Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of aspirin use, according to a new analysis of Framingham Heart Study data. The study, published online Monday and in the July 19 issue of Journal of the American College of Cardiology, assessed the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of aspirin use and found that systemic thromboxane generation is associated with all-cause and cardiovascular mortality in both aspirin users and nonusers. Led by Jeffrey J. Rade, MD, from the University of Massachusetts Chan Medical School, Worcester, and Johns Hopkins School of Medicine, Baltimore, the research team suggested that the measurement of stable thromboxane B2 metabolites (TXB2-M) and thromboxane A2 (TXA2) may be useful for therapy modification, particularly in those without cardiovascular disease (CVD). “Measuring TXA2 generation in individuals without CVD may be useful in guiding the aggressiveness of primary prevention strategies, including use of aspirin,” said the team. “These findings provide a rationale for investigating whether inhibiting TXA2 generation or blocking its effects could impact survival in individuals with CVD and potentially other conditions.” Study setup Rade and colleagues measured TXB2-M by enzyme-linked immunosorbent assay in banked urine from 3,044 participants in the Framingham Heart Study, of whom 1,363 (44.8%) were taking aspirin at the time of the index examination. Study participants had an average age of 66 years and 53.8% were female, the team said, noting that compared with aspirin non-users, aspirin users were older (68 vs. 64 years), had a higher body mass index (28.8 vs. 28.0 kg/m2), were more likely to be male (55.7% vs. 38.5%), and had a higher prevalence of CVD risk factors (including hypertension, hyperlipidemia, and diabetes) or had established CVD with associated medical therapy (including myocardial infarction [MI], peripheral vascular disease, and coronary revascularization by both percutaneous coronary intervention and coronary artery bypass grafting). The team assessed the association of TXB2-M to survival over a median observation period of 11.9 years (interquartile range [IQR]: 10.6-12.7 years) using multivariable modeling. Key findings The research team reported that in 1,363 (44.8%) participants taking aspirin at the index examination, median TXB2-M were lower than in aspirin non-users (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). They found, however, that TXB2-M were significantly associated with all-cause and cardiovascular mortality irrespective of aspirin use (hazard ratio [HR]: 1.96 and 2.41, respectively; P < 0.0001 for both) and remained significant after adjustment for mortality risk factors for similarly aged individuals (HR: 1.49 and 1.82, respectively; P ≤ 0.005 for both). Furthermore, in 2,353 participants without CVD, TXB2-M were associated with cardiovascular mortality in aspirin nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in aspirin users, while aspirin use was associated with all-cause mortality in those with low (adjusted HR: 1.46; 95% CI: 1.14-1.87) but not elevated TXB2-M. Rade and colleagues said that while aspirin reduces cardiovascular risk by inhibiting thromboxane generation in platelets, it is less effective at inhibiting thromboxane generation in other tissues – adding that this systemic thromboxane generation is associated with all-cause and cardiovascular mortality in both aspirin users and nonusers. “Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of [aspirin] use, and its measurement may be useful for therapy modification, particularly in those without CVD,” they said, noting that future studies should now set out to assess the utility of measuring systemic thromboxane generation for risk stratification, and the effect of inhibiting non-platelet thromboxane generation on cardiovascular outcomes. ‘Important and challenging’ conclusions Writing in an accompanying editorial, Carlo Patrono, MD, and Bianca Rocca, MD, PhD, from the Catholic University School of Medicine, Rome, said the new study reaches multiple “important and challenging” conclusions, including the suggestion that systemic TXA2 biosynthesis is an independent risk factor for long-term all-cause and cardiovascular mortality in an unselected cohort of older individuals, irrespective of aspirin use. Furthermore, the editorialists note that measuring the rate of TXA2 biosynthesis, as reflected by urinary TX metabolite (U-TXM) excretion, in individuals without CVD may be useful in guiding the intensity of primary prevention strategies. “Incorporating repeated measurements of U-TXM excretion into CV risk assessment may improve the efficacy and safety of antiplatelet therapy in a primary prevention setting, but the feasibility of such a precision approach must be tested,” they said. “In conclusion, unrestrained platelet TXA2 biosynthesis, as reflected by higher U-TXM excretion, increases the risk of atherothrombotic events leading to increased CV death. Consistent with the multifaceted role of platelets in cancer and inflammation, persistently high platelet activation may also account for increased all-cause death.” The expert commentators added that by selectively suppressing platelet TXA2 biosynthesis, low-dose aspirin may favor physiological tissue repair over uncontrolled progression toward vascular occlusion – noting that the pathophysiologic implications of unrestrained TXA2 biosynthesis “have clear clinical relevance for the safety of aspirin-free regimens of antithrombotic therapy.” Sources: Rade JJ, Barton BA, Vasan RS, et al. Association of Thromboxane Generation With Survival in Aspirin Users and Nonusers. J Am Coll Cardiol 2022;80:233-250. Patrono C, Rocca B. Less Thromboxane, Longer Life. J Am Coll Cardiol 2022;80:251-255. Image Credit: MQ-Illustrations – stock.adobe.com