading dose then 90 mg twice daily maintenance). PLATO and TRITON_TIMI patients continued aspirin in both branches of treatment, as part of NSTEMI current treatment. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. After 12 months, patients receiving ticagrelor had a 16% reduction of the primary endpoint, with no increased risk of major bleeding (5,6)

Nevertheless, some concerns have been raised related to other side effects due to adenosine receptor blocking effects (RESPOND study): almost 15% of patients referred had dyspnoea or bradiarrhythmias compared with 8% with prasugrel (7).



Figure 2. Long-term antiplatelet agents in STEMI/NSTEMI

Most patients

- AAS 75 to 325 mg, lifelong

- Clopidogrel: loading dose 300/600 mg plus 75/150 mg, 1 year

Prasugrel may be useful in these clinical scenarios :

- Patients at very high thrombotic risk (< 75 years; > 60 kgs), especially if  they have low bleeding risk

- Previous stent thrombosis with clopidogrel or low response to clopidogrel in platelet aggregability tests

Clopidogrel intolerance 

3.3. Costs

Costs are one of the commercial problems of new antiplatelet drugs. In Spain, 28 pills of prasugrel cost 63 euros; Clopidogrel 28 pills cost approximately 35 euros. Authorities and hospital administrations are developing protocols that, nowadays, vary from one region to the next. It happens with every new treatment, new approaches are often better but more expensive. We will most probably offer this medication to patients with previous stent thrombosis or at high risk of thrombotic events (diabetics) and, after that, will be able to offer it to a wider population. 
 

Conclusion:

New antiplatelet agents can provide better inhibition of platelet aggregation and have been shown to improve cardiovascular outcomes. Nevertheless, patients should be carefully treated considering individual clinical condition and thrombotic risk.

Oral agent prasugrel reduces cardiovascular mortality in patients undergoing ICP after ACS, but increases the bleeding risk moderately. This drug should be considered for patients with previous confirmed stent thrombosis or showing a high degree of platelet reactivity despite receiving the clopidogrel/aspirin combination.

Promising results with ticagrelor, a non-prodrug with reversible blockade of the ADP-P2Y12 receptor opens the possibility for this drug to be used in coronary patients with high thrombotic risk.

References


(1) Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119(3): 480-486.

(2) Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, et al.  Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156(6):1080-1088.

(3) Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Smal DS, 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 (1):66e9-66.e16.

(4) Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2007; 357:2001-2015.
 
(5) Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11):1045-1057.

(6) James S,  Akerblom A, Cannon CP, Emanuelsson H, Husted S, Katus H, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial.  Am Heart J. 2009; 157(4): 599-605.

VolumeNumber:

Vol8 N°32

Notes to editor


Alegría Barrero E1, Alegría Barrero A2
1Cardiology and Cardiovascular Surgery. Rotger Clinic. Palma de Mallorca, Spain. Member of the Cardiovascular Thrombosis Group of the Spanish Society of Cardiology. 2Cardiology and Cardiovascular Surgery. University of Navarre Clinic. Pamplona, Spain.

Eduardo Alegría Barrero
Instituto de Cardiología (Hemodinámica)
Clínica Rotger
c/ Santiago Russiñol, 9   07012 - Palma de Mallorca, Spain
Tel. +34 971 44 85 02    Fax +34 971 72 90 66
ealegriabarrero@secardiologia.es

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.