Compliance as a Critical Consideration in Patients Who Appear to Be Resistant to Aspirin After Healing of Myocardial Infarction Kenneth A. Schwartz, MD, Dianne E. Schwartz, BS, Khalid Ghosheh, MD, Mathew J. Reeves, PhD, Kimberly Barber, PhD, and Anthony DeFranco, MD The hypothesis that aspirin resistance is often due to noncompliance was investigated. One hundred ninety patients with a history of myocardial infarction were evaluated using arachidonic acid–stimulated light ag- gregometry at 3 different time points: while receiving their usual daily aspirin, after not receiving aspirin for 7 days, and 2 hours after the observed ingestion of aspi- rin 325 mg. At the first time point, 17 patients (9%) failed to show aspirin inhibition of platelet aggregation, but 2 hours after observed aspirin ingestion, aspirin inhibition was observed in all but 1 patient. 2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:973–975) T he mechanism of aspirin resistance remains un- clear. Compliance has been implicated as a possi- ble cause of aspirin resistance. Of 73 patients with previous myocardial infarctions studied, 21 were clas- sified as “aspirin resistant.” 1 However, 12 of the 21 admitted to not taking their aspirin, suggesting that compliance could be a major issue in aspirin resis- tance. We investigated the hypothesis that aspirin re- sistance may often be due to noncompliance. Compli- ance is best assessed when comparisons are made between the effect of aspirin inhibition of platelets measured when patients are taking their usual daily aspirin doses and the antiplatelet effect measured after observed aspirin ingestion. Using arachidonic acid– stimulated light aggregometry, the response of normal platelets can easily be differentiated from the response of platelets inhibited by aspirin. 2 We used this assay to assess compliance by comparing patients’ responses to aspirin 2 hours after they were observed to ingest aspirin 325 mg, with the aspirin response measured when the patients were presumed to be taking their prescribed daily aspirin. ••• This study was approved by the institutional review boards at McLaren Medical Center (Flint, Michigan) and Ingham Regional Medical Center (Lansing, Michigan). Patients were contacted by phone and, after a detailed explanation of the study, were invited to participate. Informed consent was obtained. Inclusion criteria were admission to 1 of the study hospitals for a myocardial infarction during the 5-year period from 1995 to 2000 and having been prescribed aspirin for 1 month before the study. Exclusion criteria were a history of noncom- pliance to aspirin, a primary care physician’s determina- tion that the patient may not be withdrawn from aspirin, a history of hemorrhagic cerebral vascular accident, cor- onary arteritis, thrombocytopenia, known hypercoagula- ble disorders, the use of nonaspirin nonsteroidal anti- inflammatory drugs (NASAIDs) or Cox-2 inhibitors during the 2 days preceding blood draw, uremia or dial- ysis or a creatinine level 3.0, and failure to provide written informed consent. Of the approximately 350 pa- tients who met the studies criteria, 210 agreed to partic- ipate, and 190 completed the study. Patients were que- ried about whether they had complied with their instructions to take or not to take aspirin as well as their daily doses of aspirin and whether the aspirin preparation was enteric coated. Aspirin inhibition of platelets was measured using arachidonic acid–stimulated light aggregometry at 3 time points: while patients were receiving their usual daily aspirin (long-term aspirin), after they had not received aspirin for 7 days, and 2 hours after patients were ob- served to ingest aspirin 325 mg. At the onset of the study, platelet aggregation was measured in patients who had been prescribed daily aspirin for 1 month (long-term aspirin). Patients were then instructed to withhold all antiplatelet agents (aspirin, NASAIDs, and Cox-2 inhib- itors) for 7 days, and aggregometry was performed for the second time. Immediately after this time point, aspi- rin 325 mg was administered by a nurse, and while the nurse watched, the patients were instructed to chew the tablet. Two hours after the observed ingestion of aspirin, aggregation was assessed for the third time. Using a 21-gauge butterfly, 5 ml of whole blood was drawn by venipuncture into a separate syringe before an additional 9 ml of whole blood was col- lected using a 10-ml plastic syringe containing 1 ml of 3.2% sodium citrate. Platelet counts were performed using a Beckman Coulter AcT (Beckman Coulter, Inc., Miami, Florida). Whole blood was centrifuged at 200g for 10 minutes for platelet-rich plasma and at 2,000g for 15 minutes for platelet-poor plasma. All aggregations were per- formed in duplicate, with the final platelet concentra- tion adjusted to 150,000/l with platelet-poor plasma. Light aggregometry using platelet-rich plasma was measured using 1.0 mmol/L arachidonic acid from Chrono-log Corporation (Havertown, Pennsylvania) on a Helena PACKS4 aggregometer (Helena Laboratories, From the Departments of Medicine and Epidemiology, Michigan State University, East Lansing, Michigan; and the Departments of Research and Cardiology, McLaren Medical Center, Flint, Michigan. This study was funded in part by Accumetrics, Inc., San Diego, California. Dr. Schwartz’s address is: Department of Medicine, B226 Life Sciences Bldg., Michigan State University, East Lansing, Michigan 48824. E-mail: schwart7@msu.edu. Manuscript received September 20, 2004; revised manuscript received and accepted December 15, 2004. 973 ©2005 by Excerpta Medica Inc. All rights reserved. 0002-9149/05/$–see front matter The American Journal of Cardiology Vol. 95 April 15, 2005 doi:10.1016/j.amjcard.2004.12.038