Residual Risk of Trimethylamine‐N‐Oxide and Choline for Stroke Recurrence in Patients With Intensive Secondary Therapy

BACKGROUND: Trimethylamine N‐oxide (TMAO) contributes to cardiovascular disease through its prothrombotic, proatherothrombotic, and proinflammatory effects. We aimed to evaluate whether residual risk of recurrent stroke of TMAO and its precursor choline remain among patients who received dual‐antiplatelet therapy and intensive lipid‐lowering therapy and with a low inflammation level (high‐sensitivity C‐reactive protein <2 mg/L on admission). METHODS AND RESULTS: Patients with ischemic stroke or transient ischemic attack were enrolled from the CNSR‐III (Third China National Stroke Registry) in China. Plasma TMAO and choline concentrations at baseline were measured in 9793 participants using liquid chromatography–mass spectrometry. The primary outcome was a new stroke within 1 year. Multivariable‐adjusted hazard ratios were calculated using Cox regression models to investigate the associations of TMAO and choline with stroke recurrence. Among all patients, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke (adjusted hazard ratios, 1.28 [95% CI, 1.12–1.45]; and 1.50 [95% CI, 1.32–1.71], respectively). Moreover, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke among patients who received dual‐antiplatelet therapy (1.65 [95% CI, 1.28–2.13]; and 1.70 [95% CI, 1.32–2.19], respectively), intensive lipid‐lowering therapy (1.49 [95% CI, 1.15–1.94]; and 1.49 [95% CI, 1.15–1.92], respectively), with high‐sensitivity C‐reactive protein <2 mg/L (1.39 [95% CI, 1.14–1.69]; and 1.88 [95% CI, 1.53–2.30], respectively), and concurrently received dual‐antiplatelet therapy, intensive lipid‐lowering therapy and with high‐sensitivity C‐reactive protein <2 mg/L (3.57 [95% CI, 1.73–7.38]; and 2.19 [95% CI, 1.16–4.16], respectively). CONCLUSIONS: TMAO and choline were risk factors for recurrent stroke independent of dual‐antiplatelet therapy, intensive lipid‐lowering therapy at discharge, and low inflammation on admission.