Nonresponse and resistance to aspirin

INTRODUCTION — Aspirin is classified among the nonsteroidal antiinflammatory drugs. It is commonly used for the secondary prevention (and occasionally for primary prevention) of cardiovascular disease (CVD) by taking advantage of its antiplatelet properties. (See "NSAIDs: Therapeutic use and variability of response in adults", section on 'Dosing and duration'.)

Aspirin, along with P2Y₁₂ platelet inhibitors, statins, and control of modifiable risk factors, is a key component of strategies to improve CVD outcomes in patients with and without CVD. When used for secondary prevention, antiplatelet therapies reduce nonfatal CVD events by approximately one-fourth and reduce fatal events by approximately one-sixth. Given the importance of aspirin in preventive strategies, failure of aspirin to achieve its potential benefit in patients at risk for CVD events is an important clinical issue. This topic will address issues of aspirin nonresponse and resistance and apparent treatment failure for patients taking aspirin [1]. The various uses of aspirin in the treatment of patients with CVD are discussed separately.

●(See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

●(See "Antithrombotic therapy for elective percutaneous coronary intervention: General use".)

●(See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●(See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)

●(See "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

●(See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

DEFINITIONS — The following terms used in this topic are defined as follows:

●Treatment failure is defined as the occurrence of occlusive cardiovascular disease (CVD) events despite the regular intake of aspirin at recommended doses [2]. Platelets are activated by multiple pathways, and thrombotic event occurrence is influenced by multiple factors in addition to platelet activation and aggregation. Therefore, a single antiplatelet treatment strategy directed against a specific receptor cannot be expected to overcome all thrombotic event occurrences. Treatment failure (occurrence of an ischemic event) during single antiplatelet therapy is not synonymous with antiplatelet resistance.

●Aspirin resistance or nonresponsiveness is a laboratory phenomenon [2]. The identification of resistance or nonresponsiveness should therefore utilize a laboratory technique that detects the activity of the target or target receptor before and after administration of the specific antiplatelet agent. The persistent presence of platelet cyclooxygenase (COX)-1 activity after treatment with aspirin is an indicator of aspirin resistance. However, antiplatelet resistance is only meaningful when it is significantly associated with clinical outcomes.

OBSERVATIONS — The following studies, each with limitations, are examples used to formulate, but not test, hypotheses concerning aspirin nonresponse [3-10].

Case series suggest that among patients with stable cardiovascular disease (CVD) who are taking aspirin, aspirin resistance was associated with worse cardiovascular outcomes and death.

●A case series of 326 patients with stable CVD who were taking aspirin (325 mg/day) for at least seven days and no other antiplatelet agent were tested for aspirin sensitivity by ex vivo optical platelet aggregation testing [4]. Using a definition based upon the degree of platelet aggregation after addition of the platelet agonists, adenosine diphosphate and arachidonic acid, "aspirin resistance" was present in 17 patients (5.2 percent). After a mean follow-up of 1.9 years, the patients with "aspirin resistance" had a significantly higher rate of the composite endpoint of death, myocardial infarction (MI), or stroke (24 versus 10 percent in the remaining 309 patients), even after multivariate adjustment for other risk factors (hazard ratio [HR] 4.14).

●In a second case series, 468 patients with stable coronary disease were tested for aspirin resistance using the VerifyNow aspirin assay at the start of the study and were followed prospectively for a mean of 379 ± 200 days for the composite endpoint of cardiovascular death, MI, stroke, transient ischemic attack, or unstable angina requiring hospitalization [6]. Aspirin resistance was an independent predictor of unfavorable clinical outcomes (HR 2.5, 95% CI 1.3-4.8).

●Another case series described the possible role of aspirin resistance in 151 patients who were taking aspirin (80 to 325 mg/day) for a least one week prior to undergoing elective percutaneous coronary intervention (PCI; 90 percent with stenting) [5]. Aspirin-induced platelet inhibition was measured ex vivo using a modified VerifyNow aspirin assay. All patients received clopidogrel 300 mg 12 to 24 hours prior to the procedure, followed by a maintenance dose of 75 mg/day; no patient received a glycoprotein IIb/IIIa inhibitor. The 19 percent of patients with aspirin resistance (indicated by >550 aspirin resistance units) had a significantly higher incidence of post-PCI elevations in serum creatine kinase MB (52 versus 25 percent) and cardiac troponin I (66 versus 39 percent).

●In the ADAPT DES registry, 8582 patients were treated with drug-eluting stents and given aspirin and clopidogrel. The prevalence of high on-treatment platelet reactivity on clopidogrel measured by VerifyNow P2Y12 assay (P2Y₁₂ reaction units >208) was 35 percent, whereas the prevalence of high platelet reactivity on aspirin using the VerifyNow aspirin assay (aspirin reaction units >550) was 5.6 percent. High on-treatment platelet reactivity on clopidogrel was strongly related to one-year stent thrombosis (adjusted HR 2.49, 95% CI 1.43-4·31) and MI (adjusted HR 1.42, 95% CI 1.09-1.86), and was inversely related to bleeding (adjusted HR 0.73, 95% CI 0.61-0.89), whereas high platelet reactivity on aspirin (aspirin reaction units >550) was not significantly associated with stent thrombosis (adjusted HR 1.46, 95% CI 0.58-3.64), MI, or death but was inversely related to bleeding (adjusted HR 0.65, 95% CI 0.43–0.99) [11].

●Using urinary 11-dh-TxB2 metabolite levels to assess aspirin responsiveness among patients at high risk for cardiovascular events enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial, it was found that patients in the upper quartile have a higher risk of MI, stroke, or cardiovascular death versus lower quartile (odds ratio [OR] 1.8, 95% CI 1.2-2.7, p = 0.009) [12]. Similarly, subanalysis of the Clopidogrel for High Athero-thrombotic Risk and Ischaemic Stabilisation, Management, and Avoidance (CHARISMA) study indicated that the highest quartile of urinary 11-dh-TxB2 metabolite levels was associated with an increased risk of stroke, MI, or cardiovascular death compared with the lowest quartile (adjusted HR 1.66, 95% CI 1.06-2.61, p = 0.03) in patients treated with aspirin. Moreover, treatment with ≥150 mg/dL aspirin was associated with lower urinary 11-dh-TxB2 levels, indicating a dose-dependent effect. These are the only studies that demonstrated a strong link between aspirin nonresponsiveness and clinical outcomes. However, it should be noted that 11-dh-TxB2 represents whole-body TxB2 production and may be influenced by nonplatelet sources, especially in pathological conditions of inflammation and high-risk cardiovascular disease [9].

●One study demonstrated that aspirin resistance is likely dependent on the type of laboratory assay used where aspirin resistance is rare when COX-1 dependent assay is used [13]. In this trial, aspirin doses of 81, 162, and 325 mg/day were randomly assigned to 120 patients with stable coronary artery disease. Aspirin resistance was rare (up to 6 percent) using methods that used arachidonic acid stimulation (light transmittance aggregometry, VerifyNow Aspirin assay, thrombelastography with platelet mapping assay) at all doses of aspirin.

•When agonists such as adenosine diphosphate, collagen, or collagen/epinephrine in the presence of shear were used in assays such as light transmittance aggregometry, thrombelastography with platelet mapping assay, or Platelet Function Analyzer-100, the prevalence of resistance was 1 to 27 percent.

•There was a dose-dependent response to aspirin treatment when collagen, adenosine diphosphate, and shear were used to activate platelets. The latter occurred in the presence of near complete inhibition of the COX-1 enzyme activity as measured by arachidonic-acid-induced platelet aggregation, indicating that aspirin may have non-COX-1-mediated dose-dependent effects in platelets.

POTENTIAL CAUSES

Genetic variability — Based on laboratory testing of platelet function in patients taking aspirin or high baseline ex vivo platelet function, a number of single nucleotide polymorphisms (SNPs) have been reported as causes of "aspirin resistance" [14,15]. No candidate SNPs have been significantly associated with death, myocardial infarction (MI), or stroke. At this time, there is no evidence for strong relation between genetic variability and aspirin resistance.

Adherence issues — Patient nonadherence is likely the most common cause of aspirin nonresponse or treatment failure. For patients with evidence of either, the clinician needs to have a discussion with the patient about adherence. Ex vivo arachidonic acid-induced platelet aggregation was studied in a case series of 203 patients undergoing percutaneous coronary intervention (PCI) who reported adherence with aspirin therapy [16]. Aspirin "resistance" was noted in seven patients (3.4 percent), all of whom later indicated aspirin nonadherence when told of the test results. All seven were found to be aspirin sensitive after in-hospital supervised administration of 325 mg of aspirin. Overall, only one patient in the total group of 223 patients with coronary artery disease (0.4 percent) was truly aspirin "resistant."

Similar results were noted in a second case series of consecutive patients undergoing coronary stenting and receiving aspirin at a dose of 75 mg/day [17]. One month after hospital discharge, 19 of the 136 patients (14 percent) were identified as nonresponders to arachidonic acid-induced platelet aggregation. After controlled administration of aspirin, all except one became responders and were identified as patients with nonadherence rather than biological resistance.

Use of enteric-coated aspirin — Enteric-coated aspirin is sometimes administered instead of non-enteric-coated aspirin (ie, dispersible or immediate-release aspirin) to prevent or reduce gastrointestinal toxicity. Delayed absorption may result in an insufficient antithrombotic effect, especially in the acute setting.

A series of 400 volunteers were screened for their response to a single oral dose of 325 mg immediate-release or enteric-coated aspirin, as determined by several ex vivo tests of platelet function [18]. Individuals who appeared "aspirin resistant" underwent repeat testing, and those who continued to appear "resistant" received one week of low-dose enteric-coated aspirin (81 mg). While there was a high frequency of apparent resistance to a single dose of 325 mg enteric-coated aspirin (up to 49 percent), this was not the case with immediate-release aspirin (0 percent). All except one individual who initially did not respond to enteric-coated aspirin subsequently did respond to one of the following: re-exposure, serial dosing with enteric-coated aspirin, change to non-enteric-coated aspirin, or addition of aspirin to their platelets ex vivo. The individual who did not respond to aspirin re-exposure and extension of the post-dosing interval also showed resistance to clopidogrel, which inhibits platelets by a separate mechanism, suggesting a more general platelet abnormality in this subject. The authors concluded that pharmacologic resistance to aspirin is rare; this study failed to identify a single case of true drug resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric-coated, but not immediate-release, aspirin administration.

Thus, for acute events, non-enteric-coated aspirin is necessary to achieve a rapid clinical antithrombotic effect. In addition, evidence in patients with stable coronary artery disease and apparently healthy volunteers suggests that the 81 mg dose of enteric-coated aspirin may have reduced clinical efficacy in the acute setting. If enteric-coated aspirin is the only available preparation, the tablet(s) should be crushed or chewed to provide an appropriate dose (ideally 325 mg). With respect to chronic administration, the totality of evidence is incomplete but suggestive that doses higher than 81 mg may be necessary if the aspirin is enteric-coated [18-22]. Issues regarding the choice of aspirin formulation in patients with cardiovascular disease (CVD) are discussed separately. The post hoc analysis of the ADAPTABLE study that was conducted in 15,076 patients with established atherosclerotic cardiovascular disease demonstrated similar risk of ischemic and bleeding outcomes in patients treated with and without enteric-coated aspirin [23]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Additional evidence supporting the use of enteric-coated aspirin as a cause of nonresponsiveness comes from a study of 40 patients with diabetes who were randomly assigned to one of three 325 mg aspirin formulations: plain aspirin, a modified-release lipid-based aspirin, and a delayed-release enteric-coated aspirin [24]. Aspirin nonresponsiveness was defined as a level of residual serum thromboxane B2 associated with elevated thrombotic risk within 72 hours after three daily aspirin doses. The rate of nonresponsiveness was 15.8, 8.1, and 52.8 percent, respectively (p<0.001 comparing regular aspirin with enteric-coated aspirin).

Use of proton pump inhibitors — Two studies have suggested that the use of proton pump inhibitors (PPIs) interferes with aspirin function:

●In a case-control study including 418 patients with coronary disease, in vitro platelet aggregation in response to arachidonic acid was significantly greater in patients treated with PPIs than in those not taking these medications [25].

●A retrospective nationwide study followed all aspirin-treated patients surviving 30 days after a first MI. Treatment with a PPI, compared with non-users of a PPI, was associated with a significantly greater risk of the combined endpoint of cardiovascular death, MI, or stroke (hazard ratio [HR] 1.46, 95% CI 1.33-1.61) [26].

Since the most plausible effect size is small to moderate, large-scale, randomized trials are needed [27].

Body weight — In patients who are treated with aspirin for the primary or secondary prevention of cardiovascular disease, treatment failure (see 'Definitions' above) attributable to causes other than genetic variability or lack of adherence is common. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Possible benefits' and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease", section on 'Efficacy'.)

A 2018 meta-analysis of individual patient data from randomized trials of aspirin for primary or secondary prevention evaluated the potential impact of body weight on aspirin efficacy and safety [28]. In a pooled analysis of 10 trials of aspirin for primary prevention (n = 117,279), the median bodyweight ranged from 60 to 81.2 kg, and 80 percent of men and nearly 50 percent of women weighed more than 70 kg.

The following findings were noted in this pooled analysis:

●The risk of major cardiovascular events (including stroke, MI, vascular death, other coronary death, and other major ischemic vascular events, excluding unstable angina and transient ischemic attack) with lower doses of aspirin (75 to 100 mg) was lower in people weighing 50 to 69 kg (HR 0.75, 95% CI 0.65–0.85) than in those weighing 70 kg or more (HR 0.95, 95% CI 0.86–1.04).

●The findings were similar in men and women, in people with diabetes, and in a separate analysis of trials of aspirin for secondary prevention.

●Higher doses of aspirin (≥325 mg) were effective in patients weighing 70 kg or more.

●An increased case rate of fatality was found in patients weighing 70 kg or more and treated with low-dose aspirin.

●The increased risk of major bleeding with aspirin, compared with control, was lost for patients who weighed 90 kg or more.

Pending further studies of this issue, we do not recommend weight-adjusted dosing of aspirin for primary or secondary prevention.

Other possible mechanisms — Biologic mechanisms by which aspirin nonresponse might occur are not well understood [2,29-32]. The following are among the hypotheses that have been proposed [29,33]:

●Aspirin nonresponders may have more advanced atherosclerosis as well as more macrophages in the atherosclerotic plaques, which may produce thromboxane A2 via cyclooxygenase (COX)-2 even in the presence of aspirin [12,31].

●There may be an intrinsic platelet mechanism that allows thromboxane production despite the presence of aspirin. Such an effect could be related to polymorphisms in the COX-1 gene that confer relative nonresponse to low-dose aspirin [12,31]; to residual thromboxane production by the platelet or other sources (eg, vascular endothelium) that may or may not be independent of COX-1 and/or COX-2 [10,32,34]; and/or to active extrusion of aspirin from the platelet by means of multidrug resistance protein-4-mediated transport [35].

●Drugs such as nonaspirin, nonsteroidal antiinflammatory drugs (NSAIDs; eg, ibuprofen) may interfere with the beneficial effect of aspirin [36], and other agents may reduce the absorption of aspirin from the gastrointestinal tract. In a nested case-control study from the Physicians' Health Study, nonadherence and concomitant use of NSAIDs (for more than 60 days per year) offered a plausible explanation for the lack of clinical benefit on first MI in subjects randomly assigned to treatment with aspirin. A randomized, controlled, open-label, parallel group study (KONTAKT study) investigated whether administration of immediate-release naproxen sodium 220 mg once or twice daily would result in a pharmacodynamic interaction when combined with a low-dose immediate-release aspirin (81 mg/day) regimen. After 10 days, irrespective of the timing and dose of naproxen in relation to aspirin dosing, a pharmacodynamic interaction (defined as lower bound of the one-sided 95% CI for serum TxB₂ inhibition <95%) occurred, which persisted after discontinuing naproxen. The clinical relevance of these observations remains unknown [37]. (See "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

●Platelet function inhibition by aspirin may be a matter of degree, rather than being "all or none." Accordingly, underdosing (see 'Body weight' above), poor absorption of aspirin, or increased platelet turnover or activation may also be a factor in aspirin nonresponse [2,3,16,30,34,38]. As an example, twice-daily dosing of low-dose aspirin may be more effective than once-daily dosing in essential thrombocythemia because of enhanced platelet turnover and, therefore, faster renewal of platelet COX-1 [39]. Ex vivo studies in patients with essential thrombocythemia or diabetes [40,41] show that 100 mg of aspirin twice daily is superior to once-daily dosing. The possible clinical relevance of these in vitro findings has not been studied. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Low-dose aspirin'.)

●Aspirin may have antithrombotic effects independent of its COX-1-dependent inhibition of platelet function (eg, reduction in thrombin generation, acetylation of fibrinogen resulting in increased fibrin clot permeability and enhanced clot lysis, and genetic variability in pathways regulating the response to platelet agonists other than arachidonic acid) [13,33,42].

CLINICAL MANIFESTATIONS AND DIAGNOSIS — Patients who have a less than optimal antiplatelet response to aspirin may experience no clinical events or, at worst, an acute thrombotic event. For those with acute thrombotic events, the presentation will be that of an acute coronary syndrome or an acute thrombotic neurologic event. (See "Diagnosis of acute myocardial infarction" and "Overview of the evaluation of stroke".)

As mentioned above, we do not recommend routinely testing for aspirin nonresponse as the cause of an acute thrombotic event. However, all patients should be queried for nonadherence. (See 'Adherence issues' above.)

LABORATORY TESTING — We do not recommend routine laboratory testing for defective ex vivo platelet response to aspirin [2,29]. (See 'Management of treatment failure' below.)

Performing laboratory testing to assess platelet nonresponsiveness may occasionally be useful for assessing adherence to aspirin, identifying some rare genetic abnormalities, and guiding patient care in some high-risk situations such as acute coronary syndrome patients with diabetes for whom a higher dose may be required.

Arachidonic acid-induced platelet activation/aggregation — Aspirin resistance has been defined as the inability of aspirin to inhibit platelet thromboxane A2 production or to inhibit tests of platelet function that are dependent upon platelet thromboxane production. This is most often demonstrated via the ability of aspirin to markedly inhibit arachidonic acid-induced platelet activation and aggregation, via aspirin's inhibitory effect on platelet cyclooxygenase (COX)-1 activity.

This effect of aspirin has shown little laboratory or genetic variability and can be demonstrated in virtually all patients taking 81 mg/day of aspirin [13,42-44]. Using this method, aspirin resistance has been generally defined as ≥20 percent platelet aggregation when using 0.5 to 1.6 mg/mL arachidonic acid as the agonist [45,46].

Aspirin response was studied in 144 patients with stable CAD by measuring COX-1 acetylation using the western blotting technique with monoclonal antibodies specific to acetylated and non-acetylated COX1 (acCOX-1 and nacCOX-1), arachidonic acid-induced TxB2 production by platelets by competitive immunoassay, and VerifyNow Aspirin Assay. acCOX-1, very low AA-induced TxB2 generation, and lower aspirin reaction units by VerifyNow assay were demonstrated, indicating an absence of aspirin resistance in all adherent patients [47].

Other ex vivo tests of platelet function — Whether the inhibition of ex vivo platelet function by aspirin, as measured by platelet aggregation responses to agonists other than arachidonic acid (eg, adenosine diphosphate, collagen, epinephrine), has clinical relevance is unclear. Resistance to these effects of aspirin, which may be only partially dependent upon or independent of COX-1, has shown laboratory and genetic variability, as well as a dose dependency, which may partially explain treatment failure with antiplatelet therapies (eg, aspirin, clopidogrel) in patients with cardiovascular disease (CVD) [1,3,13,42-44,48-50].

As an example, aspirin resistance, as defined by an Aspirin Reaction Unit score of ≥550 units, was present in 27 percent of 468 patients with stable coronary disease [3]. Multivariate predictors of aspirin resistance in these patients included anemia and aspirin dose. For patients taking 300, 150, or ≤100 mg/day of aspirin for four or more weeks, resistance was found in 0, 17, and 30 percent of patients, respectively.

Test correlations — The prevalence of "aspirin resistance," as defined by the various available tests, varies widely, being highest for the PFA-100 test (60 percent) and lowest using light transmission platelet aggregometry following addition of arachidonic acid or measurement of serum levels of thromboxane B2 (1 to 4 percent) [51,52].

These different laboratory methods for detecting "aspirin resistance" correlate poorly with one another, if at all, suggesting that they are sensitive to different parameters of ex vivo platelet function, including preexisting platelet hyperreactivity [53,54]. This variability has been shown in normal volunteers as well as in patients with coronary artery disease [55-60]. In one study performed in 951 consecutive patients receiving dual antiplatelet therapy and undergoing percutaneous coronary intervention (PCI), none of the four tests employed was able to identify patients at risk for bleeding, further limiting their usefulness [60].

In a study of six different platelet function assays in 48 young, healthy volunteers taking 100 mg/day of enteric-coated aspirin for one to eight weeks, aspirin was shown to variably suppress the following measures of platelet function [55]:

●Serum thromboxane B2 levels – 99+ percent reduction at one week (range: 96.3 to 99.9 percent), with little or no inter- or intra-individual variation.

●Arachidonic acid-induced platelet aggregation – 80 percent inhibition (range: 50 to 97 percent).

●UTXB₂ levels – 66 percent reduction at one week (range: 46 to 93 percent).

●Collagen-induced platelet aggregation – 50 percent inhibition by three weeks, with wide inter-individual variability.

●Adenosine diphosphate-induced platelet aggregation – 40 percent maximal inhibition by three weeks, with substantial inter-individual variability.

●VerifyNow Aspirin assay – 30 to 35 percent inhibition over the entire eight-week period.

Recovery of platelet function, as assessed by these functional assays, reached approximately 70 percent of baseline levels at day three post-aspirin. Of importance, using any of the above functional assays except serum thromboxane B2 levels, subjects found to be "resistant" at a specific time point were found to be responsive on previous or subsequent measurements, indicating that such resistance was not a stable phenomenon over time [56].

In a study of six different platelet function tests in 201 patients with stable coronary artery disease who were receiving >80 mg/day of aspirin, the prevalence of "aspirin resistance" varied according to the assay used, as follows [57]:

●Aggregometry after 1.6 mM arachidonic acid – 4 percent

●VerifyNow Aspirin assay – 7 percent

●Aggregometry after 5 to 20 micrometers adenosine diphosphate – 10 to 52 percent

●Whole blood aggregometry – 18 percent

●UTXB₂ – 23 percent

●PFA-100 – 60 percent

It is not known how precisely the impact of aspirin on the ex vivo response to selected concentrations of a single aggregating agonist might model its efficacy in decreasing occlusive CVD events in vivo. Multiple technical, as well as clinical, factors may confound platelet aggregometry, including body posture, time of day, smoking, exercise, and blood cholesterol, as well as the choice of agent used for anticoagulation of the blood sample [61]. In addition, platelet aggregability may recover despite sustained inhibition of thromboxane synthesis [62].

SCREENING — We do not recommend routine testing of patients for aspirin resistance/nonresponsiveness. Aspirin nonresponsiveness is rare in adherent patients and is not strongly associated with clinical outcomes in published studies.

MANAGEMENT OF TREATMENT FAILURE — Many patients with cardiovascular disease (CVD) sustain a CVD event despite the optimal use of all proven preventive strategies. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Usually, it is not possible to identify the cause of treatment failure. However, all patients should be evaluated for nonadherence to all preventive recommendations, including the use of daily aspirin. We do not recommend laboratory testing of platelets for "aspirin resistance" in patients who appear to be adherent. (See 'Adherence issues' above.)

Options for patients who have had a clinical event while taking aspirin include using a non-enteric extended-release formulation of aspirin (ER-ASA). Its pharmacodynamic effects and clinical outcomes in patients with aspirin nonresponsiveness have not been studied; however, it has been shown to provide sustained antiplatelet effects over 24 hours in patients with type 2 DM and multiple cardiovascular risk factors. In an open-label, single-center study, 40 such patients were given ER-ASA 162.5 mg/day for approximately 14 days and underwent interval measurements of platelet function [63]. All patients responded to ER-ASA 162.5 mg/day, and there was no loss of the platelet inhibitory effect by all platelet function measurements over 24 hours post-dose. The side effect profile was favorable.

Other formulations of aspirin, such as pharmaceutical lipid-aspirin complex and inhaled nanoparticle aspirin formulation, are also being studied [64,65].

Increasing the aspirin dose or adding another antiplatelet agent, depending on the clinical scenario, are other options.

Some investigators have suggested that omega-3 fatty acids may improve ex vivo platelet responsiveness in aspirin-adherent patients [66-68]. Fish oil and marine omega-3 fatty acids have potential benefits and lack of harm in those with established coronary artery disease. However, there is no strong evidence to show that fish oil supplementation will improve clinical outcomes in aspirin resistant patients.

For those individuals who have undergone laboratory testing, we do not recommend the empiric use of alternative antiplatelet agents (eg, clopidogrel) based upon the results of in vitro assays alone. If the arachidonic acid response is robust (ie, demonstrating lack of aspirin effect), this information may be useful in addressing adherence issues or adjusting the aspirin dosage, as noted above [19].

RECOMMENDATIONS OF OTHERS — Our recommendations are similar to those in the 2015 report on platelet function testing in acute cardiac care made by the European Society of Cardiology [69].

SUMMARY AND RECOMMENDATIONS

●Definition – Aspirin treatment failure is defined as the occurrence of occlusive cardiovascular disease (CVD) events despite the regular intake of aspirin at recommended doses, while aspirin resistance or nonresponsiveness is a laboratory phenomenon. (See 'Definitions' above.)

●Role of testing – We do not recommend routine testing of patients for "aspirin resistance," whether by ex vivo assessment of platelet function or by genetic testing. If such testing has been done, we do not recommend changes in therapy based on these results alone. (See 'Observations' above and 'Genetic variability' above.)

●Etiologies – Potential causes of aspirin resistance include a variety of patient and medication factors (eg, non-adherence, decreased absorption due to enteric coating, events independent of aspirin actions on platelet function). (See 'Potential causes' above.)

●Enteric coating – This can delay or reduce aspirin absorption. Thus, for acute cardiovascular events (eg, myocardial infarction [MI], occlusive stroke), non-enteric-coated aspirin is necessary to achieve a rapid clinical antithrombotic effect. If the only available preparation is enteric-coated, then the pill(s) should be crushed or chewed. For chronic administration, higher doses of aspirin may be necessary if the preparation is enteric-coated. (See 'Use of enteric-coated aspirin' above and "Aspirin in the primary prevention of cardiovascular disease and cancer".)

●Management – The initial step in management of a patient with apparent resistance to aspirin is to address issues of adherence. Additional options for patients who have had a clinical event on aspirin may include using a non-enteric formulation, increasing the dose, or adding another antiplatelet agent, depending on the clinical scenario. (See 'Management of treatment failure' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Charles Hennekens, MD, DrPH, who contributed to earlier versions of this topic review.