Antiplatelet effect of acetylsalicylic acid in patients early after cardiac valve surgery: comparative investigation of the impairment of platelet inhibition by dipyrone versus acetaminophen

Abstract

Abstract Background Low-dose acetylsalicylic acid (ASA) is recommended in current guidelines for a period of 3 months after surgical implantation of a bioprosthesis in aortic position or after surgical repair of the mitral valve. Dipyrone (D; metamizole) and acetaminophen (A; paracetamol) are frequently used non-opioid analgesics after surgery. The active metabolite of dipyrone (4-methylaminoantipyrine) is a reversible inhibitor of cyclooxygenase-1 and an interaction with the antiplatelet effect of ASA in more than 50 % of patients has been reported. Material and methods We enrolled 162 patients scheduled for cardiac surgery in this prospective investigator-initiated clinical study. Patients were randomized at day 1 after surgery to either 4 x 1g dipyrone iv/day or 4 x 1g acetaminophen iv/day. All patients were on ASA 100 mg daily (200 mg at day 1). The primary endpoint was the proportion of patients with adequate antiplatelet response to ASA assessed via determination of thromboxane B2 in platelet rich plasma after stimulation with arachidonic acid (AA) at day 4/5 after surgery (cutpoint ≤209.8 ng/ml thromboxane B2). Key secondary endpoints comprised platelet reactivity assessed by light transmission aggregometry [LTA] and by multiple electrode impedance aggregometry [MEIA]. Results 15 patients dropped out of the study. Thus, data from 71 patients randomized to dipyrone and 76 patients randomized to acetaminophen were available for data analysis. Patients had a mean age of 66.5±7.6 years and 97 were male and 50 female. Aortic valve was replaced in 92 patients, 54 underwent mitral valve reconstruction and combined surgery was performed in a single patient. The primary endpoint analyzed at day 4/5 after surgery is shown in the Figure. The proportion of non-responders was 12.5% (D) and 3.0% (A), respectively. Platelet reactivity at day 4/5 after surgery was assessed after stimulation with arachidonic acid by LTA or MEIA. No statistically significant difference between the treatment strata was determined in both assays: Maximum aggregation in LTA was 5.0% (median; 95% confidence interval [95% CI]: 4.0 - 8.0%) in D+ASA and 6.0% (95% CI: 5.0 - 11.0%) in A+ASA (p=0.528) and MEIA AUC was 345.5 AU*min (95% CI: 268.0 - 419.0) in D+ASA and 276.5 AU*min (95% CI: 241.0 - 330.0) in A+ASA (p=0.098). Plasma concentrations of MAA in patients treated with dipyrone were higher in patients identified as responders to ASA (86.6 µM; 95% CI: 67.9 - 102.4 µM) compared to non-responders (31.0 µM; 95% CI: 2.9 – 146.7 µM; p=0.0147). Summary and conclusion The proportion of non-responders to ASA is higher in patients treated with dipyrone compared to acetaminophen. The proportion of non-responders in the dipyrone-treated group in our study is substantially lower than reported in previous studies. High plasma concentrations of MAA in responders may contribute to enhanced inhibition of COX-1 in patients treated with dipyrone.