Aspirin resistance – clinically meaningful or a laboratory artefact?

Failure of aspirin to suppress platelet thromboxane production or to inhibit platelet aggregation in vitro has been convincingly linked to an inadequate protection against atherothrombotic events.
However, “aspirin resistance”, also called “aspirin non-responsiveness” or simply “treatment failure”, is a heterogeneous phenomenon, still without a generally accepted definition and with unclear clinical implications. It has been described in a variable proportion of patients with atherothrombotic diseases, i.e., up to a quarter of patients with stable coronary disease, about a third of patients with stroke, and up to 40-60% in patients with peripheral arterial disease.
How should practicing physicians respond to the increasing abundance of news regarding aspirin resistance?

The most important cardiovascular effect of aspirin is mediated by irreversible inhibition of platelet cyclooxigenase-1 (COX-1) resulting in the suppression of thromboxane (TX) A2 production.
However, this does not completely inhibit the platelet function, since release of TX A2 is only one of several amplification mechanisms in platelet activation leading to the formation of stable aggregates. In other words, even a perfect response to aspirin does not offer complete clinical protection against atherothrombotic events.
In patients at high risk, treatment with low dose aspirin offers an overall 20 – 25 % reduction in major vascular events, but large differences in the level of cardiovascular protection have been described between aspirin responders and non-responders. Non-responders with a previous ischemic stroke had a 9-fold increase in recurrent ischemic events in comparison to aspirin responders (1), non-responders among coronary artery patients were about 3 times more likely to die, suffer a myocardial infarction or a cerebrovascular accident (2), and non-responders among peripheral vascular patients had an almost doubled rate of peripheral artery reocclusion after angioplasty (3).
In a substudy of the HOPE trial, patients in the highest quartile of urinary excretion of 11-dehydroTX B2, i.e., aspirin-non-responders, were 3.5-times more likely to die than those in the lowest quartile, i.e., aspirin-responders (4).

In spite of the growing evidence of harm caused by non-responsiveness to aspirin, experts remain cautious and urge for further studies, mainly because criteria for abnormal responses have not been clearly defined and correlated with clinical outcomes (5). The effects of aspirin on platelet function can be tested with in vitro platelet aggregation essays or by measuring platelet TX production, yet no method is ideal.
Optical aggregation essays using platelet rich plasma are time-honored tests, but are quite labor-intensive and impractical for routine use.
The simple whole blood test with PFA-100 (Platelet Function Analyser, Dade Behring) which measures “closure time”, i.e., the time of formation of a stable platelet plug on an agonist-coated membrane exposed to rapid blood flow, has shown rather poor agreement with optical aggregation measurements (6), and in patients with stable coronary artery disease the risk of atherothrombotic events and death was related only to aspirin-resistance as determined optical aggregometry (2).
Even measuring platelet TX formation is not without flaws. Measurements of TX metabolites in urine reflect TX production in platelet and non-platelet sources, i.e., macrophages, including those in atherosclerotic plaques.
By combining optical platelet aggregation tests with TX production measurements aspirin resistance may be categorised into the pharmacokinetic type, the pharmacodynamic type and “pseudoresistance” where TX-independent mechanisms of platelet aggregation play a major role (Table 1) (7). Some possible causes of aspirin resistance are listed in Table 2.

Table 1. Platelet aggregation and thromboxane production differ in aspirin responders and in various types of aspirin resistance (7).

How should aspirin resistance be approached in the clinical setting? At present, the European expert consensus on the use of antiplatelet drugs does not recommend assessing the antiplatelet effect of aspirin in the individual patient (8). Since atherothrombosis is a multifactorial disease, comprehensive cardiovascular disease prevention should be practiced without relying exclusively on one type of pharmacologic intervention. Treatment failures occur with every drug, including clopidogel that has failed to suppress platelet aggregation in up to a quarter of patients with acute myocardial infarction which, in turn, has increased the subject’s risk for recurrent atherothrombotic events (9). Regarding the use of clopidogrel and combined antiplatelet therapy, current guidelines should be followed. Increasing the dose of aspirin over the low-dose range is unlikely to overcome the pharmacodynamic type of resistance and “pseudoresistance” to aspirin, but definitely escalates the risk of bleeding. At present, it seems that the most reliable strategy to prevent aspirin treatment failure is promoting patient compliance with low-dose aspirin and avoiding concurrent use of non-steroidal anti-inflammatory drugs. However, we are eagerly waiting for reliable tests of platelet function that would be clinically helpful in screening for aspirin resistance among the most vulnerable population, i.e., patients with advanced multifocal atherosclerosis, including those with peripheral arterial disease.

Table 2. Some possible causes of various types of aspirin resistance (7, 10). NSAID – non steroidal anti-inflammatory drugs, COX – cyclooxigenase, TX – thromboxane, GP – glycoprotein.

1- Pharmacokinetic type resistance

• patient non-compliance
• short-acting NSAIDs, e.g., ibuprofen
• increased turnover of platelets

2-Pharmacodynamic type

• polymorphisms of COX-1 *
• increased inducible platelet COX-2 **

3-“Pseudoresistance” to aspirin (= TX- independent platelet aggregation)

• increased exposure of platelets to collagen, e.g., vascular injury
• increased epinephrine, e.g., mental or physical stress
• increased oxidative stress
• increased shear stress, e.g., exposure to turbulent flow in stenotic arteries
• increased von Willebrand factor
• polymorphisms involving the final common pathway of platelet aggregation, e.g., GP Ib, GP IIb/IIIa

* Polymorphisms resulting in an impaired interaction between aspirin and platelet COX-1 are an attractive hypothesis, but so far no known genotype in humans is associated with aspirin resistance and one polymorphism actually improves the sensitivity of COX-1 to aspirin (11).

** It is unlikely that aspirin resistance would be caused by an increase in the inducible platelet COX-2 isoform in platelets because in the clinical setting, COX-2-selective inhibitors have not suppressed aspirin-resistant platelet TX A2 formation. In fact, they have recently shown harmful cardiovascular effects.

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.