Aspirin and Clopidogrel Resistance

doi:10.4065/81.4.518

Mayo Clinic Proceedings

Volume 81, Issue 4, April 2006, Pages 518-526

https://doi.org/10.4065/81.4.518 Get rights and content

Despite aspirin's and clopidogrel's proven benefit in reducing cardiovascular (CV) events, recurrent CV events still occur in patients receiving antiplatelet therapy. Many of these patients are resistant or only partially responsive to the antiplatelet effects of aspirin and clopidogrel, as determined by standard platelet assays. However, current clinical guidelines do not support routine screening for aspirin or clopidogrel resistance, in part because determination of the most appropriate screening test has not been established. This review attempts to (1) describe the phenomena of clinical aspirin and clopidogrel resistance (ie, treatment failure), (2) discuss the complexity of defining and identifying aspirin and clopidogrel resistance, (3) identify factors that may be responsible for aspirin and clopidogrel resistance, (4) outline several standard platelet function assays and their limitations, and (5) describe potential new antiplatelet therapies that may benefit aspirin- or clopidogrel-resistant patients.

Section snippets

ASPIRIN RESISTANCE

The term aspirin resistance has been used to describe the inability of aspirin to inhibit platelet aggregation as demonstrated by platelet function tests (eg, biochemical aspirin resistance).⁹ The term has also been used to describe the occurrence of CV events despite therapeutic aspirin intake (eg, clinical treatment failure). No consensus exists on whether the definition should be based on laboratory evidence, clinical outcomes, or both. The clinical importance of biochemical aspirin

MECHANISMS OF ASPIRIN RESISTANCE

The mechanisms of aspirin resistance are poorly understood and are likely to be multifactorial (Figure 2).²⁷ Multiple factors affect platelet aggregation, including patient posture, time of day, exercise, and serum cholesterol levels.²⁸ Additionally, cigarette smoking stimulates platelet aggregation and blunts the effect of aspirin.²⁹ Moreover, drug-drug interactions may reduce the efficacy of aspirin. For example, nonsteroidal anti-inflammatory drugs block aspirin's access to the active site

THIENOPYRIDINES

The thienopyridines, clopidogrel and ticlopidine, irreversibly bind the platelet surface P2Y12 ADP receptor, thereby inhibiting ADP-induced platelet activation (Figure 1). Although ticlopidine has proven superiority to aspirin in the prevention of atherothrombosis,⁴³ clopidogrel is more widely used than ticlopidine because it offers better safety and tolerability⁴³ with similar efficacy.⁴⁴

Patients who experience an ACS or undergo percutaneous coronary intervention (PCI) have a lower risk of

LABORATORY TOOLS TO SCREEN FOR EFFICACY OF ANTIPLATELET AGENTS

The most appropriate laboratory test for assessing aspirin and clopidogrel resistance has not yet been established.⁶⁷ Four of the more common techniques for assessing platelet function include (1) bleeding time; (2) optical aggregometry, which measures platelet aggregation in plasma after exposure to substrates such as arachidonic acid, epinephrine, collagen, or ADP; (3) PFA-100 (Dade-Behring, Deerfield, Ill), which measures high shear stress-dependent platelet aggregation in whole blood; and

POTENTIAL ALTERNATIVES FOR THE ANTIPLATELET-RESISTANT PATIENT

One potential alternative or addition to aspirin or thienopyridine therapy is cilostazol, a phosphodiesterase 3 inhibitor approved for the treatment of intermittent claudication. In patients who have had a cerebrovascular event, cilostazol monotherapy significantly reduces the risk of recurrent stoke.⁷⁰ The addition of cilostazol to aspirin or clopidogrel does not result in further bleeding time prolongation, suggesting safety of the combination therapy.⁷¹ In the Cilostazol for Restenosis Trial

CONCLUSION

Many issues remain unresolved regarding the definition, identification, and clinical importance of resistance to aspirin and clopidogrel. Given these limitations, no established consensus exists of whether aspirin- or clopidogrel-resistant patients should discontinue their antiplatelet regimen or whether additional therapy, such as cilostazol, should be added. Future studies will establish whether patients receiving antiplatelet agents should undergo platelet function studies to assess the

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Citation Excerpt :
This is the case with AR-measuring assays, for which in the same cohort of stable CAD patients, there was poor correlation among six different assays, with an AR rate varying from 6.7% to 59.5%.24 To add further complexity to platelet function tests, the majority of assay-specific resistance cutoff values are determined arbitrarily.4 Table I summarizes the most common platelet function assays and their characteristics.24,25
Aspirin resistance (AR) and clopidogrel resistance (CR) are terms used to describe a reduction in the medication's efficacy in inhibiting platelet aggregation despite regular dosing. This review gives context to the clinical role and implications of antiplatelet resistance in peripheral arterial disease (PAD).
A review of English-language literature on AR and CR in PAD involving human subjects using PubMed and MEDLINE databases was performed in April 2017. A total of 2075 patients in 22 relevant studies were identified. To give this issue context, a review of the larger, more established literature on antiplatelet resistance in coronary disease was undertaken, identifying significant research associating resistance to major adverse cardiovascular events (MACEs).
Studies in the coronary arterial disease literature have strongly associated antiplatelet resistance with increased MACE. Prevalence of AR or CR in coronary disease appears to be >55% for each in some studies. Meta-analyses of >50 studies revealed that AR and CR are significantly associated with MACE (relative risk of 2.09 and 2.8, respectively). This adds further weight to the literature reporting antiplatelet resistance as an independent predictor of and a threefold risk factor for major adverse cardiovascular events. The prevalence of resistance in PAD in this review was comparable to that in the coronary disease literature, with AR and CR prevalence up to 60% and 65%, respectively. There is evidence that the adverse effects of antiplatelet resistance are significant in PAD. In fact, research directly studying stent thrombosis populations with either coronary arterial disease or PAD revealed more significantly impaired platelet responsiveness to clopidogrel and aspirin in PAD compared with similar individuals with coronary disease. AR in PAD was found in studies to be a significant risk factor for iliofemoral stent reocclusion (P = .0093) and stroke in patients with symptomatic carotid disease (P = .018). CR was found to be a significant, independent risk factor in predicting ischemic outcomes in several recent PAD studies (P < .0001). Loss-of-function carriers of enzyme CYP2C19, important in clopidogrel metabolism, have a 30% greater risk of ischemic events (P < .001). Importantly, less antiplatelet drug resistance may be encountered with newer antiplatelet agents, including ticagrelor and prasugrel, because of reduced enzymatic polymorphisms.
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ReviewAspirin and Clopidogrel Resistance

Section snippets

ASPIRIN RESISTANCE

MECHANISMS OF ASPIRIN RESISTANCE

THIENOPYRIDINES

LABORATORY TOOLS TO SCREEN FOR EFFICACY OF ANTIPLATELET AGENTS

POTENTIAL ALTERNATIVES FOR THE ANTIPLATELET-RESISTANT PATIENT

CONCLUSION

Lancet

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

Thromb Res

Thromb Res

J Thorac Cardiovasc Surg

Thromb Res

J Am Coll Cardiol

Lancet

Am J Med

Chest

Lancet

Eur J Vasc Endovasc Surg

J Am Coll Cardiol

Thromb Res

J Am Coll Cardiol

Atherosclerosis

Am Heart J

J Am Coll Cardiol

Aspirin selectively inhibits prostaglandin production in human platelets

Nat New Biol

Acetylation of prostaglandin synthase by aspirin

Proc Natl Acad Sci U S A

Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides

Proc Natl Acad Sci U S A

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients [published correction appears in BMJ. 2002;324:141]

BMJ

Aspirin in the prophylaxis of coronary artery disease

Curr Opin Cardiol

Clinical practice: aspirin for primary prevention of coronary events

N Engl J Med

Aspirin resistance

Ann Pharmacother

Aspirin resistance [editorial]

BMJ

Antiplatelet effect of aspirin in patients with cerebrovascular disease

Stroke

In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor

Br J Haematol

Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes

Clin Pharmacokinet

Aspirin dosage and thromboxane synthesis in patients with vascular disease

Pharmacotherapy

Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery

Circulation

Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events

Circulation

Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty

Thromb Haemost

Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically

Can J Cardiol

Development of aspirin resistance in persons with previous ischemic stroke

Stroke

Review
Aspirin and Clopidogrel Resistance