Statins, as inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for hepatic cholesterol synthesis, are effective not only in lowering total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), but also in mildly lowering triglycerides (TG) and mildly raising high-density lipoprotein cholesterol (HDL-C), and are the most important drugs for the treatment of hypercholesterolemia and prevention of atherosclerotic diseases. It is the most important drug for the treatment of hypercholesterolemia and the prevention and treatment of atherosclerotic diseases. With the establishment of elevated lipids, especially LDL-C, as an important risk factor for atherosclerosis, and the increased evidence for lipid-lowering therapy for the prevention of cardiovascular disease, particularly coronary atherosclerotic heart disease and ischemic stroke, statins have received increasing clinical attention. As primary and secondary stroke prevention agents, statin therapy was associated with a 15.6% reduction in stroke incidence for every 10% reduction in LDL-C levels, and the reduction in stroke was related to the magnitude of LDL-C reduction, independent of baseline LDL-C levels. However, a 2006 secondary stroke prevention study, the SPARCL study, found that treatment with atorvastatin significantly reduced the incidence of ischemic stroke while increasing the risk of hemorrhagic stroke. This finding has called into question the safety of statins in clinical use. To better understand hemorrhagic stroke in statin use, this article reviews previous reports of hemorrhagic stroke in clinical studies and further examines the possible causes of this phenomenon in terms of cholesterol and hemorrhagic stroke to better inform safety considerations in the clinical use of statins. The epidemiology of hemorrhagic stroke in statin clinical trials To date, dozens of statin clinical trials have been conducted internationally, mostly with coronary heart disease or stroke events as the trial endpoints, and hemorrhagic stroke, a type of stroke event, has only been investigated in some clinical trials because of its different pathogenesis from ischemic stroke. clinical trials are not numerous. In 2004, Pierre Amarenco et al. conducted a systematic review and meta-analysis of all randomized trials testing the efficacy of statins published before August 2003, using a Pubmed search. Twenty-six clinical trials covering more than 90,000 individuals were selected for the meta-analysis, which focused on the effects of LDL-C-lowering therapy with statins on stroke and carotid intima-media thickness (IMT). Of the included clinical trials, 12 (including one that was not included in the efficacy assessment meta-analysis because of unsuccessful randomization – the KLIS trial) collected data on new episodes of hemorrhagic stroke, covering 49,843 randomized patients, and four of these trials did not observe hemorrhagic stroke. In the remaining eight studies, 78 patients (0.32%) in the statin group had a hemorrhagic stroke compared with 84 patients (0.36%) in the control group. The meta-analysis did not find an increased risk of hemorrhagic stroke with statins (OR=0.90, 95% CI 0.65-1.22), and this remained true even when the KLIS trial results were excluded (OR, 0.91; 95% CI, 0.65-1.26). On closer analysis of the eight clinical trials, the LIPID study showed a higher proportion of patients with hemorrhagic stroke in the statin group than in the control group (14/4512 vs 7/4502, Pravastatin), and the remaining studies had comparable or lower proportions of patients with hemorrhagic stroke between the two groups. In the HPS study published in The Lancet in 2004, which examined the efficacy of simvastatin in preventing stroke and other major vascular events in patients with cerebrovascular disease or other high-risk conditions, the incidence of hemorrhagic stroke was found to be higher in the simvastatin-treated group (40 mg/d) than in the control group (n=21, 1.3% vs n=11, 0.7%), but regression analysis did not find this difference to be statistically significant. However, regression analysis did not find this difference to be statistically significant. Because of the small sample size of stroke cases in the HPS study, it was not strong enough to find such a difference. In 2006, the New England Journal published the SPARCL study, the first study to confirm the role of statins in secondary stroke prevention, which showed that treatment with atorvastatin significantly reduced the incidence of ischemic stroke in patients with recent stroke or TIA without a significant history of coronary artery disease. Also, the study found that treatment with high-dose atorvastatin (80 mg/d) increased the risk of hemorrhagic stroke. A total of 88 hemorrhagic strokes occurred in the study, 55 in the statin treatment group and 33 in the placebo group, with a significant difference between the two (p=0.03). The relative risk of hemorrhagic stroke was increased by 66% in the statin group. The investigators concluded that, based on the fact that lowering LDL-C to 1.8 mmol/L or lower in previous large statin trials did not increase the incidence of hemorrhagic stroke, the increased risk of hemorrhagic stroke in the statin group of the trial was attributed to the inclusion of patients with a history of prior hemorrhagic stroke at enrollment and suggested that patients with prior hemorrhagic stroke should be aware of the potential risk of rebleeding when using statins The study also suggested that patients with previous hemorrhagic stroke should be aware of the potential risk of re-emitting blood. Subsequently, SPARCL researchers conducted an in-depth analysis of the phenomenon of hemorrhagic stroke and published an article in Neurology in 2008. The analysis found that 2% of patients in the study had a hemorrhagic stroke as an enrollment event at the time of patient enrollment. At the end of the study, patients with a history of hemorrhagic stroke at baseline had an increased risk of hemorrhagic stroke after treatment with atorvastatin (HR 4.06, 95% CI 0.84-19.57) and an increased risk of all types of stroke (HR 2.82, 95% CI 0.89-9.01). 5.65, 95% CI 2.82-11.30, p < 0.001), male (HR 1.79, 95% CI 1.13-2.84, p=0.01), atorvastatin treatment (HR 1.68, 95% CI 1.09-2.59, p=0.02), age (10 years stratification, HR 1.42, 95% CI 1.16- 1.74, p=0.001) were independently associated with the risk of hemorrhagic stroke, but these factors explained only 1% of the risk of hemorrhage. The study also found that elevated blood pressure was independently associated with the risk of bleeding and was greatest in patients with grade 2 hypertension, while LDL-C levels were not associated with the risk of hemorrhagic stroke. The researchers interpreted the results of this analysis as follows: first, the risk of recurrent hemorrhagic stroke is around 2.5% per year, so it is not surprising that patients with a history of hemorrhagic stroke are more likely to have a recurrence; second, consistent with previous studies, increased blood pressure prior to the onset of hemorrhagic stroke is associated with the risk of bleeding, so aggressive treatment of hypertension is recommended to reduce the risk of hemorrhagic stroke; and third, although epidemiological studies suggest that cholesterol levels are associated with the risk of hemorrhagic stroke, the risk of hemorrhagic stroke is not. Although epidemiological studies have suggested that cholesterol levels are associated with hemorrhagic stroke, recent clinical trials of statin therapy for coronary heart disease have not found this association, and this study further confirms that the two are not related. In addition, the investigators noted that the combination of antiplatelet agents, anticoagulants, or antithrombotics with statins was not found to increase the risk of hemorrhagic stroke in the SPARCL study. However, because statins have an antithrombotic component, the risk of hemorrhagic stroke due to this factor cannot be excluded. To further explore the efficacy and risk of statin therapy in patients with a history of cerebrovascular disease, in 2008, Vergouwen and colleagues conducted a comprehensive analysis of four major trials, CARE, LIPID, HPS, and SPARCL, in which 8,832 patients with a history of cerebrovascular disease were included. Of these, the HPS, SPARCL trial collected information on hemorrhagic stroke and covered 8,011 patients, including 4,008 patients in the treatment group and 4,003 in the control group, with 76 patients in the treatment group and 44 in the control group experiencing hemorrhagic stroke. After a combined analysis, the combined risk of hemorrhagic stroke was 1.73 (95% CI 1.19-2.50). The investigators further excluded patients with a history of hemorrhagic stroke from the SPARCL study, and the results obtained still suggested that patients in the treatment group had a significantly higher risk of hemorrhagic stroke compared with the placebo group (pooled RR 1.33, 95% CI 1.03-1.73). As can be seen, there are not many studies related to whether statin application increases hemorrhagic stroke, and the conclusions are not consistent. As the available data are mostly from subgroup analyses of clinical trials, the sample size is small and not strong enough to test the research hypotheses. Moreover, the results of the pooled analyses are limited by the different inclusion criteria of each clinical trial, and the unexplained or unclassifiable strokes recorded in the studies may also have an impact on the results. There is no evidence on whether statins used for coronary heart disease or stroke prevention cause a consistent risk of hemorrhagic stroke. However, this potential risk still needs to be taken into account in clinical work and more clinical studies are needed in the future to determine the factors associated with this risk. Clinical presentation and risk prediction of statin-induced hemorrhagic stroke Statin-induced hemorrhagic stroke mainly presents with cerebral hemorrhage, both lobar and deep, in patients taking statins with a history of previous intracranial hemorrhage. Statins can reduce vasospasm in patients with subarachnoid hemorrhage and may induce rebleeding if the drug is suddenly stopped. To better predict the risk of statin use in patients with intracranial hemorrhage, a recent study investigated the trade-off between the possible benefits and potential risks of statin use in patients with intracranial hemorrhage. They used a computer model to predict multiple clinical indicators of patient use or non-use of statins. Results showed that survivors of lobar hemorrhage had the highest risk of bleeding recurrence with statin use. Survivors of lobar hemorrhage without prior cardiovascular events had an additional 2.2 years of survival expectancy by avoiding statins, whereas survivors with cardiovascular events should avoid statins unless their recurrence rate of myocardial infarction was up to 90% or higher and thus favored statin use. In survivors with deep bleeding, prophylaxis also favors avoidance of statins, although the magnitude of effect is not as pronounced. Possible mechanisms of hemorrhagic stroke after statin use Following the observation in clinical trials that statin use may increase the risk of hemorrhagic stroke, investigators have begun to explore possible mechanisms for this effect, which, taken together, include several points: first, the correlation between cholesterol levels and hemorrhagic stroke; second, the possible link between microbleeds and hemorrhagic stroke; and, third, the statin's own Third, the pharmacological effects of statins themselves, in addition to LDL-C lowering. The correlation between cholesterol levels and hemorrhagic stroke has been confirmed in many epidemiological studies. As early as 1982, the MRFIT study was published in JAMA, which conducted a multiple risk factor intervention in a population of 350,000 men to assess the efficacy of the intervention on coronary heart disease mortality. A study published in The Lancet in 1998 followed blood pressure, blood cholesterol levels, and stroke events in 69,767 Chinese and Japanese men and logistic regression analysis found an increased risk of hemorrhagic stroke with decreasing cholesterol concentrations A trend towards an increased risk of hemorrhagic stroke (1.27 [0.84-1.91]) was observed with decreasing cholesterol concentrations. In the Honolulu Heart Program in the United States, researchers observed 116 hemorrhagic strokes in 7,850 Japanese Hawaiian American men without a prior history of stroke followed for an average of 18 years and found that blood cholesterol levels were only negatively associated with intracerebral hemorrhage and not with subarachnoid hemorrhage. The risk of hemorrhagic stroke was highest in the group with the lowest cholesterol values (<160 mg/dl), but no interaction with blood pressure was found. The investigators suggest that this may be related to arterial wall weakening leading to rupture of small arachnoid cerebral arteries. In addition to this, three other studies (over 100 hemorrhagic strokes, including the Honolulu Study) confirmed this finding. Although there is ample evidence from epidemiological surveys confirming the association between low cholesterol levels and high risk of hemorrhagic stroke, it is noteworthy that current trials of statins to lower cholesterol levels to prevent the occurrence of coronary heart disease or stroke have not found a negative association between LDL-C levels and the risk of hemorrhagic stroke, even when LDL-C levels are reduced very low. The different target populations of clinical trials and epidemiological surveys may explain the inconsistent findings. Furthermore, most studies did not document stroke subtype or previous history of hemorrhagic stroke, leaving the current evidence from only a few studies, which also has some impact on the conclusions. In addition, Ariesen et al. in 2003 conducted a systematic review of risk factors for intracranial hemorrhage and identified age, male sex, hypertension, and high alcohol intake as high risk factors for intracranial hemorrhage, but previous studies have failed to consider the potential impact of these factors in a comprehensive manner, which may also bias the results. Possible association of microhemorrhage with hemorrhagic stroke Some studies have shown that microhemorrhage has a prevalence of 23-40% in patients with ischemic stroke and is associated with subsequent hemorrhagic stroke. Low LDL-C levels are one of the risk factors for microhemorrhage. It can be hypothesized that statins that lower LDL-C levels may be associated with the prevalence or extent of microhemorrhage in patients without a history of ICH, and this correlation suggests that statin use may have a role in the conversion of asymptomatic microhemorrhage to clinical hemorrhagic stroke. Based on this hypothesis, one study explored whether statin use was associated with the prevalence or extent of microhemorrhage in patients with acute ischemic stroke and TIA based on information about their previous emergency MRI status and statin administration. Results found that 23% of patients had microhemorrhage, and univariate and multivariate analyses were used to show that the prevalence of microhemorrhage was higher in patients taking statins than in those not taking them, but this difference did not reach a statistical difference (OR=0.73, 95% CI, 0.36 C1.51, p=0.40). Statins were not associated with the extent of microbleeding (OR=2.31, 95% CI, 0.61C 8.75, p=0.22). This result is similar to another recent result, suggesting that hemorrhagic stroke associated with statin therapy may not be mediated by microhemorrhage. The results are limited by the study's failure to perform further analysis for possible confounding factors such as hypertension, statin dose, and years of experience. Pharmacological effects of statins Although statins were initially aimed at lowering blood cholesterol levels, several recent studies have shown that the pharmacological effects of statins are multidirectional, such as improving vascular endothelial function, anti-inflammatory, antioxidant, and plaque stabilization.Bourcier et al. found that statins reduced the synthesis of fibrinogen activator inhibitor 1 (PAI-1) in human smooth muscle cells and vascular endothelial cells and increased the synthesis of tissue-type 1) synthesis and increased tissue-type fibrinogen activator activity, thereby regulating fibrinolytic homeostasis and promoting fibrinolysis during plaque rupture to reduce thrombus formation. Also, statins can indirectly reduce leukocyte activation and inhibit platelet aggregation by increasing endothelial NO production and bioavailability, an effect that is not dependent on cholesterol levels. Thus, the pleiotropic pharmacological effects of statins may play a role in their increased risk of hemorrhagic stroke. Patients with a previous history of cerebrovascular disease, on the other hand, tend to have more fragile arterial walls and are more likely to cause bleeding. Determination and differential diagnosis of the association between hemorrhagic stroke and statin use Because there is no specificity in clinical presentation, a history of previous statin administration is an important prerequisite for determining whether hemorrhagic stroke is associated with statins. In particular, in patients with a history of previous cerebral hemorrhage, the presence of rebleeding requires careful determination of potentially relevant rebleeding factors, including hypertension. If there is no obvious etiology while taking statins, statin-induced hemorrhagic stroke should be considered. Prevention and control of hemorrhagic stroke with statin use Although the risk of hemorrhagic stroke with statin use is not well established and the associated risk factors are not fully understood, based on the available evidence, statins should be used with caution in patients with a previous history of hemorrhagic stroke, especially in patients with lobar hemorrhage. In patients who develop a hemorrhagic stroke after statin use, the drug first needs to be discontinued, followed by the principles of management of hemorrhagic stroke, reduction of intracranial pressure, control of blood pressure, and symptomatic management. It is important to note that statins prevent delayed vasospasm in subarachnoid hemorrhage and may improve its prognosis, whereas discontinuation of the drug may lead to rebleeding. In addition, because the available results are from subgroup analyses of clinical trials and can only serve as hints but not conclusions, future large-scale population samples are needed to validate this correlation, as well as its risk factors, to better guide clinical use.