Assessing and Responding to Apparent Aspirin Resistance

Aspirin resistance is a controversial issue with important clinical implications for neurologists and patients.

By James C. Grotta, MD

A 68-year-old man is seen with a second hemispheric TIA in the last year on aspirin 81mg daily. There is a history of well-controlled hypertension and hyperlipidemia on medication (blood pressure 110/70 and LDL of 60). There is no coronary disease and no cardiac embolic source with a normal EKG, cardiac stress test, and transthoracic echocardiogram.

Could this patient have aspirin “resistance”? If he is switched to clopidrogrel, should he be tested for possible resistance? Should resistance for either drug be routinely tested? Can resistance be treated by using a higher dose of medication? Are there medications that interfere with clopidrogel?

This case represents a common dilemma: the patient on antiplatelet therapy who continues to have ischemic events. What should be our response? The first consideration is to ask whether this is a patient with “aspirin failure” or “diagnostic failure”?

First, we should re-evaluate the mechanism underlying the symptoms, looking for a condition that would mandate alternative treatment. Is there an occult underlying cardiac source of embolization such as paroxysmal atrial fibrillation, carotid stenosis, or even a seizure disorder simulating a TIA?

Second, we should be sure that other risk factors, such as hyperlidemia and hypertension, have been addressed and optimally managed. While these issues all seem to have been addressed in the current case, recent data from the SPARCL study indicate that all four risk factors—blood pressure, LDL, HDL and triglycerides—have an effect on stroke risk and that control of each of them has an additive effect on risk reduction. I, like most clinicians, tend to focus too much on the LDL without also controlling HDL and triglycerides.

In this case, then, the first steps I would take would be to obtain good arterial imaging with MRA or CTA to be sure there is no significant stenosis, do a Holter monitor and possibly a TEE to look for an occult cardiac source of emboli, take a good history of the event and consider an EEG to exclude a seizure, and be sure the HDL and and triglycerides are as well controlled as the LDL.

The second consideration is to ask the patient if he is taking his medication. In several studies, the most common cause of variability in platelet function tests in patients taking aspirin or clopidogrel is poor patient compliance. Patients tend to underestimate the importance of taking aspirin. It is not uncommon for them to even leave out mentioning they are on the drug when they are asked to list their medications. In this case, I would stress to the patient the importance of taking their aspirin daily.

The third consideration is drug interactions. Aspirin works by inhibiting cyclo-oxygenase-1. Nonsteroidal anti-inflammatory drugs such as ibuprofen interfere with aspirin induced COX-1 acetylation. In the case of clopidogrel, proton pump inhibitors, especially omeprazole (Prilosec), and the H2-blocker cimetidine, reduce the enzymatic activity of the cytochrome P450 enzyme CYP2C19, which is needed to convert clopidogrel to its active metabolite in the liver. This seems to be less the case with pantoprazole (Protonix) and the H2-blockers, such as ranitidine, famotidine, or nizatidine. Patients on antiplatelet agents need to know about these potential drug interactions. In this case, I would ask the patient if he is taking an NSAID and warn him not to do so.

Having taken those steps, what about raising the aspirin dose or switching to clopidogrel? At present, the level 1, class A evidence-based response from randomized stroke prevention trials would be that the aspirin dose should not be raised and that clopidogrel has no advantage over aspirin. However, there are less certain data that might guide us in this particular case. This raises the issue of aspirin or clopidogrel “resistance.” There is ample evidence that patients may vary in their response to antiplatelet drugs as measured by various platelet function assays, even after compliance and drug interactions are taken into consideration. Diabetic patients in particular may have heightened platelet reactivity that is more resistant to platelet inhibition than non-diabetics.

Genetic polymorphisms also play a role. Recent studies have shown that up to 30 percent of patients have a polymorphism in CYP2C19 that is associated with a higher rate of cardiovascular events. A recent meta-analysis shows that patients with laboratorydefined aspirin resistance are 3.78 times more likely to have a cardiovascular event than those without.

However, aspirin assays often give inconsistent results from one test to the next, especially those not specific for COX-1 signaling, or those not using arachidonic acid as the stimulant for aggregation. There is also a multiplicity of tests for clopidogrel responsiveness, and standardized criteria for nonresponsiveness have not been determined. Therefore, guiding antiplatelet therapy on the basis of platelet function assays is not recommended, and I would not send our patient for such tests.

Clinically, one can always use the “bruising index.” If a patient is noticing more bruising on their current dose of aspirin or clopidogrel, then you can conclude that platelet function is being inhibited, though the reverse may not be true—absence of bruising does not mean the drug is not working. No study has shown that adjusting therapy based on platelet function assays results in better clinical outcomes.

If we can’t rely on platelet function tests to guide us in managing our patient, then how can we decide about dosing or switching drugs? Increasing the dose of aspirin does not increase COX-1 inhibition, and doses above 81mg do not show greater anti-ischemic effect but do increase the risk of bleeding in clinical studies. With clopidogrel, loading with 300-900mg results in faster and more complete platelet inhibition and fewer ischemic events in patients having coronary interventions. A recent study of diabetic patients randomized to the conventional recommended 75mg dose vs. 150mg found reduced aggregation with the higher dose, but the safety and efficacy of the higher dose is still being studied.

Finally, adjunctive treatment with cilostazol in addition to aspirin or clopidogrel is being tested but is still of unproven efficacy. Therefore, in this case, after takinwg the steps mentioned above, I would most likely switch the patient to clopidogrel 75mg daily.

Reprinted from "Broca's Area," the Texas Neurological Society Newsletter, with permission.
James C. Grotta, MD is Professor and Chair, Department of Neurology and Director of the Vascular Neurology Program, University of Texas-Houston Medical School.
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