Association of Thromboxane Generation With Survival in Aspirin Users and Nonusers

Abstract

Background: Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.

Objectives: This study sought to determine the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of ASA use.

Methods: Stable thromboxane B₂ metabolites (TXB₂-M) were measured by enzyme-linked immunosorbent assay in banked urine from 3,044 participants (mean age 66 ± 9 years, 53.8% women) in the Framingham Heart Study. The association of TXB₂-M to survival over a median observation period of 11.9 years (IQR: 10.6-12.7 years) was determined by multivariable modeling.

Results: In 1,363 (44.8%) participants taking ASA at the index examination, median TXB₂-M were lower than in ASA nonusers (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). TXB₂-M were significantly associated with all-cause and cardiovascular mortality irrespective of ASA use (HR: 1.96 and 2.41, respectively; P < 0.0001 for both) for TXB₂-M in the highest quartile based on ASA use compared with lower quartiles, 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). In 2,353 participants without CVD, TXB₂-M were associated with cardiovascular mortality in ASA nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in ASA users, while ASA 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.

Conclusions: Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of ASA use, and its measurement may be useful for therapy modification, particularly in those without CVD.

Keywords: aspirin; isoprostane; mortality; platelets; thromboxane.

Figure 1.. Thromboxane generation in aspirin users and non-users.

Systemic thromboxane generation was quantified by measuring urinary thromboxane B₂ metabolites (TXB₂-M) in 1681 aspirin (ASA) users and 1681 ASA non-users. Median values with interquartile rages (boxes), 5% and 95% confidence intervals (bars) and individual outliers are shown.

Figure 2.. Aspirin use and all-cause mortality risk.

All-cause mortality risk was significantly greater in the 1363 aspirin (ASA) users (blue line) compared to the 1680 ASA non-users (red line) at the time of the index examination. Number at risk over time in each group is indicated.

Figure 3.. Thromboxane generation and all-cause mortality risk.

Systemic thromboxane generation was quantified by measuring urinary thromboxane B₂ metabolites (TXB₂-M). In 1363 aspirin (ASA) users (A), 1680 ASA non-users (B) and their combination (C) at the time of the index examination, all-cause mortality risk was greatest in participants with TXB₂-M in the highest quartile compared to lower quartiles. Number at risk over time in each group is indicated.

Figure 4.. Thromboxane generation and all-cause mortality risk by participant characteristics.

Systemic thromboxane generation was quantified by measuring urinary thromboxane B₂ metabolites (TXB₂-M) and participant subgroups were stratified by respective quartile 4 versus quartiles 1–3 based on aspirin (ASA) use at the time of the index examination. Urinary TXB₂-M in the highest quartile was associated with increased all-cause mortality risk in a wide array of participant subgroups, irrespective of ASA use. Number of participants at risk shown in parentheses. HR=unadjusted hazard ratio; UCL=upper 95% confidence limit; LCL=lower 95% confidence limit. ASA=aspirin; BMI=body-mass index; CAD=coronary artery disease; eGFR=estimated glomerular filtration rate; LVEF=left ventricular ejection fraction.

Figure 5.. Aspirin use and mortality risk in participants without cardiovascular disease.

All-cause mortality (A) but not cardiovascular mortality (B) risk was greater in the 898 participants taking ASA (blue line) compared to the 1455 not taking ASA (red line) at the time of the index examination. Number at risk over time in each group is indicated.

Figure 6.. Thromboxane generation and mortality risk in participants without cardiovascular disease.

Systemic thromboxane generation was quantified by measuring urinary thromboxane B₂ metabolites (TXB₂-M) in 2353 participant stratified by aspirin (ASA) use and without cardiovascular disease at the index examination. Urinary TXB₂-M in the highest quartile (blue line) was associated with grater all-cause mortality risk compared to lower quartiles (red line) in 898 ASA users (A) and 1455 ASA non-users (B) and was associated with increased cardiovascular mortality risk in ASA non-users (D) but not in ASA users (C). Number at risk over time in each group is indicated.

Figure 7.. Interaction of aspirin use and thromboxane generation with mortality risk.

Systemic thromboxane generation was quantified by measuring urinary thromboxane B₂ metabolites (TXB₂-M) in 2353 participant without established cardiovascular disease stratified by aspirin (ASA) use at the index examination. Interaction analyses revealed all-cause and cardiovascular mortality risk was greater in ASA non-users, but not ASA users with urinary TXB₂-M in the highest quartile (A) as well as in ASA users with urinary TXB₂-M in the lowest quartiles (B), even after adjustment for modifiable cardiovascular risk factors. Numbers of participants at risk shown in parentheses. HR=unadjusted hazard ratio; UCL=upper 95% confidence limit; LCL=lower 95% confidence limit. ASA=aspirin; BMI=body mass index. ^aUnadjusted. ^bAdjusted for systolic blood pressure, total cholesterol/HDL ratio, smoking status, BMI and hemoglobin A1C.

Central Illustration. Schematic of systemic thromboxane generation and association with long-term mortality.

Aspirin (ASA) effectively suppresses thromboxane A₂ (TXA₂) generation in platelets but not in endothelial cells under oxidative stress or activated inflammatory cells. TXA₂ generation and signaling through cellular thromboxane-prostanoid receptors has been implicated in multiple disease processes and increased systemic TXA₂ generation, as evidenced by elevated levels of stable urinary thromboxane B₂ metabolites (TXB₂-M), is associated with reduced long-term survival irrespective of ASA use. In individuals without established cardiovascular disease, measurement of urinary TXB₂-M may be useful to identify those who would benefit from or be harmed by ASA therapy for primary prevention.