- The benefits of statin therapy in reducing ASCVD risk including the reduction in risk of myocardial infarction, cardiovascular death, and ischemic stroke greatly outweigh the reported small increase in incidence of hemorrhagic stroke.
- More studies to investigate the association between statins, low LDL-C and HS are warranted, before implying any specific causation between these outcomes.
Commentary based on Sanz-Cuesta BE, Saver JL. Lipid-lowering therapy and hemorrhagic stroke risk: comparative meta-analysis of statins and PCSK9 inhibitors. Stroke 2021;Jun 22:[Epub ahead of print].1
Stroke is one of the leading causes of morbidity and mortality, and most strokes are ischemic in nature, either from thrombotic phenomena owing to underlying atherosclerosis and elevated blood cholesterol, or from cardioembolic sources.2 Over the past several decades, there has been significant progress in prevention of atherosclerotic cardiovascular disease (ASCVD) through lowering of blood cholesterol.
The 2006 Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, involving 4,731 patients, showed that an 80 mg daily dose of atorvastatin reduced the overall incidence of strokes and cardiovascular events in patients with recent stroke or transient ischemic attack, without any known coronary heart disease.3 The study also notably raised the concern of a small increase in incidence of hemorrhagic stroke (HS) with statin therapy.3 Several epidemiologic studies have suggested an association between low blood cholesterol levels and intracerebral hemorrhage;4,5 however, despite this weak association, the overall benefit of stroke prevention made statin therapy one of the most important medical advances in the 21st century.6
There has been ongoing concern that low levels of low-density lipoprotein cholesterol (LDL-C) contributes to HS, given several off-target (not cholesterol-lowering) pharmacological effects including possible mild anticoagulant, antiplatelet, and fibrinolytic effects.7 With the advent of newer cholesterol-lowering medications including proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i), there is a question of whether such medications may be more advantageous, especially in patients with a history of intracerebral hemorrhage or increased propensity to develop intracerebral hemorrhage.8 A recent comparative meta-analysis investigated this further by analyzing prior trials of statin and PCSK9i therapy and rates of HS in these patient populations.
Methods and Scope
The authors conducted a systematic comparative meta-analysis to assess rates of HS across all randomized clinical trials (RCTs) involving statin and PCSK9i treatment for at least 3 months. They also took into consideration dose-response relationships and prior intracerebral vascular events (acute ischemic stroke, transient ischemic attack, hemorrhagic stroke). Inclusion criteria were RCTs of statins versus no therapy, high dose versus low dose statin therapy, PCSK9i versus no therapy, high dose versus low dose PCSK9i therapy, treatment duration of at least 3 months, and reporting of intracerebral hemorrhage or HS.
The selected RCTs were statistically analyzed in four main groupings: (1) trials enrolling all patients (with and without prior stroke) and comparing all dose combinations (low dose vs. control, high dose vs. control, low dose vs. high dose), (2) trials enrolling patients with prior cerebral ischemia (acute ischemic stroke or transient ischemic attack) and comparing all dose combinations, (3) trials enrolling all patients, but only comparing high dose versus control, and (4) trials enrolling patients with prior HS and comparing all dose combinations.
Rates of HS in Trials of Statin Therapy and PCSK9i Therapy
A summary of the key findings and statistical analyses by group is provided in Table 1, with a graphical representation of relative risk for certain study groups in Figure 1. Rates of HS were higher in patients treated with statin therapy (any dose) compared to controls, and in patients treated with high dose statins compared to low dose statins, regardless of prior history of cerebral ischemia or HS. Rates of HS were not increased in patients treated with PCSK9i added to maximally tolerated statins compared to maximally tolerated statins alone, regardless of prior history of cerebral ischemia.
The authors conclude that statins may modestly increase the risk of HS while PCSK9i do not. Furthermore, this risk is amplified in a dose-dependent manner, with prior history of vascular brain injury also playing a role. Based on this, they suggest that PCSK9i may be a preferred class of lipid-lowering medication in patients with prior history of HS.
Table 1: Quantified risk of hemorrhagic stroke in the different study groups. Courtesy of Rao SJ, Martin SS, Sharma G.
|Group||n||RR/HR (95% CI)||P value||Group||n||RR/HR (95% CI)||P value|
|1||203305||1.15 (1.00-1.32)||0.04||1||76140||0.93 (0.58-1.51)||0.77|
|2||9772||1.43 (1.02-2.02)||0.04||2||5337||0.99 (0.47-2.07)||0.97|
Figure 1: Relative risk of HS with statin or PCSK9i therapy in certain study groups. Error bars denote the 95% confidence interval. Courtesy of Rao SJ, Martin SS, Sharma G.
Implications on Current Practice
Despite periodic concerns about the potential for statins to cause HS, the benefits of statin therapy on reducing ASCVD events are tremendous. Prior studies have shown weak and inconsistent associations between low blood cholesterol, specifically LDL-C, and a potentially mild increased risk of HS; such associations, however, do not imply causation, due to several confounding factors.
Conditions predisposing to intracerebral hemorrhage – such as alcoholism, malnutrition, frailty, and liver disease – may be observed in individuals with very low LDL-C, in addition to other factors reflective of poor health status.9 Furthermore, statins may also play a role in neuroprotection in spontaneous intracerebral hemorrhage, with clinical studies observing improved functional outcomes and lower mortality rates in patients initiated on or continued on statins after intracerebral hemorrhage.10
The authors of the study conclude that statins modestly increase the risk of HS whereas PCSK9i do not, and given those findings, PCSK9i may be a preferred agent for lipid-lowering in patients with elevated risk of HS. Their explanation for this observation pertains to statins having off-target, antithrombotic effects.
The conclusions of the study will need to be taken into clinical context and interpreted judiciously. If antithrombotic effects with statins were clinically significant findings, one might expect to find an increased incidence of generalized bleeding owing to this effect, versus isolated intracerebral hemorrhage specifically. Furthermore, one must consider the era in which many of the statin trials were conducted versus the PCSK9i trials, as there may be other factors playing a role, such as strictness of blood pressure control in the different patient populations. The Forest plot analyses convey statistical significance (P < 0.05) for relative risk of statins and HS in patient groups 1-3, but do not reach statistical significance for group 4 which included patients with a prior history of HS. Moreover, the patients analyzed in the PCSK9i trials were those that were taking PCSK9i usually in addition to maximally tolerated statins, which may further complicate and confound the results.
Overall, given the lack of clear causation and presence of confounders, clinical practice should not change in response to the results presented in this meta-analysis. The benefits of statin therapy in reducing ASCVD risk – including the reduction in risk of myocardial infarction, cardiovascular death, and ischemic stroke – greatly outweigh the reported small increase in incidence of HS. More studies are warranted to further investigate the association between statins, low LDL-C and HS, before implying any specific causation between these variables.
- Sanz-Cuesta BE, Saver JL. Lipid-lowering therapy and hemorrhagic stroke risk: comparative meta-analysis of statins and PCSK9 inhibitors. Stroke 2021;Jun 22:[Epub ahead of print].
- Hindy G, Engström G, Larsson SC, et al. Role of blood lipids in the development of ischemic stroke and its subtypes: a Mendelian randomization study. Stroke 2018;49:820-27.
- Amarenco P, Bogousslavsky J, Callahan AI III, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.
- Ma C, Gurol ME, Huang Z, et al. Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: a prospective study. Neurology 2019;93:e445-e457.
- Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Lipid levels and the risk of hemorrhagic stroke among women. Neurology 2019;92:e2286-e2294.
- Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453-63.
- Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation 2013;127:251-57.
- Yvan-Charvet L, Cariou B. Poststatin era in atherosclerosis management: lessons from epidemiologic and genetic studies. Curr Opin Lipidol 2018;29:246-58.
- Michos ED, Martin SS. Achievement of very low low-density lipoprotein cholesterol levels: is it time to unlearn concern for hemorrhagic stroke? Circulation 2019;140:2063-66.
- Chen CJ, Ding D, Ironside N, et al. Statins for neuroprotection in spontaneous intracerebral hemorrhage. Neurology 2019;93:1056-66.
Clinical Topics: Anticoagulation Management, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins
Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, LDL, Brain Ischemia, Fibrinolytic Agents, Ischemic Attack, Transient, Anticoagulants, Blood Pressure, Cardiovascular Diseases, Stroke, Cerebral Hemorrhage, Atherosclerosis, Myocardial Infarction, Cerebrovascular Trauma, Liver Diseases, Health Status, Malnutrition, Coronary Disease, Proprotein Convertases, Subtilisins, Primary Prevention
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The sensitivity analysis confirmed our results that statins decrease ischemic stroke risk and increase the risk of hemorrhagic stroke significantly.Why statins are not prescribed in hemorrhagic stroke? ›
In summary, mathematical decision analysis of the available data suggests that, because of the high risk of recurrent ICH in survivors of prior hemorrhagic stroke, even a small amplification of this risk by statins suffices to recommend that they should be avoided after ICH.What does the American Heart Association say about statins? ›
The ACC/AHA guidelines also recommend statins for patients with diabetes without having to also calculate a person's 10-year risk score and recommend statins for those patients with extremely high levels of cholesterol.Can lipitor cause hemorrhagic stroke? ›
But using Lipitor was a less significant risk factor for hemorrhagic stroke than having had a previous brain bleed or having uncontrolled high blood pressure, researchers say.What is the most likely cause of the hemorrhagic stroke? ›
The most common cause of a hemorrhagic stroke is high blood pressure (hypertension). This is especially true when a person's blood pressure is very high, stays high for a long time, or both.What is the biggest risk factor for hemorrhagic stroke? ›
Hypertension (high blood pressure) is the most important risk factor for hemorrhagic stroke. Anticoagulant (blood thinning) medications make bleeding into the brain more likely, especially if taken improperly or in large doses.What is the best medication for hemorrhagic stroke? ›
Intravenous phytonadione is recommended for life-threatening bleeding, including intracerebral hemorrhage complicating warfarin therapy, although it carries a small risk of anaphylaxis.What medications can cause hemorrhagic stroke? ›
Gorelick discussed the stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, vitamin E, statins, hormone replacement therapy (HRT), and testosterone replacement therapy. “These drugs have a small risk of stroke, but there is a risk of stroke,” said Dr. Gorelick.Which statin is best for stroke prevention? ›
The Heart Protection Study (HPS) firmly established the efficacy of simvastatin in reducing stroke and other vascular events among 20, 536 adults with cerebrovascular and other occlusive arterial disease or diabetes.Why do patients refuse statins? ›
Fear of side effects and perceived side effects are the most common reasons for declining or discontinuing statin therapy. Willingness to take a statin is high, among both patients who have declined statin therapy and those who have never been offered one.
You usually have to continue taking statins for life because if you stop taking them, your cholesterol will return to a high level. If you forget to take your dose, do not take an extra one to make up for it.What is the new cholesterol drug that is not a statin? ›
In studies, Nexletol also appears to reduce the risk of muscle pain, a common complaint of people on statins. Nexletol (bempedoic acid) is a new cholesterol-lowering drug.Does cholesterol cause hemorrhagic stroke? ›
Hypercholesterolemia is a risk factor for ischemic stroke. However, a meta-analysis observed that total and low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the risk of hemorrhagic stroke, while no association was seen for high-density lipoprotein cholesterol (HDL-C).Can Crestor cause hemorrhagic stroke? ›
Crestor prevents recurrence of ischemic stroke. But statins may increase the risk of hemorrhagic strokes. Several studies have found a higher risk of hemorrhagic stroke in populations with low cholesterol levels. Scientists have not determined the exact cause.
Stroke can result from various toxic exposures including illicit drugs, with cocaine being one of the more frequently cited agents. Cocaine is known to be an important risk factor for ischemic and hemorrhagic stroke in young individuals.What is the number one symptom of a hemorrhagic stroke? ›
Hemorrhagic strokes that result from a rupturing blood vessel can have serious, immediate, and life-threatening symptoms such as: Sudden, severe headache near the back of the head. Many people have described this as the “worst headache of your life.” Losing consciousness.How do you prevent a hemorrhagic stroke? ›
Preventing a hemorrhagic stroke
Keeping your blood pressure under control is the best way to control your risk. Talk to your doctor about how to lower your blood pressure if it's too high. Alcohol and drug use are also controllable risk factors. Consider drinking in moderation and avoid any type of drug abuse.
Intracerebral haemorrhage (ICH) is where blood leaks out of a blood vessel into the brain tissue, sometimes deep inside the brain. ICH is the most common type of haemorrhagic stroke, and around two thirds of all haemorrhagic strokes are ICH.What is the target BP in hemorrhagic stroke? ›
For those with a stroke or TIA, a BP-lowering goal of <130/80 mm Hg may be reasonable (IIb/B-R).What is the gold standard for diagnosing a hemorrhagic stroke? ›
Computed tomography (CT) is widely considered as the gold standard to image brain hemorrhage. The main argument not to use MRI in acute stroke patients is its assumed low sensitivity for intracranial blood.
Part of the heart beats so fast that it stops working efficiently as a pump. Blood pools inside the heart, which can clot, travel to the brain and cause a stroke. One factor nobody can avoid is their genes. Some people are just more likely to have a stroke than others and it can run in families.What medication is contraindicated with hemorrhagic CVA? ›
All medications that increase the risk of bleeding, such as warfarin, aspirin, and heparin, should be discontinued in a patient having a hemorrhagic stroke.Is aspirin good for hemorrhagic stroke? ›
Stroke is a medical emergency. If you experience stroke warning signs, call 911 immediately. Taking aspirin isn't advised during a stroke, because not all strokes are caused by blood clots. Some strokes are caused by ruptured blood vessels and taking aspirin could make these bleeding strokes more severe.Why aspirin is not used in hemorrhagic stroke? ›
Aspirin is typically prescribed for people at risk of having an ischemic stroke to prevent blood clots. Because aspirin may cause bleeding, it is typically avoided in people who have had a hemorrhagic stroke, also called intracerebral hemorrhage.What drug is associated with ischemic and hemorrhagic stroke? ›
For example, stimulants such as amphetamines, cocaine and their derivatives are associated with both types of stroke, acute ischemic (cerebral infarcts) and hemorrhagic (intracerebral hemorrhages, subarachnoid hemorrhages), where the involved mechanisms differ [21,22].What drug is most associated with stroke? ›
The illicit drugs more commonly associated with stroke are psychomotor stimulants, such as amphetamine and cocaine. Less commonly implicated are opioids and psychotomimetic drugs, including cannabis.What is the most gentle statin? ›
According to a research review people who take simvastatin (Zocor) or pravastatin (Pravachol) may experience fewer side effects.Do people on statins still have strokes? ›
A study of more than 135,000 people at risk for a heart attack or stroke found that those who took statins had a 25% lower risk of having a heart attack or stroke compared to those who did not take statins. Statins are among the safest and most studied medications.What is the safest and most effective statin? ›
Which cholesterol-lowering drug is the safest? Overall, statins are safe as a class of drugs. Serious adverse events are very rare. Among the individual medications, studies have shown that simvastatin (Zocor®) and pravastatin (Pravachol®) seem to be safer and better tolerated than the other statins.What can I do instead of taking statins? ›
- Fibrates. Mostly used for lowering triglyceride levels in patients whose levels are very high and could cause pancreatitis. ...
- Plant stanols and sterols. ...
- Cholestyramine and other bile acid-binding resins. ...
- Niacin. ...
- Policosanol. ...
- Red yeast rice extract (RYRE) ...
- Natural products.
having a history of liver disease. regularly drinking large quantities of alcohol. having a history of muscle-related side effects when taking a statin or fibrate (another type of medicine for high cholesterol) having a family history of myopathy or rhabdomyolysis.Why do doctors push statins? ›
Because many factors are involved, your cholesterol numbers may be considered normal and yet you may still be found to be at an elevated risk for heart problems. As a result, statin medications are now used to lower the risk of heart disease and heart events in most anyone found to be at high risk.Can you get off statins once you start? ›
If you're taking a statin medication to lower your cholesterol, you will need to keep taking your prescription, or your cholesterol will likely go back up. Stopping your statin can put you at risk of having heart disease and other preventable health problems like stroke and heart attack from high cholesterol.Which statins cause memory loss? ›
Results: Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued.How can I lower my cholesterol without statins? ›
- Reduce saturated fats. Saturated fats, found primarily in red meat and full-fat dairy products, raise your total cholesterol. ...
- Eliminate trans fats. ...
- Eat foods rich in omega-3 fatty acids. ...
- Increase soluble fiber. ...
- Add whey protein.
There are many non-statin medications your doctor might prescribe: Bile acid-binding resins, like cholestyramine (Locholest, Prevalite, Questran), colesevelam (WelChol), and colestipol (Colestid) stick to cholesterol-rich bile acids in your intestines and lower your LDL levels.What is a natural alternative to statin drugs? ›
For patients who can't tolerate cholesterol-lowering statins, natural remedies like bergamot, garlic and green tea may be a useful alternative, based on a recent statement published in the Journal of the American College of Cardiology.Does CoQ10 lower cholesterol? ›
Although more studies are needed, some research suggests that CoQ10 may help reduce low-density lipoprotein (LDL) cholesterol and total cholesterol levels in people with diabetes, lowering their risk of heart disease.Can statins cause hemorrhagic stroke? ›
The sensitivity analysis confirmed our results that statins decrease ischemic stroke risk and increase the risk of hemorrhagic stroke significantly.Is statin recommended for hemorrhagic stroke? ›
Expert Analysis. The benefits of statin therapy in reducing ASCVD risk – including the reduction in risk of myocardial infarction, cardiovascular death, and ischemic stroke – greatly outweigh the reported small increase in incidence of hemorrhagic stroke.
Background and Purpose—
It has been suggested that statins increase the risk of intracerebral hemorrhage in individuals with a history of stroke, which has led to a precautionary principle of avoiding statins in patients with prior intracerebral hemorrhage.
New initiation of statins within 3 days after ischemic stroke did not affect risk of subacute ICH within 6 months but might be associated with improved functional outcome and lower mortality.Why should you not take Crestor? ›
You should not take rosuvastatin if you are allergic to it, or if you have: liver disease; or. if you are pregnant or breast-feeding.Should all over 60s take statins? ›
Statins work for people of all ages
Statins can help reduce the risk of heart attack and stroke in older people, just as they do in younger people, according to research part-funded by the BHF.
Liver damage due to too much alcohol can stop the liver from making substances that help your blood to clot. This can increase your risk of having a stroke caused by bleeding in your brain.Which drugs is routinely given to patients suffering an ischemic stroke if the onset of the stroke was less than 4.5 hours ago? ›
Most people will be given aspirin straight after having an ischaemic stroke.Can Viagra cause a hemorrhagic stroke? ›
Studies have shown that sildenafil acts on phosphodiesterase-1, -2 and -5 receptors and leads to a secondary increase in intracerebral circulation and vasodilatory effects, leading to sympathetic overactivity which increases the risk for intracranial bleeding.What drugs can cause hemorrhagic stroke? ›
Drugs of abuse increase the risk of both ischemic stroke and intracerebral hemorrhage. Stimulants such as amphetamines, cocaine, and phencyclidine cause a sympathetic surge with elevated blood pressure and vasospasm.Do statins cause bleeding in the brain? ›
Statins may increase the risk of intracerebral haemorrhage (ICH) in individuals with previous stroke. It remains unclear whether this applies to individuals with no history of stroke.What type of drugs are contraindicated for patients with hemorrhagic strokes? ›
Background and Purpose—Antiplatelet medicines are commonly perceived as contraindicated after intracerebral hemorrhage (ICH).
Stroke can result from various toxic exposures including illicit drugs, with cocaine being one of the more frequently cited agents. Cocaine is known to be an important risk factor for ischemic and hemorrhagic stroke in young individuals.What supplements help hemorrhagic stroke? ›
- Folic acid, vitamin B-6, and vitamin B-12. Certain B vitamins could help to lower levels of the amino acid homocysteine. ...
- Betaine. Research shows that the amino acid betaine may lower levels of homocysteine.
- Vitamin C. ...
- Vitamin D. ...
- Vitamin E. ...
- Omega-3 fatty acids. ...
Permeability of statins into brain was strongly associated with drug lipophilicity and pravastatin permeability was similar to sucrose and it was concluded that pravastatin did not cross the blood-brain barrier 16.Is hemorrhagic stroke caused by stress? ›
One stressed out day won't necessarily affect your stroke risk, but unmanaged chronic stress may. In fact, chronic stress and anxiety, in addition to high cholesterol, high blood pressure and diabetes, are key factors that affect stroke risk.