Peeling Back the Layers on Coated Aspirin

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Bhatt DL, Grosser T, Dong JF. et al. Enteric Coating and Aspirin Nonresponsiveness in Patients with Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2017;69:603-12.

More than 15 million Americans have coronary heart disease and most should be taking aspirin daily.1  Given aspirin’s ubiquity in cardiovascular medicine and patients’ pill boxes, it is shocking that there are still so many unanswered questions about aspirin use.  Which dose and dosage forms should be prescribed?  How common is aspirin resistance?  What is the relationship between platelet inhibition and clinical outcomes?

 

The notion of aspirin “resistance” is controversial and lacks a consensus definition. Aspirin resistance varies widely among patient populations, aspirin formulations, and assays to measure platelet function.2,4  Serum thromboxane B2 (TXB2) generation is a commonly used marker for platelet inhibition and a potential surrogate marker for cardiovascular benefit. Obesity, diabetes, and enteric coating all appear to impact a patient’s response to aspirin – at least in terms of platelet function tests. 2,3,4  While obesity and diabetes may be considered “non-modifiable” factors that lead to reduced aspirin absorption and increasing platelet turnover (respectively), the use of enteric coated (EC) aspirin is modifiable. 

 

EC aspirin has been widely marketed to patients and practitioners as safer than uncoated aspirin formulations.  Unfortunately, the data simply to do not support this claim.  Two separate case control analyses conducted in the United Kingdom and the United States failed to show any protective benefit of EC aspirin versus plain aspirin with regard to rates of upper gastrointestinal bleed events.5,6  Conversely, a novel oral aspirin delivery system, PL2200, using a non-covalent complex of aspirin-phosphatidylcholine significantly reduced rates of endoscopically identified gastroduodenal erosions when compared to plain aspirin in one 7-day study.7 Given the short-term nature of this trial, additional studies are obviously needed to evaluate the benefits and risks of this novel dosage form.  Thus, it is in this context that Bhatt and colleagues evaluated PL2200, plain, and EC aspirin to determine their pharmacodynamic profiles and rates of aspirin resistance based on antiplatelet activity.8 

 

The study was a prospective, randomized, triple-crossover study rotating patients through 3-day trials of PL2200, plain, and EC aspirin.  The aspirin dose was 325mg daily.  There was a 2-week washout period between trials.  The authors enrolled 40 obese patients with type 2 diabetes mellitus (T2DM) without known atherosclerotic cardiovascular disease (ASCVD).  A total of 35 patients completed all three trials and were included in the analysis.  To ensure compliance and to standardize the conditions under which the aspirin dose was taken, patients were admitted for supervised initial dose administration during each treatment trial. The primary endpoint of the study was the time to ≥99% inhibition of TXB2 quantified by ex-vivo generation measures. The secondary endpoint was the incidence of aspirin responsiveness, defined as ≥99% inhibition of TXB2 or a TXB2 concentration of <3.1 ng/mL, a marker of residual antiplatelet effect, within 72 hours of the first aspirin dose. 

 

Treatment with either PL2200 or plain aspirin resulted in significantly faster inhibition of TXB2 generation than EC aspirin.  The time to ≥99% inhibition was 12.5 hours (PL2200), 16.7 hours (Plain asprin), and 48.2 hours (EC aspirin) [p<0.0001 for comparisons of both PL2200 and plain aspirin to EC aspirin]. In regard to the incidence of aspirin resistance, 56% of patients failed to respond to EC aspirin during the 3-day trial period compared with 11% and 18% of patients when given PL2200 and plain aspirin (p < 0.0001). The authors concluded that the reduced response rate with EC aspirin was attributable to lower aspirin exposure.  The Cmax for serum acetylsalicylic acid concentrations was lower and time to Cmax longer during EC aspirin use when compared to PL2200 and plain aspirin use.

 

The data corroborates previous studies that found a reduced pharmacodynamic effect when an EC formulation is used.2,3   Further, it provides additional evidence to support the use of the investigational aspirin formulation (PL2200) in clinical practice. A strength of the trial is that patients were admitted for aspirin administration removing non-compliance as a confounding factor for “resistance.”  This is an important consideration as non-responsiveness rates drop from 9% to 0.5% and 14% to 4.2% when aspirin administration was witnessed versus self-reported in two previous studies.3,10 None-the-less, extrapolation and application of the trial data are limited by several issues. 

 

First, the study population included only patients with obesity and T2DM without ASCVD.  The consistent presence of obesity and T2DM controls for possible confounding given the independent effects of these disease states have on aspirin responsiveness rates. This allows the study to focus on the specific effects of different aspirin dosage forms. Inclusion of patients with known ASCVD would be unethical given the aspirin washout periods between dosing trials.  While these inclusion and exclusion points are appropriate in this study and increase the internal validity of the findings, they inherently limit the external validity and prevent us from extrapolating the findings to other patient populations. 

 

Second, the aspirin dose (325mg daily) is higher than what is recommend and most commonly used in clinical practice for cardiovascular risk reduction (75-100mg daily). Further, the short 3-day treatment period likely biased the findings given that EC aspirin has a slower onset of antiplatelet activity.  Previous studies have shown that chronic use of EC aspirin mitigates the differences in TXB2 inhibition when compared to plain aspirin.2 However, in high-risk patients any reduction in effect could predispose patients to increased rates of CV events.  Early and effective platelet inhibition would obviously be preferred. 

 

A final point of concern deals with the use of laboratory assays to predict clinical outcomes. Theoretically, the reduced TXB2 inhibition seen with EC aspirin would be expected to result in higher rate of cardiovascular events when compared to plain aspirin; however, we are unaware of any prospective data to support the use of TXB2 inhibition as a surrogate marker that can predict clinical outcomes.2,3

 

With these limitations in mind clinicians are left with three possible interpretations of this study.  First, EC aspirin should be avoided in patients with obesity and diabetes because of increased rates of aspirin “resistance.”  Second, PL2200 is a potential alternative to plain aspirin.  Or third, the data are merely a proof of concept that requires further study. 

 

We believe that the third interpretation is the most appropriate but the first interpretation can’t be dismissed.  Given there is no clear safety benefit to using EC aspirin and there is a potential for risk — admittedly based on a surrogate marker of unproven merit — in obese patients with T2DM, plain aspirin should be preferred over EC aspirin. This recommendation is supported by a previous study which evaluated the use of low-dose chewable versus enteric coated aspirin and documented similar findings.9  Whether plain aspirin should be preferred in other patient populations is even less clear but reasonable until proven otherwise.  Indeed, the USPSTF recommendations regarding the use of aspirin for primary prevention of cardiovascular events state “there is no evidence that enteric-coated or buffered formulations of aspirin reduce the risk for serious GI bleeding.”11  Thus, in the absence of a safety benefit, why risk it?  Regarding PL2200, the data so far are promising but larger and longer studies are needed.

 

Should these data change practice?  In an obese patient with stable coronary artery disease and diabetes, what formulation do you recommend?  Should we consistently recommend, prescribe, and stock only uncoated aspirin products?

 

Editor's Note:  The opinions expressed in this commentary and podcast are solely the authors and do not represent the official positions or opinions of the U.S. Department of Veterans Affairs or U.S. Department of Health and Human Services