Most brain strokes could be prevented

Brain stroke is one of the leading causes of death and the most common reason for acquired disability in adulthood. A further increase in stroke incidence is expected in the coming years. A healthy lifestyle combined with consistent treatment of vascular risk factors can reduce the risk of stroke by 80%.

Brain stroke is one of the leading causes of death and the most common reason for acquired disability in adulthood. Considering the demographic development, a further increase in the incidence of cerebral stroke is expected in the coming years. A significant increase in new cases has also been observed in younger people in recent years. This is why the WHO calls stroke the coming epidemic of the 21st century.

This gives special importance to stroke prevention, since according to one study, 85% of stroke events could theoretically be prevented [1]. Lifestyle modification is of particular interest, especially since the incidence of stroke has relatively decreased by approximately 42% in the developed world over the past 30 years, but has increased by 100% in the developing world. People in these countries are increasingly adopting the unfavorable achievements of the Western world (fast food, less exercise, obesity, nicotine consumption, etc.), while we in Europe are paying more and more attention to healthy eating, exercise and prevention of risk factors [2]. These observations underscore the importance of lifestyle, independent of drug therapies.

Arterial hypertension

Hypertension is the most important treatable risk factor for stroke. The relationship is highly significant, independent of other risk factors and directly linear to systolic blood pressure [3,4]. Uncontrolled hypertension is also associated with cognitive impairment, including dementia (vascular dementia and Alzheimer’s dementia) [4]. In the INTERSTROKE and Global Burden of Disease (GBD) study, BP was identified as the most important risk factor for stroke with an estimated risk of stroke of 47.9% and 64,1%. This difference between the 2 studies is probably due to a different BP value (INTERSTROKE ≥140 mmHg, GBD ≥120 mmHg) [5,6]. A reduction in systolic blood pressure (SBD) of 2 mmHg resulted in a relative reduction in stroke incidence of 25% [7], whereas a reduction in diastolic blood pressure (DBD) of 10 mmHg reduced stroke risk by 50% [7,8]. Likewise, a reduction in borderline BP values (SBD 130-139 mmHg and DBD 85-89 mmHg) resulted in a decrease in stroke risk [7]. In those who were not considered hypertensive, a direct risk increase for stroke was observed with increasing BP levels [9]. Reduction of isolated SBD >160 mmHg to 145 mmHg in patients >80 years also showed a 30% reduction in stroke risk [10]. In healthy individuals, regular BP monitoring 1×/year is recommended; in patients with known hypertension, more frequent monitoring (depending on the effective BP setting) may be appropriate, but always with recommendations for additional lifestyle measures (low-salt diet, avoidance of obesity and alcohol overconsumption and nicotine use, regular physical activity). Prevention of hypertension by the aforementioned lifestyle measures should always be aimed for, because even patients with already established hypertension and optimal drug BP control still had a higher risk of cardiovascular events than healthy individuals without hypertension. In patients with hypertension, antihypertensive therapy should be started at values >140/90 mmHg (primary and secondary prevention) [11,12]. Recent work tends toward lower target values of SBD <130 mmHg [13] or <120 mmHg [14,15]. Although a greater BP reduction to systolic 121.4 mmHg was associated with a higher adverse event rate (hypotension, syncope, renal failure) compared with a less severe BP reduction (systolic 136.2 mmHg), it was also associated with significantly lower rates of cerebrovascular accident and myocardial infarction and reduced all-cause mortality [15]. In contrast, another recently published study did not demonstrate a significant increase in adverse event rates with intensive BP lowering to 120 mmHg [14]. Although a stricter BP setting <140/90 mmHg is not generally recommended in the guidelines to date. However, we recommend that lower target values be evaluated individually in each patient depending on the vascular risk profile (eg, lacunar infarcts, diabetes mellitus, moderate- to high-grade carotid stenosis), although lowering the SBD <120 mmHg cannot be generally recommended at this time.

In the treatment of hypertension, the choice of drug class is less important than effective BP control with regard to stroke prevention [16]. In the HOMED-BP trial, it was shown that evening blood pressure variability (BDV) (measured by patients), independent of the measured blood pressure level or average value before antihypertensive therapy, may be a significant predictor of serious cardiovascular events. However, the choice of antihypertensive therapy (calcium channel blocker, ACE inhibitor, angiotensin receptor blocker [ARB]) did not significantly affect BDV [17]. The selection of substance classes should therefore be primarily based on the patients’ concomitant diseases. In some meta-analyses and studies, there is a trend toward slight superiority of calcium channel blockers [13,18] and ACE inhibitors [18], whereas beta-blockers are less protective in terms of stroke prevention in hypertensive patients without heart disease [13]. Further, for patients with metabolic risk factors treated with thiazide diuretics or beta-blockers, the risk of new-onset diabetes mellitus may be increased compared with those on ARBs and ACE inhibitors [19].

Dyslipidemia

Hypercholesterolemia is considered a validated risk factor for coronary heart disease (CHD), and the association with stroke risk is weaker compared with CHD [20]. In previous studies, an increased risk of ischemic stroke was observed at levels of total cholesterol ≥7 mmol/l [21] and an increased risk of hemorrhagic stroke was observed at levels <4.14 mmol/l [22]. An LDL reduction <2.6 mmol/l is associated with a 16% risk reduction for stroke; whereas an LDL reduction of 1 mmol/l is associated with a 21% reduction in stroke risk [23] resp. of all-cause mortality of 9% [24] showed. In a subanalysis of the SPARCL trial, intensive LDL reduction (<1.8 mmol/l vs. <2.6 mmol/l) showed a 28% reduction in stroke risk with no increased risk of hemorrhagic stroke [25,26].

The role of HDL is controversial. Although some studies reported an inverse correlation with stroke risk [27–32], a large meta-analysis failed to demonstrate an association between HDL levels and stroke risk [33].

The influence of triglycerides (TG) is also controversial. While some studies showed a direct-proportional increase in stroke risk with elevated TG levels [34] to 50% [35], other studies found no increase in either ischemic [33,36,37] or hemorrhagic [33] strokes. Overall, however, the risk seems to depend on the cause: there is a stronger association of lipid levels in cerebral stroke of macroangiopathic origin than in other causes [38].

Statins have an established role in secondary prevention of stroke and can reduce the risk of recurrence by 18% [23]. The target values recommended in the guidelines are LDL <2.6 mmol/l and total cholesterol <5.0 mmol/l, although in individual cases (e.g., high-risk patients, carotid stenosis) statin therapy can also be used independently of these guideline values or dosed higher.

Its use in healthy individuals to prevent stroke (primary prevention) cannot be generally recommended, although some studies have published positive results in this regard [39]. The NNT was quite high and not cost effective overall. The preventive effect may well be higher in high-risk patients, so we consider statin use for primary prevention in this selective group to be reasonable, using the AGLA risk chart, among others, for risk stratification.

In contrast to statins, the other lipid-lowering agents (fibrates, niacin) have not yet been shown to have a preventive effect on cerebral stroke, which is best explained by the pleiotropic properties of statins.

Diabetes mellitus

Diabetes mellitus is associated with a twofold increased risk of cerebrovascular accident, with increased risk in both younger and older patients. Cerebral stroke is the cause of death in approximately 20% of patients with diabetes mellitus [40]. Patients with prediabetic metabolic status are also at increased risk of stroke [41]. Diabetes promotes cerebral microangiopathy and causes predominantly lacunar cerebral infarcts [42]. Disease duration also seems to play a role: Patients with a DM duration of ≥10 years have a higher risk of stroke than patients with a disease duration of five to ten years resp. zero to five years (HR 1.7, 1.8, and 3.2, respectively) [40].

Additional therapy with statins can reduce the risk of stroke in diabetics by 24% [43]. The benefit of statins in diabetics is also well established for primary stroke prevention: According to a meta-analysis of 14 randomized trials involving approximately 18 500 diabetic patients, statin therapy resulted in a 21% (95% CI 0.67-0.93) reduction in cerebral stroke for every 1 mmol/l reduction in LDL cholesterol [44]. Therefore, the indication for statins should be generous in diabetic patients, especially when multiple vascular risk factors are present. In the ACCORD trial of 10 251 patients, intensive compared with moderate blood glucose lowering (_HbA1c <6% vs. 7-7.9%) did not demonstrate a reduction in stroke risk. The study even had to be stopped because of a significant increase in all-cause mortality in the group with intensive blood pressure lowering [45]. Only in patients with a BMI of >30 ^kg/m2 does intensive glycemic control appear to reduce the risk of stroke [46]. Therefore, overly aggressive blood glucose lowering is discouraged (especially in patients at risk for hypoglycemia), and _HbA1c <7% is recommended as a target value [47]. Strict blood pressure control and consistent statin therapy are likely to reduce the risk of stroke in diabetics more efficiently.

Regarding the choice of antidiabetic therapy, a recent meta-analysis of approximately 56,600 adults with type 2 diabetes found no significant difference between the nine available agents in terms of reduction in cardiovascular risk (including occurrence of stroke) and all-cause mortality. However, metformin has been suggested as a first-line agent because of its greater _HbA1c reduction as well as its more favorable side effect profile (no hypoglycemia or weight gain) compared with sulfonylureas, thiazolidinediones, or DPP 4 inhibitors [48].

The American Diabetes Association (ADA) recommends metformin as the first-line agent for diabetics. If this does not result in sufficient glycemic control, dual antihyperglycemic therapy (often a sulfonylurea) is recommended [49].

Atrial fibrillation

Atrial fibrillation (VHF) is associated with a four- to fivefold increased risk of stroke [50]. VCF is common, with one in four middle-aged adults in Europe and the United States developing one [51–53]. Regular palpatory checks of the pulse [11], followed by ECG examination in case of an irregularly felt pulse, increase the detection rate of VCF in patients >75 years [54]. After an ischemic stroke or transient ischemic attack of unclear cause, cumulative cardiac rhythm monitoring of approximately 30 days within the first six months is recommended to look for (intermittent) atrial fibrillation [12].

In healthy individuals without a history of stroke/TIA, the indication for oral anticoagulation (OAC) for nonvalvular VCF depends on risk stratification, using the _CHA2DS2-VASc score. If the _CHA2DS2-VASc score is ≥2 points, OAK is recommended. With a score of 1, for example, patients younger than 75 years with VCF without additional risk factors may not require OAK [11]. Acetylsalicylic acid is not an equal alternative to OAK because the preventive effect on stroke is much smaller. Compared with acetylsalicylic acid, OAK reduces stroke risk by 39% [55,56].

After cerebral stroke, combination therapy with aspirin and OAK is not recommended, but this may be evaluated in individual cases (eg, coronary artery disease). In the case of increased risk for hemorrhagic transformation (extensive infarction, hemorrhagic transformation on initial imaging, uncontrolled hypertension, or a hemorrhagic tendency), delayed initiation of OAK therapy is recommended (>14 d after cerebral stroke), although this time can be bridged with acetylsalicylic acid [12].

The new oral anticoagulants (NOACs) are safe and also show a reduced risk of cerebral hemorrhage compared with vitamin K antagonists (VKAs) [57].

Carotid stenosis

The incidence of carotid stenosis increases with age and in patients with coronary artery disease, nicotine use, or diabetes mellitus [58]. In symptomatic higher-grade carotid stenosis, rapid revascularization (carotid endarterectomy, or stenting in younger patients or after radiotherapy) is recommended because the risk of recurrence of another stroke in the following days to weeks is significantly increased.

In asymptomatic carotid stenosis (incidental finding), a more rigorous risk-benefit assessment is needed, as an annual stroke risk of <1% has been observed in these patients under “best medical treatment” in recent studies [59–61]. Carotid endarterectomy in asymptomatic patients can be discussed if there is a ≤3 percent perioperative risk, this with consideration of other factors (eg, young age, high risk profile, plaque morphology such as hypoechogenic or “soft, unstable” plaques, or even asymptomatic or “silent” ischemia on cerebral imaging). The indication for carotid endarterectomy in asymptomatic carotid stenosis should be made at interdisciplinary indication conferences; the benefit of carotid stenting in asymptomatic patients is not sufficiently proven.

Hyperhomocysteinemia

Hyperhomocysteinemia as an independent risk factor for stroke is controversial in the literature. While some studies report a two- to threefold increased risk [62–68], other studies showed no benefit in terms of stroke risk despite a ≥20 percent reduction in hyperhomocysteinemia with folic acid therapy [69]. Overall, hyperhomocysteinemia-reducing therapy with a vitamin B complex (vitamins B6, B12, folic acid) may be considered for primary and secondary prevention of cerebral stroke, but a benefit has not been proven so far; accordingly, routine screening is not recommended [11,12].

Migraine

Migraine with aura appears to be associated with a statistically increased risk of stroke in women <55 years [70], although the absence of nausea and vomiting showed a stronger association [71]. The absolute risk of stroke is relatively small, but increases significantly in the presence of additional risk factors such as nicotine use and oral contraceptives [72]. In these situations, a particularly strict cessation of risk factors (nicotine cessation, non-hormonal contraceptive methods, etc.) is recommended.

Sleep related breathing disorder

Sleep-disordered breathing is recognized as a risk factor for stroke [73,74], but it can also occur secondary to stroke [75,76]. The prevalence of sleep-disordered breathing can be as high as 75% in patients with a stroke/TIA [77–88]. In addition, a higher risk of further stroke recurrence was also observed in untreated patients [89]. Whether treatment of sleep-disordered breathing reduces the risk of stroke is still unclear [11]. Overall, however, this treatment may reduce cardiovascular morbidity and mortality [90,91].

Open foramen ovale and atrial septal defect

Patent foramen ovale (PFO) is present in approximately 15-25% of adults, and atrial septal defect (ASA) is present in approximately 1-4%. While paradoxical emboli may occur with a PFO due to a right-to-left shunt, the ASA is a source for thrombosis formation [92–98]. The risk of recurrence after cryptogenic stroke is likely to be increased, especially in younger patients (<55 years) with PFO and atrial septal aneurysm [99], whereas the correlation with PFO size was low [93,100–104]. After cerebral stroke, PFO closure with an Amplatzer device seems to be justifiable especially in younger patients without other vascular risk factors and without other causes of stroke, but not in older patients with multiple risk factors [105,106]. The optimal drug therapy for a PFO (platelet aggregation inhibition vs. anticoagulation) is the subject of current studies.

Antiplatelet agents

General platelet aggregation inhibition in healthy individuals cannot be recommended for primary prevention of stroke, even in diabetics [107,108].

For secondary prevention after a previous stroke of noncardioembolic origin, acetylsalicylic acid, clopidogrel, or a combination of acetylsalicylic acid with dipyridamole showed an average reduction in the recurrence risk of stroke of approximately 22% [109]. Whereas the use of dipyridamole was associated with a higher rate of headache and gastrointestinal discomfort [110] (twice daily dosing required). A dose dependence for acetylsalicylic acid (50-1300 mg/d) was not found [111–114]. Clopidogrel appears to have better benefit in patients with a high vascular risk profile (i.e., peripheral arterial disease, diabetes mellitus) [115]. However, clopidogrel may be used, particularly in patients allergic to ASA [12]. If antacid therapy is needed in patients on clopidogrel, an H2 blocker is recommended. Proton pump blockers should be used restrictively. In this regard, ^Pantozol® showed less interaction with clopidogrel than omeprazole [116]. Combination therapy of acetylsalicylic acid and clopidogrel versus clopidogrel showed no reduction in stroke risk [117]. However, combination therapy is used, for example, in patients with symptomatic high-grade intracranial stenosis or in the first 12 months after a myocardial infarction or insertion of a coronary stent.

Lifestyle change

Diet: Several aspects of diet can lead to hypertension and thus increased risk of stroke. These include, in particular, increased salt consumption, lower potassium intake, obesity, and increased alcohol consumption [118].

The average salt consumption in most Western countries is about 10 g per day, with international recommendations suggesting a salt consumption of 5-6 g per day. Higher salt consumption is associated with an increased risk of ischemic and hemorrhagic stroke [119]. Reducing salt consumption by one teaspoon per day (equivalent to 5-6 g salt) lowers systolic and diastolic BP by 7 and 4 mmHg, respectively; especially in patients with salt-sensitive hypertension, this effect may be more pronounced [120,121]. With increased consumption of prepackaged foods, controlling salt consumption is much more difficult. Overall, a reduction in salt consumption of half a teaspoon per day can result in a 20% reduction in cardiovascular events [122].

In addition, a rich diet with plenty of fruits, vegetables, fish and a low proportion of saturated fatty acids is recommended for lowering blood pressure (Class I; LOE A) and thus also for reducing the risk of stroke. In addition, a reduction in stroke risk with a Mediterranean diet has been found in patients with a high cardiovascular risk profile [123].

Smoking: Tobacco use is considered a strong risk factor for the occurrence of a first ischemic stroke, especially in boys. It doubles the risk of ischemic stroke [124–126]. Smoking potentiates the effect of other risk factors such as hypertension [127] or oral anticonceptives [128,129]. For example, smokers using oral anticonceptives have a 7.2-fold increased risk of ischemic stroke compared with nonsmokers without oral anticonceptives [128]. Smoking cessation should generally be recommended. One year after smoking cessation, cardiovascular risk (heart attack and stroke) is reduced by 15%, and by 27% after two years (compared with continued tobacco use) [130]. The risk of stroke is vanishingly small after two to four years [131–134].

Physical activity: regular physical activity can reduce the risk of stroke by 10-30% [135–140], although this effect is sometimes attributed to more optimal control of other vascular risk factors such as hypertension, diabetes mellitus, and obesity [141–143]. At least moderate physical activity (fast walking) three to four times per week for at least 30-40 minutes each time is recommended. Whether a dose-response relationship exists-that is, maximal risk reduction from maximal physical activity-is unclear [11].

Overweight: Ob esity is common and increasing. In 2012, 41% [144] of the Swiss population was overweight or obese; in 2014/15, the figure was already 43.4% [145]. There is a linear relationship of obesity with stroke risk. Per unit (1 ^kg/m2), the risk of cerebrovascular accident increases by 5%. Overweight should be avoided. However, underweight with consecutive malnutrition should also be avoided.

Overall, the association between obesity and stroke risk is better established for truncal obesity measured by abdominal circumference or waist-to-hip ratio than for general obesity measured by BMI [146,147]. Some studies speak of a so-called “obesity paradox”: According to this, overweight people have a better prognosis after a stroke. However, we think that methodological errors underlie these statements. This “obesity paradox” was not found in patients receiving intravenous thrombolysis [148].

Alcohol: The relationship between alcohol and stroke risk resembles a J-curve. Light to moderate alcohol consumption might reduce the risk of ischemic stroke, but alcohol consumption above this level significantly increases the risk of stroke [1,149–151]. Therefore, overconsumption of alcohol should be strongly discouraged.

Global lifestyle change

A general change in lifestyle is more effective overall than changing only individual risk factors. It was shown that patients who consistently implemented all five criteria of a healthy lifestyle (nonsmoking, regular physical activity ≥30 minutes per day, healthy diet, moderate alcohol consumption, aiming for a normal weight) had an 80% lower risk of stroke than patients who did not meet any of these five criteria [152].

Conclusion

Arterial hypertension continues to be considered the most important treatable risk factor in stroke prevention. Antihypertensive therapy is generally recommended for blood pressure values >140/90 mmHg; depending on the risk profile, lower target values may be acceptable. Effective blood pressure reduction is more important than the choice of drug class. Additional non-drug measures (low-salt diet, avoidance of excess weight, increased physical activity) play a key role.

Statins are firmly established in secondary prevention after cerebral stroke and are superior to fibrates in preventing vascular complications. The guidelines recommend a target LDL <2.6 mmol/l. For primary prevention, its use is useful only in high-risk patients.

Diabetes mellitus particularly favors cerebral microangiopathy with lacunar infarcts. Consistent control of vascular risk factors appears to reduce vascular risk more efficiently than overly strict glycemic control.

Atrial fibrillation is associated with up to a five-fold increased risk of stroke. Regular pulse examination in patients >75 years of age followed by ECG checks can substantially increase the detection rate of atrial fibrillation. After an ischemic stroke or transient ischemic attack without a clear cause, rhythm screening of a cumulative 30 days in the first six months is recommended to look for AF.

In symptomatic carotid stenoses, rapid revascularization (surgery or angioplasty) is clearly superior to conservative therapy, whereas in asymptomatic stenoses, a conservative approach with optimal control of vascular risk factors has comparable value.
A healthy lifestyle combined with consistent treatment of vascular risk factors can reduce the risk of stroke by 80%.

Take-Home Messages

• Arterial hypertension is considered the most important treatable risk factor in stroke prevention.
• Statins have an established place in secondary prevention after cerebral stroke. For primary prevention, its use is useful only in high-risk patients.
• In diabetics, consistent control of vascular risk factors appears to reduce vascular risk more efficiently than overly strict glycemic control.
• Atrial fibrillation is associated with up to a five-fold increased risk of stroke.
• In symptomatic carotid stenoses, rapid revascularization is clearly superior to conservative therapy, whereas in asymptomatic stenoses, a conservative approach with optimal control of vascular risk factors has comparable value.
• Healthy lifestyle combined with consistent treatment of vascular risk factors can reduce stroke risk by 80%.

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