Low-Dose Enteric-Coated Aspirin Does Not Inhibit Thromboxane B2 and Prostaglandin E2: Data-Derived Hypothesis Formulation
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Research Article Low-dose enteric-coated aspirin does not inhibit thromboxane B2 and prostaglandin E2: data-derived hypothesis formulation Clin. Invest. (2012) 2(7), 747–752 Background: All usual daily doses of plain aspirin inhibit thromboxane B2 Charles H Hennekens*1,2,3, Scott 4 5 (TXB2) as well as prostaglandin E2 (PGE2). The role of 81-mg enteric-coated Hetzel , Michael Pfeffer , Ricky aspirin (ECA) is controversial. Method: In a randomized, double-blind trial, Schneider2, Steven Borzak1,2,3, Wendy 37 patients (25 men and 12 women) with chronic stable coronary disease Schneider1, Victor Serebruany6 taking ECA 81 mg at baseline were assigned to plain aspirin 81, 162.5, 325, & David DeMets4 650 or 1300 mg daily for 12 weeks. At baseline and 12 weeks, blood was 1Charles E Schmidt College of Medicine, Florida Atlantic University, FL, USA tested for TXB2 and PGE2. Results: All doses of plain aspirin produced virtually 2Department of Medicine & Preventive Medicine, identical reductions in TXB2 and PGE2. For all doses combined, the mean ratio of the 12-week to baseline value was 0.03 for TXB (p < 0.001) and 0.63 Nova Southeastern University, FL, USA 2 3Department of Family Medicine & Community for PGE2 (p < 0.001). Conclusion: These data indicate that ECA 81 mg daily Health, University of Miami Miller School of does not inhibit TXB2 and PGE2, markers of acute and systemic responses Medicine, FL, USA to aspirin. Randomized trials designed a priori to test this hypothesis are 4Department of Biostatistics & Medical necessary. Informatics, University of Wisconsin, WI, USA 5Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine, NY, USA Keywords: enteric-coated aspirin • lack of platelet inhibition • low dose 6HeartDrug™ Research, LLC, MD, USA *Author for correspondence: In secondary prevention among a wide range of patients who have survived a E-mail: [email protected] prior occlusive vascular event, including myocardial infarction (MI), stroke, transient ischemic attack, chronic stable angina or peripheral vascular disease, aspirin produces statistically significant and clinically important reductions in MI, stroke and cardiovascular (CV) death [1]. Specifically, in the Antithrombotic Trialist’s Collaboration amongst the 170,000 randomized patients, there were no significant differences in clinical benefits in doses ranging from approximately 50 to over 1300 mg daily, the vast majority of which were plain aspirin. During acute MI [2,3] or occlusive stroke [4], plain aspirin is preferable to enteric coated aspirin (ECA), which must be crushed or chewed to achieve a rapid clinical antithrombotic effect. When given during acute MI, aspirin also produces statistically significant and clinically important benefits to MI, stroke, and CV death. In primary prevention, plain aspirin reduces the risk of a first MI, but the data on stroke and CV death remain inconclusive [5]. The most plausible mechanism for these benefits is that aspirin irreversibly inhibits platelet-dependent COX, which is responsible for the production of thromboxane B2 (TXA2), a powerful promoter of aggregation [6]. Specifically, aspirin acetylates COX-1 causing it to be irreversibly inactivated. Since platelets lack the ability to synthesize significant amounts of protein, inactivation of COX-1 by aspirin blocks TXA2 synthesis for the lifetime of the platelet. Platelets that do not synthesize TXA2 normally have impaired stimulation by adenosine diphosphate, epinephrine, arachidonic acid and low doses of collagen and thrombin, but normal responses to the major platelet agonists, collagen and thrombin. Prostaglandin E2 (PGE2) is produced by activated platelets and by severalother cells, including capillary endothelial cells. PGE2 exerts a dualeffect on platelet aggregation: inhibitory at high concentrations and potentiating at 10.4155/CLI.12.56 © 2012 Future Science Ltd ISSN 2041-6792 747 Research Article Hennekens, Hetzel, Pfeffer et al. Low-dose enteric-coated aspirin & platelets Research Article low concentrations. measured by ELISA. Each sample was measured in Table 1. Baseline characteristics of randomized daily dose of aspirin treatment groups. These mechanisms seem sufficient to explain the duplicate, and the overall intra-assay coefficients Baseline characteristic Randomized daily dose of aspirin treatment groups p-value† risks as well as the benefits of aspirin on clinical of variation were between 2.8 ± 0.3% for TXB2 and 81 mg (n = 8) 162 mg (n = 7) 325 mg (n = 7) 650 mg (n = 7) 1300 mg (n = 8) cardiovascular disease events. With respect to risks, 7.9 ± 1.2% for PGE2, with plasma recovery rates gastrointestinal side effects and bleeding are well between 87.6 and 98.9%, respectively. Mean age ± SD (years) 61.8 ± 9.7 67.8 ± 8.0 61.2 ± 9.0 67.2 ± 6.0 62.6 ± 10.8 0.484 known and have been well described [1–6]. Although Analysis of variance was used to test for the Mean height ± SD (inches) 68.3 ± 3.5 68.7 ± 3.7 65.8 ± 4.3 66.4 ± 4.2 66.3 ± 2.6 0.424 a dose response for gastrointestinal side effects seems significance of differences between doses at baseline Mean weight ± SD (lb) 218.9 ± 37.7 192.4 ± 30.0 185.4 ± 60.9 202.6 ± 45.3 174 ± 28.4 0.284 apparent only at ≥325 mg daily, there has been an and 12 weeks, and for the paired differences between Mean BMI ± SD (kg/m2) 33 ± 3.8 28.6 ± 3.2 29.7 ± 7.1 33.8 ± 5.8 27.8 ± 3.9 0.098 increasing tendency to prescribe 81 mg daily. There the two time points for TXB2 and PGE2. For all is also an increasing tendency to prescribe 81 mg ECA randomized daily doses of aspirin from 81 to 1300 mg, Caucasian (n; %) 8 (100) 6 (85.7) 6 (85.7) 7 (100) 6 (75) 0.632 as increasing attempts to decrease gastrointestinal the paired differences showed virtually identical levels PCI (n; %) 4 (50) 3 (42.9) 2 (28.6) 3 (42.9) 4 (50) 0.943 side effects and bleeding. Low-dose ECA has been as well as very similar reductions in the levels of TXB2 CABG (n; %) 2 (25) 3 (42.9) 1 (14.3) 1 (14.3) 3 (37.5) 0.715 increasingly used despite some suggestions that this and PGE2 relative to baseline. Therefore, we combined Statin (n; %) 8 (100) 7 (100) 5 (71.4) 6 (85.7) 6 (75) 0.409 dose and formulation may not produce adequate, the data for all doses of aspirin and tested for statistical Other lipid lowering 2 (25) 3 (42.9) 3 (42.9) 1 (14.3) 1 (12.5) 0.555 [7–10] or in some instances any, platelet inhibition . differences between baseline levels on 81 mg ECA and agent (n; %) A randomized trial was designed and conducted randomized dose of plain aspirin after 12 weeks using ACE inhibitor (n; %) 3 (37.5) 5 (71.4) 5 (71.4) 3 (42.9) 4 (50) 0.616 to test the effects of various doses of plain aspirin paired Student’s t-tests for both TXB2 and PGE2. We from 81 to 1300 mg daily, on NO as well as platelet also used paired Student’s t-tests to determine whether Diuretic (n; %) 2 (25) 3 (42.9) 1 (14.3) 1 (14.3) 1 (12.5) 0.715 b-blocker (n; %) 7 (87.5) 3 (42.9) 7 (100) 5 (71.4) 6 (75) 0.152 and inflammatory biomarkers, specifically TXB2 there were significant modifications of the effects of and PGE2, at 12 weeks. The population studied were aspirin by age (above or below the median), gender Calcium blocker (%) 1 (12.5) 5 (71.4) 2 (28.6) 1 (14.3) 1 (12.5) 0.067 patients with chronic stable coronary disease, all of (men or women), BMI (above or below the median) Reported as mean (SD) or frequency (%). whom had been taking 81 mg ECA for at least one and race (Caucasian, African-American or other). †p-value from analysis of variance test or Fisher’s exact test based on data type. year previously. These circumstances afforded us a For each of the two markers, TXB2 and PGE2, we CABG: Coronary artery bypass graft; PCI: Percutaneous coronary intervention. unique opportunity to contribute relevant data to the used as a measure of strength of association the mean formulation of – but not to test – the hypothesis that ratios (MRs), which we calculated as the mean level inhibitors (54%) and b-adrenergic blockers (75%). Conclusion low-dose ECA does not inhibit two markers of acute for week 12 divided by the corresponding mean level Of the 37 randomized patients, 33 (one missing data In a randomized, double-blind trial of 37 patients with and systemic response to aspirin. at baseline. For each MR, we calculated 95% CI by point for each dose except 81 mg) had complete baseline chronic stable coronary disease, who had been taking computer simulation derived from the estimated and follow-up data for TXB2 and 36 (one missing data ECA 81 mg at baseline for at least 1 year prior, it was Method distributions of each outcome. All significance tests point for 650 mg) had complete data for PGE2. In found that plain aspirin, at all doses in the usual range The protocol was approved by the Institutional Review were conducted using a two-sided a-level of 0.05. those patients treated with low-dose ECA at baseline, employed in clinical practice – including 81, 162.5, 325, Board at Florida Atlantic University (FL, USA). All all clinically relevant doses of aspirin, including 81, 650 and 1300 mg – produced significant reductions in Role of the funding source patients were recruited from two private cardiology 162.5, 325, 650 and 1200 mg daily, produced virtually TXB2 and PGE2 after 12 weeks.