Pharmacologists Question Aspirin Resistance

December 07, 2012

Aspirin resistance is an almost nonexistent phenomenon, one group of pharmacologists is claiming [1]. In a study of 400 healthy individuals, they demonstrate that what appears to be "aspirin resistance" is simply due to the delayed release of the drug from an enteric-coated product.

"The implications for patient care are that true aspirin resistance is really very rare, and, based on our study, we would not recommend routinely testing for aspirin resistance, because the likelihood of finding it is small," lead author Dr Tilo Grosser (Institute for Translational Medicine and Therapeutics, Philadelphia, PA) told heartwire .

True aspirin resistance is really very rare, and we would not recommend routinely testing for it, because the likelihood of finding it is small.

Grosser says the story for patients is not to bother with the more expensive enteric-coated aspirin products because they don't appear to provide a benefit--at least not one that has been proven. And while such products do eventually inhibit platelets, this takes some time and could cause problems with chronic therapy if compliance is not 100%, he says.

Grosser and colleagues report their work online December 4, 2012 in Circulation. While Grosser acknowledges that these experiments were performed in healthy individuals, he says if they were repeated in people with cardiovascular disease, "my gut feeling is that there would still be no aspirin resistance. Of course, when you go to people with disease, there are multiple reasons why they might not respond to aspirin. One example is drug-drug interactions, but this is not 'true' aspirin resistance," he added.

In a statement provided to heartwire , Dr Gisela Lenz, media relations, Bayer HealthCare, said: "The authors' suggestion that use of enteric-coated aspirin should be questioned, based on these study results, is of concern given the study population and methodology used, neither of which reflect real-world clinical use. The platelet-reactivity testing was done in healthy, young subjects (median age 26 years).  This is clearly not the typical population for which aspirin would be used to prevent cardiovascular events." 

But the study "does provide important additional information supporting the position that in situations where platelet reactivity is not or only partially inhibited by aspirin, a more accurate definition may be 'variable response,' " she observes. 

Reduced response after coated aspirin is all a result of pharmacokinetics

The 400 healthy nonsmoking volunteers tested were aged 18 to 55 years of age and predominantly white; 57% were female. They were first screened for their response to a single oral dose of 325 mg of aspirin: 40 were given immediate-release aspirin, and their response was measured eight hours after dosing (group 1); 210 took enteric-coated aspirin, and response was assessed after eight hours (group 2); the remaining 150 had enteric-coated aspirin, and response was gauged at four hours (group 3).

All of the 40 patients given immediate-release aspirin were responders, defined as a reduction in platelet aggregation of more than 60% (ie, they were not deemed aspirin resistant). In group 2, the individuals assessed eight hours after the enteric-coated aspirin, 17% qualified as nonresponders (or aspirin resistant), while 49% in group 3 were nonresponders.

It can all be explained by pharmacokinetics, the speed of absorption, which is actually surprisingly slow for the coated version.

"With the coated aspirin, there was quite a high percentage of nonresponders, but that depended entirely on when we actually looked," Grosser says. "So it can all be explained by pharmacokinetics, the speed of absorption, which is actually surprisingly slow for the coated version."

Lenz says: "Enteric coating is designed to delay the release of aspirin until it reaches the small intestine to help improve gastrointestinal tolerability. As a result, if measurements of platelet reactivity taken only a few hours after ingestion of enteric-coated aspirin in the acute or single-dose setting suggest reduced response, this would not be unexpected."

Second and third phases of testing strengthen findings

The researchers then went on to retest everyone who appeared aspirin resistant with the enteric-coated version in two further phases. In the second phase, 108 nonresponders from the first phase and 149 responders (acting as controls) went through a washout period and were then tested again with a single 325-mg dose of aspirin.

Individuals received the same kind of aspirin they got in the first phase; responders came from all groups and so got immediate-release aspirin if they had had that in the first phase or enteric-coated if they had gotten that first time around. Individuals were assessed at the same time point (either four or eight hours after taking aspirin) as they had been first time around.

All responders on immediate-release aspirin were again responders in the second phase.

Some patients who were taking enteric-coated aspirin and responded the first time around did not respond on the second test. Conversely, many who were aspirin resistant in the first phase of testing (all of whom were taking enteric-coated product) did respond during the second phase, again taking the coated aspirin. These findings do not lend support to the "phenotype" of aspirin resistance, says Grosser.

And in a final, third phase, they took everyone who could be traced who had had two occasions of nonresponse in the first two phases (n=27) into a third phase, where they were given low-dose enteric-coated aspirin--81 mg--every day for a week, in an attempt to mimic typical, chronic aspirin prophylaxis. The 25 responders were age- and gender-matched as controls and were given exactly the same regimen.

Just one patient of the 27 nonresponders failed to respond to the low-dose enteric-coated aspirin in this extended period of testing, while two of the responders who were controls subsequently appeared to be resistant. Grosser said ex vivo testing of the platelets of these three individuals suggests that they did not take the medication as instructed, "but we cannot prove that."

True resistance rare; testing for it will not offer clinical value

"Coated aspirin will eventually have the desired effect," Grosser notes, "but you have to take it very reliably every day, and the onset of action takes a few days--which is no problem for chronic therapy, but the compliance issue may be."

Coated aspirin will eventually have the desired effect, but onset of action takes a few days. This is no problem for chronic therapy, but the compliance issue may be.

He and his colleagues conclude that pharmacological 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."

Lenz says she agrees with the authors' conclusions that "because of variability associated with timing of platelet-reactivity testing and issues related to acute vs chronic dosing, particularly for enteric-coated aspirin, point-of-care testing for platelet inhibition may not offer clinical value."

Don't bother with enteric-coated aspirin products

Grosser says the difference in price between plain aspirin and enteric-coated aspirin is not much, around 1¢ a tablet vs 5¢ to 6¢. But enteric-coated products "were developed with the idea of making aspirin safer for the stomach," he observes. And while there have been endoscopic studies that have shown fewer erosions with this kind of drug, "there has never been a study looking at the really key outcome, which is bleeding," he says. "In the end we don’t know if [enteric-coated aspirin] is safer; it has never been shown.

"So people who take coated aspirin basically pay a little more but have no additional proven benefit from it, and they may increase their chances for a slightly more complicated therapy. For example, if they are ever tested for aspirin resistance they may show up as aspirin resistant and really not be. They may then be put on a higher dose of aspirin or another antiplatelet drug and be at even higher risk of bleeding, for no additional benefit." Also, if they are taking enteric-coated aspirin chronically and are not 100% compliant, they may have problems with platelet reactivity, as has been illustrated in this study.

He stresses, however, that "no one should stop taking the drug they are familiar with" without first consulting their physician.

Lenz says: "Enteric-coated aspirin has been shown to inhibit platelet aggregation at levels comparable to nonenteric aspirin. In addition, it has been shown to reduce risk of cardiovascular events in clinical trials, including studies that utilized endoscopic assessments and demonstrated reduced rates of gastric side effects."

This work was supported by the National Heart Lung and Blood Institute, the National Center for Research Resources, the American Heart Association, and Bayer HealthCare, which supplied both the immediate-release and enteric-coated aspirin used. Grosser has received consultancy fees from PLxPharma. Disclosures for the coauthors are listed in the paper.