Elevated ratio of urinary metabolites of thromboxane and prostacyclin is associated with adverse cardiovascular events in ADAPT.

Abstract

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B(2) (Tx-M) to 2'3-donor-6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F(2)-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F(2)-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F(2)-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.

• Authors: Thomas J Montine, Joshua A Sonnen, Ginger Milne, Laura D Baker, John C S Breitner
• Journal: PloS one (PLoS One) Vol. 5 Issue 2 Pg. e9340 (Feb 19 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20174466 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• F2-Isoprostanes
• Pyrazoles
• Sulfonamides
• Thromboxane B2
• Naproxen
• 6-Ketoprostaglandin F1 alpha
• 11-dehydro-thromboxane B2
• Celecoxib
• Aspirin

Topics

• 6-Ketoprostaglandin F1 alpha (urine)
• Aged
• Aged, 80 and over
• Alzheimer Disease (prevention & control)
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects, therapeutic use)
• Aspirin (therapeutic use)
• Cardiovascular Diseases (chemically induced, prevention & control, urine)
• Celecoxib
• Drug Therapy, Combination
• F2-Isoprostanes (blood, urine)
• Female
• Humans
• Male
• Naproxen (adverse effects, therapeutic use)
• Pyrazoles (adverse effects, therapeutic use)
• Sulfonamides (adverse effects, therapeutic use)
• Thromboxane B2 (analogs & derivatives, urine)
• Treatment Outcome