Sex difference in the association between triglyceride and intracerebral bleeding risk after intravenous thrombolysis for acute ischemic stroke, a multi-center retrospective study

Background

Symptomatic intracerebral hemorrhage (sICH) accounts for the most feared complication after intravenous thrombolysis with recombinant tissue plasminogen activator (r-tPA) for acute ischemic stroke (AIS) (Cordonnier et al., 2018; Powers et al., 2019). Previous studies have identified different predictors of sICH after r-tPA thrombolysis, such as diabetes, hypertension, elevated serum glucose, and lower platelet count (Nisar, Hanumanthu & Khandelwal, 2019). Epidemiological studies have shown potential associations between lower cholesterol levels and the risk of hemorrhagic stroke. The Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) study showed that among 35,314 patients, lower total cholesterol levels were associated with a higher risk of sICH (Escudero-Martínez et al., 2023). Data from Eastern Asia showed that decreasing serum cholesterol levels had trends towards a lower risk of non-hemorrhagic stroke (odds ratio (OR) for 0.6 mmol/L decrease, 0.77 [0.57–1.06]) and an increased odds of hemorrhagic stroke (1.27 [0.84–1.91]) (Anonymous, 1998). A large observational study of 45,079 AIS patients treated with intravenous alteplase showed that although there was no difference in the rate of sICH (p = 0.13), male sex was associated with a higher risk of sICH (OR 1.25, 95% CI [1.04–1.51], p = 0.02) after adjustment for confounding variables (Lorenzano et al., 2013). Several previous studies have indicated an association between low-density lipoprotein cholesterol (LDL) and symptomatic hemorrhagic transformation in a mixed population of patients undergoing IV thrombolysis, suggesting sex may influence the association between lipid profile and intracerebral bleeding risk (Bang et al., 2007; Uyttenboogaart et al., 2008). To our knowledge, sex differences in the relationship between lipid profile and the risk of sICH after intravenous r-tPA for AIS have not been fully understood. Knowledge of sex differences might be of importance in improving preventive and in-hospital treatment strategies in the AIS population. We aimed to investigate the association of the traditional harmful lipid profiles (including the evaluation of total cholesterol, low-density lipoprotein (LDL), and triglyceride) with the odds of sICH according to sex in this retrospective study.

Methods

Results

We included 957 participants (median age 68 [IQR 59–75], 628 men [65.6%]) in the final analysis (Fig. 1), with 56 sICH events (5.7% in men and 6.1% in women) observed. The median baseline NIHSS score was 6 [IQR 3–12].

Table 1 summarizes the baseline characteristics and univariate comparisons among male and female patients. Compared to female participants, male participants were younger (66 [58-74] vs. 70 [60-77], p < 0.001), more likely to be a current smoker (294 [46.8%] vs. 4 [1.2%], p < 0.001) and an often drinker (110 [17.5%] vs. 6 [1.8%], p < 0.001), more likely to have a previous stroke (100 [15.9%] vs. 34 [10.3%], p = 0.018) and had a less severe stroke (a NIHSS score of 6 [3–11] vs. 8 [4–14], p = 0.002). The proportion of atrial fibrillation in men was lower than in women (147 [23.4%] vs. 134 [40.7%], p < 0.001). The serum levels of total cholesterol (mmol/L, 4.48 ± 1.16 vs. 4.74 ± 1.04, p < 0.001) and LDL (mmol/L, 2.98 ± 1.13 mmol/L vs. 3.19 ± 1.12 mmol/L, p = 0.005) were lower in men than in women. The serum level of triglyceride was higher in men than in women, although the difference did not reach statistical significance (mmol/L, 1.29 [IQR 0.91–1.88] vs. 1.20 [0.87–1.75], p = 0.065). There were no significant difference between the sexes in terms of pre-stroke statin use (44 [7.8%] vs. 24 [8.1%], p = 0.863).

Baseline characteristics among patients with and without sICH events in men and women are shown in Table 2. In comparison, in men, the variables associated with sICH in the univariate analysis were increasing age (p = 0.001), atrial fibrillation (p = 0.002), hyperlipidemia (p = 0.004), increasing initial NIHSS score (p < 0.001), lower blood platelet count (p = 0.005), pre-thrombolysis blood glucose (p = 0.001), and serum levels of triglyceride (p < 0.001, Table 2). In comparison, in women, the variables associated with sICH in the univariate analysis were age (p = 0.015), diabetes (p = 0.013), atrial fibrillation (p = 0.001), initial NIHSS score (p = 0.001), and pre-thrombolysis blood glucose (p = 0.004). Female patients with and without sICH had similar serum levels of total cholesterol, LDL, and triglyceride. Stroke subtypes in patients with and without sICH were significantly different in both men and women (p < 0.05, respectively, Table 2).

Table 3 and Tables S1, S2 show the associations of lipid profile with the risk of sICH. Univariable regression analysis showed that serum level of triglyceride was inversely associated with the risk of sICH (vs lowest tertile, medium tertile OR 0.39, 95% CI [0.17–0.88], top tertile OR 0.29, 95% CI [0.12–0.71], p for trend = 0.004, overall p = 0.008; per mmol/L increase, OR 0.26, 95% CI [0.12–0.56], p = 0.001) in men. This association was not found in women (vs lowest tertile, medium tertile OR 0.91, 95% CI [0.28–2.96], top tertile OR 1.49, 95% CI [0.52–4.25], p for trend = 0.464, overall p = 0.646; per mmol/L increase, OR 1.18, 95% CI [0.80–1.74], p = 0.417, Table 3). After adjustment for age and NIHSS (model 1), a higher level of triglyceride was inversely associated with the risk of sICH in men, but not in women. This association remained in the multiple regression Model 2 in men (vs lowest tertile, medium tertile OR 0.39, 95% CI [0.17–0.91], top tertile OR 0.33, 95% CI [0.13–0.63], p for trend = 0.006, overall p = 0.021; per point increase, adjusted OR 0.29, 95% CI [0.13–0.63], p = 0.002, Table 3), but not in women. Neither serum levels of total cholesterol (Table S1) nor LDL (Table S2) was associated with sICH risk both in men and in women.

Discussion

The current study showed that in men, with increasing serum levels of triglyceride there was a trend towards a lower risk of sICH. However, neither serum levels of total cholesterol nor LDL was associated with sICH in men. In women, none of the lipid profiles was related to sICH after intravenous thrombolysis for acute ischemic stroke.

Several previous studies explored the relationship between baseline lipid profile and intracerebral bleeding risk in AIS population, yielding conflicting findings (Uyttenboogaart et al., 2008). A prospective hospital-based study of 252 AIS patients showed that high admission triglyceride levels were significantly associated with a higher risk of sICH after intravenous r-tPA, while total cholesterol, LDL, and pre-stroke statin use had no influence on the occurrence of sICH (Uyttenboogaart et al., 2008). A secondary analysis of the Get With The Guidelines-Stroke (GWTG-Stroke) cohort of thrombolyzed AIS patients showed that serum triglyceride level was modestly associated with sICH. However, neither total cholesterol nor LDL was associated with sICH (Messé et al., 2013). A retrospective observational study of 1,066 AIS patients did not detect the associations of sICH with a higher level of LDL (OR 0.96, 95% CI [0.36–2.60], p = 0.942), triglyceride (OR 1.74, 95% CI [0.84–3.56], p = 0.132), and a lower level of HDL (OR 1.78, 95% CI [0.68–4.65], p = 0.279) (Rocco et al., 2012). Data from the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) rt-PA Registry showed that of 489 enrolled AIS patients (171 women, 70.8 ± 11.6 years old), there were no significant associations between ICH and any lipid levels (Makihara et al., 2012). In a hospital-based cohort of consecutive ischemic stroke patients, total cholesterol (OR 0.98, 95% CI [0.98–0.99]; p = 0.006) and LDL (OR 95% CI 0.98, [0.97–0.99]; p = 0.023) were significantly associated with poor prognosis at 90 days in men, but not in women (Cuadrado-Godia et al., 2009). The heterogeneity in the above-mentioned studies may be attributed to a heterogeneous population with different treatment modalities. However, whether the relationship of sICH with lipid profiles may vary by sex has been scarcely reported in the literature. The present study, to the best of our knowledge, is the first to show an association between increasing serum levels of triglyceride and a lower risk of sICH only in men, but not in women, suggesting the potential relationship of sICH with lipid profiles may vary by sex. Even if not separated by gender a meta-analysis showed that the benefits of lipid lowering therapy in prevention of ischemic stroke greatly exceed the risk of ICH. Concern about sICH should not discourage the use of lipid lowering therapy for secondary prevention of ischemic stroke (Judge et al., 2019).

Several possible explanations exist for the relationship between increasing triglyceride level and decreased risk of sICH. First, since triglyceride-enriched lipoproteins are accompanied by elevations in factor VII clotting activity and plasminogen activator inhibitor (PAI-1), a higher level of triglyceride may be associated with an imbalance of coagulation over fibrinolysis (Rosenson & Lowe, 1998). This hypothesis is supported by a case-control study showing that PAI-1 antigen levels fell by 40% in individuals with a triglyceride-lowering of 20% or more (Mussoni et al., 1992). Second, hypotriglyceridemic may be related to the change in viscosity of blood and plasma, which is associated with pathological conditions including hypotension, hypertension, and hemorrhage (Martini et al., 2006; Otto, Richter & Schwandt, 2000). Third, the proportion of cardioembolic stroke in men was higher than in women (105 (31.9%) vs. 140 (22.3%)); thus the paradoxical association between hyper triglyceridemic and sICH may be influenced by this specific distribution of stroke etiology in men (Amarenco & Steg, 2007). However, adjusting for initial stroke severity and subtypes did not change our findings. Therefore, a plausible explanation for the protective role of the so-called “harmful lipid” in male AIS patients is still lacking. Future studies with larger sample sizes are essential to address the prognosis according to etiological subtypes. The reason that high serum levels of triglycerides correlate with a lower risk of sICH in men but not in women remains unclear, which may be attributable to sex differences in lipids metabolism (Yost et al., 1998). Further research is required to better elucidate this interesting uncertainty.

Conclusions

The association between serum levels of triglyceride and sICH may vary by sex. In men, increased triglyceride levels decrease the risk of sICH; in women, this association was lost. Further studies on the biological mechanisms for sex differences in stroke risk associated with triglyceride are needed.

Supplemental Information