Response to Letter Regarding Article, “Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization”
Our conclusion that “poor clinical outcomes of aspirin-treated patients is due in part to incomplete cyclooxygenase-1 (COX-1) inhibition, but is also due in part to COX-1–independent platelet hyperreactivity” is based on the independent association of both high residual serum thromboxane B2 (TXB2) and shortened platelet function analyzer (PFA-100) collagen/ADP closure time (CADP CT; indicative of COX-1–independent platelet hyperreactivity) with adverse outcomes in aspirin-treated patients.1 These findings help define factors that contribute to the risk for adverse events in aspirin-treated patients and thus, we hope, will improve the design of future studies of treatment strategies. For example, “the finding of an association of the PFA-100 CADP CT with adverse clinical events suggests the possibility that greater inhibition of ADP-induced platelet activation would result in improved outcomes in this patient group.”1 As Dr Violi and colleagues suggest, an explanation for the presence of high residual serum TXB2 despite aspirin treatment would be helpful in the development of a clinically relevant treatment strategy. Thus, we previously reported2 that up to 2% of patients in this population may have been underdosed or noncompliant based on the ability of added aspirin or indomethacin to inhibit arachidonic acid–stimulated platelet activation.2 The remaining 98% of subjects showed arachidonic acid–inducible platelet activation that was independent of both COX-1 and COX-2 inhibitors.2 Aspirin noncompliance results in residual uninhibited platelet COX-1, which in turn permits arachidonic acid–stimulated platelet activation. Yet, arachidonic acid–inducible platelet reactivity measured by 4 independent assays was not associated with the occurrence of major adverse cardiac events (see our Figure 2),1 whereas high serum TXB2 was. Additional information that could help to explain the high TXB2 levels was reported in Table 3 in our article1; that is, patients with residual serum TXB2 >3.1 ng/mL were more often taking COX-2 antagonists and antidepressants and had a higher body mass index and platelet count than patients with residual serum TXB2 <3.1 ng/mL. Thus, high residual TXB2 may be due in part to interactions with comedications (COX-2 antagonists and antidepressants) in patients with high body mass index or platelet count, or to aspirin underdosing.
Drs Frelinger, Furman, and Michelson have been principal investigators on research grants to the University of Massachusetts Medical School from Dade Behring, Lilly/Daiichi Sankyo, McNeil Consumer Healthcare, and Sanofi Aventis/Bristol-Myers Squibb. Dr Christie is an employee of Siemens Healthcare Diagnostics. The other authors report no conflicts.
Frelinger AL III, Li Y, Linden MD, Barnard MR, Fox ML, Christie DJ, Furman MI, Michelson AD. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation. 2009; 120: 2586–2596.
Frelinger AL III, Furman MI, Linden MD, Li Y, Fox ML, Barnard MR, Michelson AD. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation. 2006; 113: 2888–2896.