Ischemic stroke has long been a focus of research because of its high morbidity and mortality rates and the residual symptoms of limb paralysis and aphasia in survivors, which place a heavy burden on patients, families, and society. Previously, ischemic stroke has been treated with a focus on treatment and less attention has been paid to the prevention and treatment of risk factors. However, in reality, ischemic stroke is one of the most preventable serious diseases, and active prevention can often achieve twice the result with half the effort [1]. In recent years, as research into the pathogenesis and pharmacological prevention of ischemic stroke continues, impressive progress has been made in its preventive treatment.
1, Antiplatelet therapy Atherosclerosis is one of the most important risk factors for ischemic stroke, and atherosclerotic plaques can form as early as 20 to 30 years of age. Under the influence of inflammation and hypertension, the vascular endothelium is damaged and expresses vascular cell adhesion molecules, prompting leukocytes (monocytes and T lymphocytes) to migrate to the damaged endothelium and enter the intima, initiating and maintaining a local inflammatory response. Monocytes transform into macrophages and then absorb lipids to become foam cells; T lymphocytes express inflammatory cytokines that prompt macrophages, endothelial cells and smooth muscle cells to proliferate, and with the involvement of platelets and fibrin, eventually form atheromatous plaques, leading to thinning of the vascular vessel and obstruction of blood flow. However, in practice, symptoms do not appear until more than 70% of the vessels are narrowed, and acute rupture of atherosclerotic plaques is a major cause of cerebrovascular events and death [2].
The mechanism of action of aspirin (ASA), currently the main drug for primary and secondary prevention of ischemic stroke, is the irreversible inhibition of platelet cyclooxygenase activity, thereby preventing the formation of thromboxane A2. /As a primary prevention drug, ASA can reduce the onset of ischemic stroke in high-risk patients, but may increase the risk of intracranial and external bleeding; the application of ASA within 48 h after stroke can prevent recurrence, thus achieving secondary prevention. According to the results of meta-analysis, ASA reduces major vascular events by 19% overall and ischemic stroke by 13% in patients with arterial disease, and the difference may be due to different pathophysiological mechanisms [4]. It has been suggested that the lack of response to aspirin in some patients is the result of COX-1 gene variants [5]. If transient ischemic attack (TIA) occurs during aspirin therapy, it is not possible to simply switch to another antiplatelet agent and leave it at that, but the diagnosis must be reconsidered and examined for causes other than arterial-arterial embolism, where platelets may still aggregate through pathways other than COX-1 inhibition after complete acetylation [4].
A more pronounced reduction in the risk of stroke recurrence has been demonstrated with the combination of dipyridamole (Pansentin) in ASA [3]. Bimatoprost inhibits platelet aggregation by increasing cyclic adenosine monophosphate and cyclic guanosine monophosphate levels, but because it can cause coronary vasodilation, resulting in increased blood flow to non-stenosed coronary arteries, the result may induce myocardial ischemia during exercise [2]; however, application of extended-release doses of bimatoprost does not increase cardiac events in patients with coronary artery disease [6]. The extended-release dipyridamole/aspirin combination (Aggrenox 25/200 mg Bid) was approved by the US FDA in 1999 and was effective in reducing nonfatal strokes but not myocardial infarction or fatal strokes [4]. In the European Stroke Prevention Study II, Aggrenox reduced stroke recurrence by 19% compared with aspirin alone and by 37% compared with placebo [6].
Thienopyridines (thienopyridines) block adenosine diphosphate-mediated platelet aggregation [7]. Among them, thienopyridine (ticlopidine) was first used for stroke prophylaxis and is absorbed 80% to 90% after oral administration, with peak plasma concentrations at 1 to 3 h [3]. In the TIA or Mild Stroke Ticlopidine/Aspirin Stroke Study (TASS), the incidence of stroke was 21% lower in the ticlopidine group compared with the aspirin group at the end of 3 years of dosing, but because ticlopidine has serious side effects, including diarrhea, rash, and serious hematologic side effects such as neutrophil deficiency, aplastic anemia, various types of hemocytopenia, erythroleukemia, and thrombotic platelet thrombocytopenic purpura (TTP), thus limiting its clinical use and practically discarding it [1].
Clopidogrel, a second-generation thienopyridine, has a mechanism of action similar to that of ticlopidine, reducing ADP-mediated platelet aggregation within 4 h without significant neutropenia or side effects such as bleeding; its preventive effect on stroke is similar to that of ASA [3]. However, TTP was recently reported in 11 cases with clopidogrel, mostly within 14 d of administration, and in some cases with other drugs, including 5 with statins, 3 with atenolol, and 1 with cyclophilin A. The CURE trial in acute coronary syndrome suggested a significant effect of clopidogrel in combination with aspirin, but with an increased risk of bleeding. There is no evidence for combining aspirin or clopidogrel in stroke patients; the ongoing MATCH trial aims to compare the role of clopidogrel alone and in combination with aspirin in secondary stroke prevention [4].
In recent years, as new antiplatelet agents have become available, the number of options has increased to the point that the previous concern of “what is the best dose of aspirin for secondary prevention” has been replaced by “what is the best antiplatelet agent for secondary prevention”. However, to date, there is no clear answer to either of these questions [3]. With the exception of ticlopidine and clopidogrel, which belong to the same class of drugs, the various antiplatelet agents have different mechanisms of action and thus the benefit of combination therapy over monotherapy is theoretically greater, but needs further confirmation. The widely cited American College of Cardiothoracic Surgeons guidelines recommend ASA, clopidogrel, or aspirin/dipyridamole as first-line options for secondary stroke prevention; aspirin/dipyridamole is “probably” more effective than ASA with similar side effects; the effectiveness of combining ASA and clopidogrel for stroke prevention remains to be confirmed [7].
An analysis of antiplatelet prescriptions for secondary prevention of stroke at Indiana University Hospital showed that ASA is the first-line drug for secondary prevention of cerebrovascular disease; ticlopidine and clopidogrel are commonly used as second-line treatment for “ASA failure”; and the new drug extended-release dipyridamole/ASA has not been widely used, and it appears to have no effect other than recurrent cerebrovascular events [3]. It seems to have no effect other than recurrent cerebrovascular events [3].
AF induces left atrial thrombosis, which increases the risk of stroke 6-fold and may increase even more with continued aging of the population. Anticoagulation therapy is the mainstay of stroke prevention in patients with AF [8].
The main anticoagulants are heparin and warfarin. Although heparin reduces ischemic stroke recurrence in the short term, it can significantly increase hemorrhagic strokes and is therefore not recommended; ASA and moderate doses of warfarin are effective in reducing stroke risk in patients with AF [9]. Warfarin is a vitamin K antagonist that produces anticoagulant effects by blocking the vitamin K-dependent activation of coagulation factors II, VII, IX and X. Long-term warfarin therapy leads to an international normalized ratio (INR) of 2.0 or more, reducing not only the risk of stroke but also its clinical severity and the risk of death [10]. Its efficacy is better than that of ASA, but the risk of causing intracranial and external bleeding is twice that of aspirin, and the risk is greater in those with a history of bleeding, in the elderly, and in those with polymorphisms in the genes encoding the liver microsomal enzymes CYP2C9 and the prepropeptide of factor IX [11]. One study showed that the annual risk of ischemic stroke or systemic embolism was higher after low-intensity anticoagulation combined with ASA therapy than in those with adequate anticoagulation, without a significant reduction in serious bleeding complications. The bleeding side effects of warfarin are partly attributed to its narrow therapeutic window and interactions with a variety of other drugs and foods, so its use requires routine monitoring of coagulation parameters and frequent dose adjustments. Warfarin has a slow onset of action and slow elimination, and has a teratogenic risk. As a result, less than half of the AF patients suitable for warfarin therapy are actually able to receive it. However, ischemic stroke prevention with warfarin is less costly than stroke treatment. It has been suggested that about 1/3 of people with AF are at low risk and should be treated with aspirin; about 1/3 are at high risk and should be treated with Warfarin if safe; and those at moderate risk should be monitored for anticoagulation [12].
Patients with placed mechanical heart valves are at high risk of thromboembolic stroke and require anticoagulation therapy determined by valve type. If systemic embolism occurs despite anticoagulation with adequate warfarin therapy to achieve an INR of 3.0, ASA 80-100 mg/d should be added. patients with biologic valves require anticoagulation only for the first 3 months after valve implantation, and thereafter, ASA alone is sufficient. After acute anterior wall infarction, especially when combined with severe left heart dysfunction, anticoagulation therapy is recommended for 1 to 3 months. The risk of stroke is increased 3 to 9 times in the presence of large atheromatous plaques of 4 mm or more in thickness, further increased if the plaque is active or non-calcified, and limited evidence suggests that anticoagulation is preferable to antiplatelet therapy for prevention of embolism in this setting [2]. PFO (patent foramen ovale) may increase the risk of ischemic stroke through right-to-left shunt paradoxical embolization, and a meta-analysis suggests that anticoagulation is superior to antiplatelet therapy for secondary prevention of stroke in patients with PFO. For noncardiogenic stroke, warfarin (target INR 1.4 to 2.8) did not differ from ASA in reducing the risk of recurrence and increased risk of intracranial hemorrhage [2].
Ximelagatran is an oral direct inhibitor of thrombin developed by Astra-Zeneca as a precursor drug to melagatran [13]. It is rapidly absorbed from the intestine after oral administration and takes effect by conversion to its active form, melagatran. The latter reaches its peak concentration 1.6-1.9 h after oral administration, is not metabolized in the body and is not bound to plasma proteins, and is mainly cleared by the kidneys (about 80%) with a half-life of 4-5 h. Therefore, the drug needs to be taken twice daily [11]. The commonly used dose is 36 mg, bid, and data suggest that it is still well tolerated at 60 mg, bid [14].
Ximelagatran has a rapid onset of action, its efficacy is not affected by patient age, gender, weight, race or food intake, its pharmacokinetic properties are predictable without dose adjustment (except for patients with renal insufficiency who require dose reduction or longer dosing intervals), and it does not require monitoring of coagulation markers, making it a broader indication than warfarin [11]. The drug reduces the risk of stroke in AF patients, and the results of the recent phase III clinical trial of simeplagatran for the prevention of stroke attacks in patients with non-valvular AF (SPORTIF) confirmed that the drug is no less effective than warfarin in preventing AF-associated stroke with fewer bleeding complications [15]. The disadvantage of ximelagatran is the increased liver enzyme activity in a small number (6%) of patients, but it is usually transient and therefore liver function needs to be monitored within 6 months of treatment initiation; since ximelagatran is mainly cleared by the kidneys, renal function needs to be measured during administration. In addition, the drug is more expensive than warfarin, which is a disadvantage. Ximelagatran is best suited for patients with high-risk AF who cannot be treated with warfarin, such as the elderly (>80 years), those with a history of bleeding, and those with known polymorphisms in the gene encoding the hepatic microsomal enzyme CYP2C9 and mutations in the factor IX prepropeptide ALA-10 [11].
The risk of stroke is known to be significantly associated with increased levels of daily systolic blood pressure (SBP) and diastolic blood pressure (DBP), with a doubling of the risk of stroke for every 7.5 mmHg increase in diastolic blood pressure [16] and a 1/3 reduction in stroke risk for a 5 mmHg decrease in diastolic blood pressure [17]; the risk of stroke is higher in isolated systolic hypertension, especially in middle-aged men, where the risk of stroke is almost 5 The risk of isolated systolic hypertension is higher, especially in middle-aged men, with an almost 5-fold increased risk of stroke [2]. Blood pressure control is currently the most active area of stroke prevention research, and a meta-analysis of large primary prevention trials of some thiazide diuretics and β-blockers confirmed a 38% reduction in the relative risk of first stroke in those with a 5-6 mmHg reduction in diastolic blood pressure over 5 years. Antihypertensive therapy can prevent vascular events in patients with previous TIA or stroke, and the preventive effect is positively correlated with the magnitude of blood pressure reduction [17]. Many guidelines for the treatment of hypertension emphasize that the target blood pressure should be less than 140/90 mmHg and 130/85 mmHg for those who have had a previous cerebrovascular event and those with diabetes or other vascular disease, respectively.
Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are all used for stroke prevention. Although restoration of normotension remains key to stroke prevention, the HOPE study with ACE inhibitors or ARBs confirmed a limited reduction in stroke incidence with decreasing blood pressure [18]. It is known that angiotensin II increases VCAM-1 expression and inflammatory cytokine production, thereby promoting atherosclerosis formation; therefore, inhibition of angiotensin II may have a protective effect against atheroma formation in addition to lowering blood pressure, but this has not been confirmed. The ALLHAT trial found that the calcium channel blocker amlodipine, the ACE inhibitor lisinopril, the β-blocker doxazocin and the thiazide diuretic chlorthalidone all prevented stroke [20]. chlorthalidone) all prevent stroke, with a trend towards lower stroke rates in the chlorthalidone group compared with lenopril, by an unknown mechanism [21]. It has been suggested that all stroke patients should be treated with antihypertensive therapy, either an ACE inhibitor or ARB with diuretics, unless hypotensive or otherwise contraindicated to treatment [1].
It is generally accepted that both thiazides and ACE inhibitors can be used as first-line therapeutic agents for hypertension, but the choice of which one to use remains inconclusive. Some studies favor thiazides, others favor ACE inhibitors, while others find no difference between the two. Most patients clinically require more than one antihypertensive agent to achieve normotension, thus leaving more room for choice [2]. In general, patients with hypertension without other serious complications are suitable for treatment with diuretics or β-blockers; those at high risk of congestive heart failure and diabetic patients should be treated with ACE inhibitors; patients at very low risk of coronary artery disease (no other risk factors and family history) can be treated with calcium antagonists [22].
Because hyperlipidemia is not as closely associated with stroke as it is with myocardial infarction, cholesterol has long been underappreciated as a risk factor for stroke. However, there is growing evidence that drugs used to treat hyperlipidemia, particularly 3-hydroxy-3-methylglutaraldehyde coenzyme A (HMG-CoA) reductase inhibitors (statins), have vascular event-protective effects [1,2].
Statins reduce hepatocyte cholesterol levels by inhibiting HMG-CoA reductase, the rate-limiting enzyme for cholesterol synthesis in the liver and other tissues, and increase the expression of low-density lipoprotein (LDL) cholesterol receptors, typically reducing LDL cholesterol by 25 to 50%. Statins also reduce levels of isoprenoid derived from intermediates of the cholesterol biosynthesis pathway. These intermediates, such as farnesylpyrophosphate, play an important role in cell growth, signal transduction, and mitogenic pathways as post-translationally modified lipid linker molecules for a variety of proteins including heterotrimeric G proteins and small G proteins such as Ras and Rho. Statins may prevent stroke through a number of mechanisms: modulating thrombosis in large arteries and carotid arteries in the brain, thus preventing plaque rupture and arterial-arterial thromboembolism (plaque stabilization); improving endothelial homeostasis by directly upregulating brain endothelial NO synthase (NOS) and increasing NO bioavailability, reducing free radicals, reducing infarct size, and improving neurological function; and their possible anti-inflammatory effects may also The possible anti-inflammatory effects may also produce neuroprotective and stroke preventive effects; in addition, statins have an anti-platelet aggregation effect [23].
Meta-analyses have shown that statins significantly reduce ischemic stroke and do not increase the risk of hemorrhagic stroke [2], and in recent years the Heart Protection Study (HPS) has further lowered the threshold for lipid-lowering therapy in high-risk groups, confirming that a reduction in basal LDL to 2.5 mmol/L significantly reduces all vascular events, regardless of age, sex, and other treatments [24]. Although the clinical benefit of statins is largely dependent on LDL cholesterol reduction, a growing body of data suggests that their pleiotropic effects are the result of isoprenoid depletion. Some data suggest that statins may reduce the incidence of dementia in addition to reducing the risk of stroke. Cholesterol lowering should undoubtedly be used as part of stroke prevention. In the National Cholesterol Education Program (NCEP) Adult Treatment Protocol, 3rd edition (ATP III), published in 2001, strong cholesterol-lowering therapy is indicated for patients with coronary or peripheral vascular disease and diabetes mellitus; symptomatic carotid artery disease is also an indication for cholesterol-lowering; and there are no clear indications for statin therapy in patients with stroke and TIA without evidence of coronary artery disease or peripheral vascular disease [25]. There is no clear indication for statin therapy in stroke and TIA patients without evidence of coronary artery disease or peripheral vascular disease [25]. A meta-analysis of non-statin interventions showed that lowering total cholesterol to less than 6 mmol/L with fibrates, niacin and controlled diet reduced the risk of stroke, but the safety and efficacy of fibrates in combination with statins is unknown [2].
Conclusion
In conclusion, the concept of stroke treatment is no longer limited to emergency treatment after the onset of stroke, and the idea of preventive treatment, especially the appropriate application of preventive drugs to reduce stroke incidence, is gaining attention. In general, to avoid stroke, those with risk factors for stroke such as hypertension should be actively treated with appropriate primary prevention, TIA is the prime time for secondary prevention of stroke, and those who have already had TIA or stroke should be treated with secondary prevention [26]. Due to the wide variety of stroke prophylactic drugs with different mechanisms and widely varying prices, the appropriate drug should be selected according to the individual. In general, ASA remains the first-line treatment for secondary prevention after the first episode of atherosclerotic stroke; clopidogrel is recommended for patients who cannot tolerate ASA. Patients with atrial fibrillation and prosthetic heart valves should be anticoagulated with warfarin. Either thiazides or ACE inhibitors can be used as first-line treatment for antihypertension. All patients who have had TIA, ischemic stroke, or have high risk factors for vascular disease established by HPS should be treated with statins regardless of their serum cholesterol levels [2].