The Concept of Aspirin Resistance

Platelet inhibition with aspirin has long been a cornerstone in the treatment and prevention of cardiovascular disease.^1,2 In patients at high risk for cardiovascular events, antiplatelet therapy reduces the risk of serious events and death from cardiovascular causes.³ However, a significant number of patients experience a recurrent ischemic event while on aspirin. Although part of this residual risk can be attributed to poor compliance and the multiple pathways of platelet activation,⁴ variable platelet inhibition during aspirin treatment has also been demonstrated.⁵ A suboptimal biochemical response to aspirin, popularly designated aspirin resistance, is further associated with recurrent ischemic events,^6,7 but estimates of its prevalence differ widely due to distinct drug doses, definitions, and platelet function tests.⁸ Increased platelet activation and aspirin resistance may be particularly common among patients with greater weight and impaired glucose metabolism.^9-11

Measurement of Aspirin Response

Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, which catalyzes the rate-limiting step in the biosynthesis of thromboxane A₂ (TXA₂) by mature platelets. This decreases platelet activation and aggregation, and, because platelets cannot synthesize new cyclooxygenase, the inhibitory effect of aspirin lasts for their entire lifespans.¹² The degree to which COX-1 is inhibited is often measured through serum concentrations of thromboxane B₂ (TXB₂), a biologically inert metabolite formed by non-enzymatic hydrolysis of TXA₂.¹³ TXB₂ is highly specific for platelets, and its levels are sensitive to antiplatelet therapy. Aspirin (acetylsalicylic acid and the main active metabolite, salicylic acid) concentrations can also be directly measured. Finally, platelet activation and aggregation can be assessed through a wide variety of tests of platelet function, each with its own strengths and limitations.¹⁴

Potential Influence of Aspirin Formulation

Inadequate absorption is a potential cause of aspirin nonresponsiveness.⁴ For example, delayed and reduced absorption may be more common, and platelet inhibitory response more variable, for enteric-coated (EC) aspirin than for immediate-release aspirin (plain aspirin).¹⁵ A modified-release lipid-based aspirin formulation (PL2200 aspirin) was approved for cardiovascular disease prevention by the U.S Food and Drug Administration in 2016. But until now, its pharmacological properties had not been compared with those of plain aspirin and EC aspirin.

Aspirin Formulation, Bioavailability, and Response

The association between aspirin response and its oral bioavailability, for three different aspirin formulations, was recently examined in a pharmacokinetic/pharmacodynamic trial.¹⁶ Forty obese patients (body mass index = 30-40 kg/m²) with type 2 diabetes, but without cardiovascular disease, were randomized in a single-blind (study staff), triple-crossover fashion to receive a plain aspirin tablet, the PL2200 aspirin capsule, and a delayed-release EC aspirin caplet, each at a dose of 325 mg for 3 consecutive days. The washout period between each stage was 14 days. Various serial measurements were made, of which the time to complete (≥99% from baseline) suppression of serum TXB₂ was the primary endpoint. Based on prior studies, nonresponsiveness to aspirin was defined as <99.0% inhibition of serum TXB₂ or a serum TXB₂ concentration >3.1 ng/mL within the first 72 hours.^17,18 Plasma concentrations of aspirin were also determined.

Thirty-five patients completed all crossover stages. Complete aspirin response was achieved significantly more quickly with PL2200 aspirin and plain aspirin versus EC aspirin (p < 0.001 for both comparisons), whereas there was no significant difference between PL2200 aspirin and plain aspirin (p = 0.41) (Figure 1). Per the <99% serum TXB₂ inhibition criterion, rates of incomplete aspirin response were similar between PL2200 aspirin (8.1%) and plain aspirin (15.8%; p = 0.30 for difference) but were significantly greater with EC aspirin (52.8%; p < 0.001 for both comparisons). Comparable results were obtained with the serum TXB₂ concentration >3.1 ng/mL criterion, and the two definitions were well-correlated. The areas under the curve for aspirin concentration from time = 0 to the last time measured were similar for PL2200 aspirin and plain aspirin (p = 0.14) but were significantly lower for EC aspirin (p < 0.001). Of note, insufficient response on EC aspirin was significantly associated with lower plasma aspirin levels (p = 0.03). Only two individuals did not adequately respond to any aspirin formulation (i.e., the rate of aspirin resistance per se was low).

Figure 1: Time to 99% Inhibition of Serum TXB₂ Concentration

Gastrointestinal Complications of Aspirin

Aspirin treatment is frequently complicated by gastrointestinal complications, such as gastric and duodenal ulcers and bleeding. EC aspirin appeared to reduce mucosal damage in early studies.^19,20 However, a subsequent large case-control study found no difference in the risk of endoscopically confirmed major upper gastrointestinal bleeding with plain aspirin versus EC aspirin.²¹ Recently, a randomized 7-day study demonstrated a potential protective effect of PL2200 aspirin on gastroduodenal erosion and ulceration when compared with plain aspirin.²²

Optimizing Cardiovascular Protection With Aspirin

The recent aspirin pharmacokinetic/pharmacodynamic study, albeit small and short-term, showed favorable pharmacological characteristics of plain aspirin and PL2200 aspirin over EC aspirin, at a daily dose of 325 mg.¹⁶ Patients with low response to EC aspirin also had lower levels of plasma aspirin, indicating decreased absorption as the main underlying cause. Although these results cannot be directly extrapolated to clinical events, they do indicate that use of EC aspirin among individuals at high a priori risk for suboptimal aspirin response should be reconsidered. This may be particularly important in subjects with diabetes because they are intrinsically more prone to atherothrombotic events.²³ Furthermore, the classic assumption that EC aspirin conveys gastrointestinal protection does not seem to hold, whereas PL2200 aspirin may be beneficial, though more work is necessary to confirm that finding.²²

Given the short duration of the study, these findings may be most important for those needing a relatively rapid antiplatelet response, though for patients with acute myocardial infarction or patients undergoing primary percutaneous coronary intervention, 325 mg of plain aspirin chewed and swallowed appears best. Generalizability to patients without diabetes or in those with a previous cardiovascular event is likely but needs to be established with further studies. Another potential shortcoming is the use of the 325 mg aspirin dose because lower maintenance doses are usually recommended for prevention of recurrent ischemic events.²⁴ However, because low-dose aspirin may be an independent risk factor for aspirin nonresponsiveness, it is likely that its use would only have augmented the obtained results.²⁵ Certainly, long-term study of PL2200 aspirin in terms of both cardiovascular efficacy and gastrointestinal safety is warranted.

In conclusion, despite the controversies associated with aspirin nonresponsiveness, a simple and common explanation may be a formulation-dependent impairment in absorption. Future studies are needed to clarify more precisely the role of the lipid-based aspirin formulation and how to overcome true aspirin resistance.

References

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Keywords: Acute Coronary Syndrome, Angina, Stable, Aspirin, Blood Platelets, Body Mass Index, Cardiovascular Diseases, Cyclooxygenase 1, Diabetes Mellitus, Type 2, Duodenal Ulcer, Glucose, Hydrolysis, Metabolic Syndrome, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation Inhibitors, Platelet Function Tests, Primary Prevention, Prostaglandin-Endoperoxide Synthases, Risk Factors, Thromboxanes, Salicylic Acid

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