Gut Microbiota-Dependent Trimethylamine N-oxide and Cardiovascular Outcomes in Patients With Prior Myocardial Infarction: A Nested Case Control Study From the PEGASUS-TIMI 54 Trial

Baris Gencer, Xinmin S Li, Yared Gurmu, Marc P Bonaca, David A Morrow, Marc Cohen, Deepak L Bhatt, P Gabriel Steg, Robert F Storey, Per Johanson, Zeneng Wang, Stanley L Hazen, Marc S Sabatine, Baris Gencer, Xinmin S Li, Yared Gurmu, Marc P Bonaca, David A Morrow, Marc Cohen, Deepak L Bhatt, P Gabriel Steg, Robert F Storey, Per Johanson, Zeneng Wang, Stanley L Hazen, Marc S Sabatine

Abstract

Background Trimethylamine N-oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor. Methods and Results PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow-up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case-control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs-TnT [high-sensitivity troponin T], hs-CRP [high-sensitivity C-reactive protein], NT-proBNP [N-terminal-pro-B-type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06-1.93, P trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28-3.96, P trend=0.003) and stroke (OR 2.68, 95% CI, 1.39-5.17, P trend<0.001). After adjustment for clinical factors, the association persisted for cardiovascular death (ORadj 1.89, 95% CI, 1.03-3.45, P trend=0.027) and stroke (ORadj 2.01, 95% CI, 1.01-4.01, P trend=0.022), but was slightly attenuated after adjustment for cardiovascular biomarkers (cardiovascular death: ORadj 1.74, 95% CI, 0.88-3.45, P trend=0.079; and stroke: ORadj 1.82, 95% CI, 0.88-3.78, P trend=0.056). The reduction in MACE with ticagrelor was consistent across TMAO quartiles (P interaction=0.92). Conclusions Among patients with prior myocardial infarction, higher TMAO levels were associated with cardiovascular death and stroke but not with recurrent myocardial infarction. The efficacy of ticagrelor was consistent regardless of TMAO levels. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: PEGASUS-TIMI 54, NCT01225562.

Keywords: antiplatelet therapy; cardiovascular death; gut microbiota; myocardial infarction; stroke; ticagrelor; trimethylamine N‐oxide.

Figures

Figure 1. TMAO concentrations comparing cases vs…
Figure 1. TMAO concentrations comparing cases vs controls for MACE, cardiovascular death, recurrent MI, and stroke events.
The P values were obtained using Wilcoxon ranking test. Values beyond the 99% percentile are not graphed to avoid an excessive y axis. CV indicates cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction; and TMAO, trimethylamine N‐oxide.
Figure 2. Risks of cardiovascular death, myocardial…
Figure 2. Risks of cardiovascular death, myocardial infarction, and stroke by TMAO quartiles adjusted for clinical variables (black) and biomarkers (red).
MACE was defined as a composite of cardiovascular death, myocardial infarction, and stroke. In the clinical variable model (black), the ORs were adjusted for age, sex, estimated glomerular filtration rate, hypertension, hypercholesterolemia, diabetes mellitus, peripheral artery disease, qualifying index event, smoking, region, BMI, aspirin dosage, and treatment arm. In the clinical and biomarkers mode (red), further adjustment was done for hs‐CRP (high‐sensitive C‐reactive protein), hs‐TnT (high‐sensitivity troponin T); and NT‐proBNP (N‐terminal‐pro hormone BNP). The trend P value was calculated by testing the coefficient of an ordinal TMAO variable from the logistic regression model. MACE indicates major adverse cardiovascular events; OR, odds ratio; and TMAO, trimethylamine N‐oxide.
Figure 3. Treatment effect of ticagrelor vs…
Figure 3. Treatment effect of ticagrelor vs placebo on the primary end point of cardiovascular death, MI, and stroke by TMAO quartiles.
CV indicates cardiovascular disease; MI, myocardial infarction; OR, odds ratio; and TMAO, trimethylamine N‐oxide.

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