Baseline Serum Bilirubin and Risk of First Stroke in Hypertensive Patients

Abstract

Background: Data concerning the association between serum bilirubin and the risk of stroke is limited and inconclusive. We aimed to evaluate the association between serum bilirubin and the risk of first stroke, and examine any possible effect modifiers in hypertensive patients. Methods: Our analyses included a total of 19,906 hypertensive patients from the China Stroke Primary Prevention Trial (CSPPT). In the CSPPT, a total of 20,702 hypertensive patients without major cardiovascular diseases were randomly assigned to a double-blind, daily treatment with either 10mg enalapril and 0·8mg folic acid or 10 mg enalapril alone. The median treatment duration was 4·5 years. Findings: There was a significant inverse association between serum total bilirubin (TBiL) (per-SD increment; HR, 0·90; 95%CI: 0·81, 0·99) or direct bilirubin (DBiL) (HR, 0·83; 95%CI: 0·74, 0·93) and the risk of first ischemic stroke. When TBiL and DBiL were assessed as tertiles, the adjusted HR for first ischemic stroke for participants in tertile 3 was 0·74 (95%CI: 0·58, 0·93) for TBiL and 0·73 (95%CI: 0·57, 0·93) for DBiL, compared with those in tertile 1. Furthermore, the serum DBiL-first ischemic stroke association was significantly stronger in participants without the use of antiplatelet drugs during the treatment period (vs. with antiplatelet drugs usage; P-interaction=0·033). However, there was no significant association between serum TBiL or DBiL and first hemorrhagic stroke. Interpretation: In Chinese hypertensive patients, there was a significant inverse association between serum DBiL and the risk of first ischemic stroke, especially among those without antiplatelet drugs usage during the treatment period. Funding Statement: The study was supported by funding from the following: the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003]; the National Natural Science Foundation of China [81730019, 81973133]; the Science and Technology Planning Project of Guangzhou, China [201707020010]; the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143]; the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]; the President Foundation of Nanfang Hospital, Southern Medical University [2017C007, 2018Z009]; the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009]. Declaration of Interests: Dr. Xiping Xu reports grants from the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX09301034003], the Science and Technology Planning Project of Guangzhou, China [201707020010], the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143], and the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]. Dr. Xianhui Qin reports grants from the National Natural Science Foundation of China [81730019, 81973133], and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009]. Dr. Youbao Li reports grants from the President Foundation of Nanfang Hospital, Southern Medical University [2017C007, 2018Z009]. No other disclosures were reported. Ethics Approval Statement: The parent study (the CSPPT: Clinical Trials. gov, NCT00794885) and the current study were approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number: FW1263). All participants provided written informed consent. The data that support the findings of this study will be available from the corresponding authors upon request, after the request is submitted and formally reviewed and approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University.