Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults

Abstract

Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China^1,2. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS^1,2. Stroke incidence and ICH proportion are higher in China than in Western populations^3-5, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD)^6,7, but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD^8-10. Mendelian randomization studies of LDL-C and IS have reported conflicting results^11-13, and concerns about the excess risks of ICH associated with lowering LDL-C^14,15 may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.

Extended Data Fig. 1. Effect of progressive adjustment for potential confounders on risk of ischaemic stroke and intracerebral haemorrhage with usual LDL-C

Cox regression was used to estimate adjusted rate ratios (RR) (95% confidence intervals [CI]) for risk of different stroke types per 1 mmol/L higher concentrations of usual LDL-C. Each square has an area inversely proportional to the variance of the log risk. The horizontal lines represent the 95% CI.

Extended Data Fig. 2. Associations of usual LDL-C with risk of ischaemic stroke and intracerebral haemorrhage in population subgroups at baseline

Cox regression was used to estimate the adjusted rate ratios (RR) (95% CI) for risk of different stroke types per 1 mmol/L higher concentrations of usual LDL-C. Chi-square tests were used to assess heterogeneity and trend, and the degrees of freedom are provided as subscripts. All P-values (two-sided) were uncorrected for multiple testing. Symbols and conventions as in Extended Data Fig. 1.

Extended Data Fig. 3. Adjusted rate ratios (RR) for risk of ischaemic stroke by usual concentrations of LDL-C and HDL-C in observational analyses in CKB

Symbols and conventions as in Extended Data Fig. 1. The number of ischaemic stroke cases and controls were 5475 and 6290, respectively.

Extended Data Fig. 4. Adjusted rate ratios (RR) for risk of ischaemic stroke and intracerebral haemorrhage by usual concentrations of apolipoprotein B, apolipoprotein A1, and lipoprotein (a) in observational analyses in CKB

Cox regression was used to estimate the rate ratios (RR) (95% CI) for ischaemic stroke (N = 5475) and intracerebral haemorrhage (N = 4776) by fifths of (a) usual apolipoprotein B, (b) usual apolipoprotein A1, and (c) usual lipoprotein (a), respectively. The line represents the slope from a weighted linear regression with weights based on the inverse variance of the log RR. Symbols and conventions as in Extended Data Fig. 1.

Extended Data Fig. 5. Associations of the genetic risk score (GRS) for LDL-C with major vascular risk factors

SD=Standard deviation. The analyses were conducted in 17,567 CKB participants with available data, adjusted for sex, age, age-squared, and case status. General linear regression was used to estimate SD differences in all traits (after rank-inverse-normal transformation) per 1 SD higher GRS. All P-values (two-sided) were uncorrected for multiple testing.

Extended Data Fig. 6. Meta-analysis of randomised trials of LDL-C-lowering treatment with statins, ezetimibe, or PCSK9 inhibitor and risk of ischaemic stroke and intracerebral haemorrhage

The study-specific rate ratios (RR) (95% CI) were obtained from the published results of the LDL-C-lowering trials. The overall RR (95% CI) were obtained by inverse-variance-weighted meta-analysis of the study-specific RR per 1 mmol/L lower LDL-C concentration.

Fig. 1. Adjusted rate ratios (RR) for risk of ischaemic stroke and intracerebral haemorrhage by fifths of usual concentrations of LDL-C, HDL-C, and triglycerides in observational analyses in CKB

Cox regression was used to estimate the rate ratios (RR) and 95% confidence intervals (CI) for ischaemic stroke (N = 5475) and intracerebral haemorrhage (N = 4776) by fifths of (a) usual LDL-C, (b) usual HDL-C, and (c) usual triglycerides. Each square has an area inversely proportional to the variance of the log risk in the specific group. The line represents the slope from a weighted linear regression with the weights based on the inverse variance of the log RR.

Fig. 2. Adjusted rate ratios (RR) for risk of ischaemic stroke and intracerebral haemorrhage associated with 1 mmol/L lower LDL-C in observational and genetic analyses in CKB, and in randomised trials of LDL-C-lowering drug treatment in Western populations

The values shown are the RR (95% CI) per 1 mmol/L lower LDL-C concentrations. The number of cases of ischaemic stroke and of intracerebral haemorrhage, and controls in the observational analyses were 5475, 4776, and 6290, respectively; and in the genetic analyses were 5567, 4911, and 9742, respectively. In the randomised trials, the number of ischaemic stroke cases were 2431 in the treated and 3045 in the placebo groups, and the corresponding numbers of intracerebral haemorrhage cases were 494 in the treated and 404 in the placebo groups, respectively. Chi-square tests were used to test for heterogeneity. P-values (two-sided) were uncorrected for multiple testing.

Fig. 3. Predicted number of events avoided for ischaemic stroke, major coronary events, and intracerebral haemorrhage per 10,000 patients treated by lowering LDL-C by 1 mmol/L with statins for 5 years in Chinese adults with different levels of vascular risk

The estimated number of events (and their standard deviations) avoided by lowering LDL-C by 1 mmol/L, obtained by applying the rate ratios from the LDL-C-lowering trials to low, medium and high-risk population subgroups in CKB, are shown below the figure.