RCTs provide evidence that stroke risk is reduced by several risk factor control strategies reviewed in this chapter: adhering to a Mediterranean Diet , avoiding long-term estrogen hormone replacement, and treating severe obesity with gastric balloons or bariatric surgery. In addition, observational evidence suggests stroke risk is reduced by quitting smoking, controlling blood glucose, losing weight in moderately obese individuals, exercising regularly, abandoning heavy alcohol consumption, and improving diet (less salt and more unsaturated fats) via other approaches. Optimal goals for risk factor control are delineated in the American Heart Association Life’s Simple 7 ideal targets. The beneficial effects of these measures are likely largely mediated by amelioration of well-established risk factors such as blood pressure, cholesterol, diabetes, and coagulation status. To achieve these lifestyle changes, both the individual and the community must contribute. Governments have a responsibility to: improve public education; increase access to healthy foods and built environments with pedestrian, bicycle, and exercise infrastructure; and use regulation, legislation, and taxation to discourage hazardous lifestyle behaviours (e.g. smoking, alcohol, and perhaps salt or sugar in foods). Continued cultural change is also required among individuals and communities to promote regular physical activity, a healthy diet, and minimal exposure to smoking in everyday life.
Diabetes prevalence is increasing in low-, middle-, and high-income countries, affecting 451 million people worldwide (Whiting et al., 2011), and is a well-established risk factor for ischaemic stroke. The extent to which diabetes affects stroke risk varies by age, sex, and race. In the Greater Cincinnati/Northern Kentucky Stroke Study, the risk ratio for ischaemic stroke in patients younger than 65 years of age was 5.2 (95% confidence interval [CI]: 3.6–6.9) for black people compared with 12.0 (95% CI: 8.8–15.2) for white. Among those 65 years or older, the risk ratio was 2.1 (95% CI: 1.5–2.7) for black people and 2.7 (95% CI: 2.1–3.4) for white (Khoury et al., 2013). A systematic review of 64 cohort studies representing 775,385 individuals and 12,539 strokes revealed that the pooled maximum adjusted risk ratio (RR) of stroke associated with diabetes was 2.28 (95% CI: 1.93–2.69) in women and 1.83 (95% CI: 1.60–2.08) in men. Compared with men with diabetes, women with diabetes had a 27% greater RR for stroke when baseline differences in other major cardiovascular risk factors were taken into account, RR 1.27 (95% CI: 1.10–1.46) (Peters et al., 2014). In the INTERSTROKE case–control study of 26,919 participants from 32 countries, among 10 common vascular risk factors, diabetes contributed to 7.5% (95% CI: 5.0–11.1%) of all ischaemic strokes (population attributable risk) (O’Donnell et al., 2016). Diabetes is also an independent risk factor for stroke recurrence: in a meta-analysis of 18 studies involving 43,899 participants with prior stroke, the increased hazard of recurrent stroke associated with diabetes was hazard ratio (HR) 1.45 (95% CI: 1.32–1.59) (Shou et al., 2015).
Pre-diabetes is also associated with greater stroke risk. A meta-analysis of 15 prospective cohort studies including 760,925 participants revealed that when prediabetes was defined as fasting glucose 110–125 mg/dL (5 studies), the adjusted relative risk for stroke was 1.21 (95% CI: 1.02–1.44; p = 0.03) (Lee et al., 2012).
The prevalence of diabetes among stroke survivors in the United States has been increasing. Data from the United States Nationwide Inpatient Sample revealed that from 1997 to 2006, the absolute number of acute ischaemic stroke hospitalizations declined by 17%; however, the absolute number of acute ischaemic stroke hospitalizations with comorbid diabetes rose by 27% (from 97,577 [20%] to 124,244 [(30%]). Factors independently associated with higher odds of diabetes in acute ischaemic stroke patients were black or ‘other’ (versus white) race, congestive heart failure, peripheral vascular disease, and history of myocardial infarction, renal disease, or hypertension (Towfighi et al., 2012).
Effective strategies to reduce the risk of stroke in diabetics include:
1. Preventing or delaying the onset of diabetes of patients with prediabetes. A meta-analysis of randomized controlled trials (RCTs) found that diet, exercise, and pharmacological interventions reduced diabetes onset (RR 0.83, 95% CI: 0.80–0.86), and reduced fatal and nonfatal strokes (RR 0.76, 95% CI: 0.58–0.99) (Hopper et al., 2011).
2. Preventing atherogenesis by optimally controlling risk factors such as high blood pressure (Emdin et al., 2015), high blood cholesterol (Cholesterol Treatment Trialists, et al., 2008; Sabatine et al., 2017), high blood glucose (Brunstrom and Carlberg, 2016), and smoking (Pan et al., 2015).
4. Recanalizing a cervical carotid artery with atherosclerotic stenosis that is moderate–severe and symptomatic or severe and asymptomatic by means of carotid stenting or endarterectomy (Rothwell et al., 2003; Moresoli et al., 2017).
Randomized trials have shown that more intensive treatment of hyperglycaemia results in fewer microvascular complications (retinopathy and renal damage) of diabetes type 2, but has limited impact upon macrovascular complications (Marso et al., 2010; Zoungas et al., 2017). A meta-analysis of 4 RCTs including 27,544 patients revealed that those randomized to intensive glucose control did not have a reduction in stroke risk compared with those with conventional glucose control; however, there was a 14% reduction in non-fatal myocardial infarction (odds ratio [OR] 0.86, 95% CI: 0.77–0.97) (Marso et al., 2010).
A meta-analysis of 40 RCTs of blood pressure (BP) lowering among 100,354 participants with diabetes revealed a lower risk of stroke (RR 0.73, 95% CI: 0.64–0.83; absolute risk reduction [ARR] 4.06, 95% CI: 2.53–5.40) (Emdin et al., 2015). While benefits of blood pressure lowering in diabetic patients with systolic blood pressure (SBP) >140 mm Hg are present for all major cardiovascular and stroke endpoints, differential benefits and harms accrue with blood pressure lowering therapy for patients with SBP <140 mm Hg. Using lower targets, such as SBP <130 mm Hg, tends to further reduce stroke events, but tends to increase cardiovascular mortality. In a meta-analysis of 49 trials of blood pressure lowering enrolling 73,738 diabetic patients, among patients whose baseline SBP was <140 mm Hg before randomization to more aggressive antihypertensive therapy, stroke events had RR of 0.81 (95% CI: 0.53–1.22) but cardiovascular mortality had RR of 1.15 (95% CI: 1.00–1.32 (Brunstrom and Carlberg, 2016). Similarly, regardless of entry SBP level, among patients during trial conduct whose attained SBP on more aggressive antihypertensive therapy was <130 mm Hg, stroke events had RR of 0.65 (95% CI: 0.42–0.99) but cardiovascular mortality had RR of 1.26 (95% CI: 0.89–1.77).
Diet and pharmacological cholesterol-lowering have both shown evidence of benefit in reducing stroke risk in patients with prediabetes and diabetes. It is important to note that statins are associated with a small increase in diabetes incidence; in a meta-analysis of 13 trials enrolling 91,140 nondiabetic patients, statins increased diabetes onset, OR 1.09 (95% CI: 1.02–1.17) (Sattar et al., 2010). However, the absolute effect was small, an increase of 0.49% over 5 years of therapy, and is outweighed by the benefit in averting cardiovascular and neurovascular events. In a meta-analysis of 14 trials enrolling 90,056 patients, statins substantially reduced major vascular events and stroke among both diabetics and nondiabetics (Cholesterol Treatment Trialists et al., 2008). In diabetics, the effect on major vascular events was RR 0.79 (95% CI: 0.72–0.86), with an absolute reduction of 4.2% over 5 years; the effect on strokes was RR 0.83 (95% CI: 0.77–0.88), with an absolute reduction of 1.2% over 5 years. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors added to statin therapy in diabetic patients further reduce the frequency of major vascular events, including stroke. In the FOURIER trial, among 11,031 patients with diabetes, allocation to a PCSK9 inhibitor reduced the composite of cardiovascular death, myocardial infarction, and stroke, HR 0.82 (95% CI: 0.72–0.93), with a homogeneous effect on the component stroke endpoint, HR 0.79 (95% CI: 0.62–1.01) (Sabatine et al., 2017).
Early detection of diabetes and prediabetes, followed by careful control of glycaemia and atherosclerotic vascular risk factors to optimal levels are likely to reduce stroke and other major vascular events (Fox et al., 2015). In diabetics, rigorous long-term control of blood pressure and blood cholesterol is essential to reduce stroke risk. Control of blood glucose levels to a moderate target, glycosylated haemoglobin ≤7%, also is likely to reduce future stroke incidence; more aggressive control to intensified targets, though beneficial for retinal and renal health, is not likely to confer substantial additional reduction of incident stroke.
Although prothrombotic, oestrogen has other effects that potentially could reduce vascular events, including improving lipid profiles, enhancing endothelial function, and improving insulin sensitivity. Large observational studies suggested that, among postmenopausal women, hormone replacement therapy (HRT) was associated with reduced frequency of stroke and other vascular events. However, RCT data indicate that the use of oestrogen plus progestin, as well as oestrogen alone, increases stroke risk in postmenopausal, generally healthy women and provides no protection for postmenopausal women with established coronary heart disease (CHD) and recent stroke or transient ischaemic attack (TIA). One systematic review of 28 RCTs assessing the effect of HRT on subsequent risk of stroke in a total of 39,769 subjects showed that random assignment to HRT was associated with a significant increase in total stroke (OR 1.29, 95% CI: 1.13–1.47), non-fatal stroke (OR 1.23, 95% CI: 1.06–1.44), stroke leading to death or disability (OR 1.56, 95% CI: 1.11–2.20), and ischaemic stroke (OR 1.29, 95% CI: 1.06–1.56). HRT was not associated with haemorrhagic stroke (OR 1.07, 95% CI: 0.65–1.75) (Bath and Gray, 2005).
It appears that the timing of HRT initiation may play a critical role in the effect of HRT. Another meta-analysis of 19 trials enrolling 40,410 post-menopausal women examined the timing of HRT start, finding a beneficial effect on coronary disease events when HRT was started less than 10 years after menopause onset, but not later. However, there was no heterogeneity for the increased risk of stroke in both time frames: within 10 years of menopause, RR 1.37, 95% CI: 0.89–2.34, versus more than 10 years after menopause, RR 1.21, 95% CI: 1.06–1.38 (Boardman et al., 2015) (Figure 17.1) Venous thromboembolism was also increased in both time frames.
Figure 17.1 Forest plot showing the effects of hormone replacement therapy for stroke prevention, started within versus more than 10 years after menopause, among 22,722 patients.
There is reasonably strong evidence from RCTs that HRT increases the risk of stroke in postmenopausal women with or without a history of vascular disease. Therefore, long-term oestrogen or oestrogen plus progestin is not indicated as a long-term stroke prevention therapy. However, the risks of HRT are small in absolute terms for short duration therapy. Accordingly, HRT remains a suitable option for women with bothersome menopausal symptoms, but they should understand that there are some risks involved and should regularly re-assess their need for treatment with their clinician. It is prudent to use the lowest effective dose for the shortest period.
There have been no large RCTs of oral, transdermal, or vaginal hormonal contraceptive use versus nonhormonal barrier methods, so high-level evidence is lacking. But there is a large body of evidence from observational studies, though these are prone to bias and confounding, as highlighted in Chapter 2. When initial observational studies indicated increased risk of stroke, myocardial infarction, and venous thrombosis with early oestrogen and combined oestrogen and progestin contraceptives, later generation agents were developed with lower oral oestrogen doses, progestin-only formulations, and different variants of hormonal molecules, seeking to reduce thrombotic risk. Oestrogen doses declined from 50 μg (first generation) to 20–35 μg (second and later generations).
Several meta-analyses of cohort and case–control studies have shown that oral contraceptive (OC) therapy increases the risk of ischaemic stroke by 1.5- to 3.0-fold, with a lesser but still significant risk associated with later generation agents. A meta-analysis of 16 case–control and cohort studies between 1960 and 1999 estimated a 2.75-fold increased odds (95% CI: 2.24–3.38) of stroke associated with OC use (Gillum et al., 2000). A second meta-analysis of 20 studies published between 1970 and 2000 found no increased risk of stroke in the cohort studies but an increased risk with OC use in case-control studies (OR 2.13, 95% CI: 1.59–2.86) (Chan et al., 2004). Only 2 of the 4 cohort studies reported strokes by subtype, and risk was increased for ischaemic but not haemorrhagic strokes. A more recent meta-analysis of 18 case–control and cohort studies between 1970 and 2014 found an overall increased risk of first-ever ischaemic stroke, OR 2.47 (95% CI: 2.04–2.99). The risk of ischaemic stroke among current OCP users declined with decreasing oestrogen dose: oestrogen doses of ≥50 μg had OR 3.28 (95% CI: 2.49–4.32); 30–40 μg had OR 1.75 (95% CI: 1.61–1.89), and 20 μg had OR 1.56 (95% CI: 1.36–1.79) (Xu et al., 2015) A similar oestrogen dose-related pattern was seen in a meta-analysis evaluating the composite outcome of stroke or myocardial infarction (Roach et al., 2015)(Figure 17.2). The risk of ischaemic stroke was not increased with progestin-only agents, OR 0.99 (95% CI: 0.71–1.37).
Figure 17.2 Forest plot showing the effects of oral contraceptives of three oestrogen dose levels on the composite of myocardial infarction and stroke.
Risk factors for stroke on hormonal contraceptives include older age, cigarette smoking, hypertension, migraine headaches, obesity, and hypercholesterolaemia (Chang et al., 1999; Kemmeren et al., 2002; Xu et al., 2015). In addition, an increased risk of stroke was seen in those with heterozygosity for factor V Leiden (OR 11.2, 95% CI: 4.2–29.0), the methyltetrahydrofolate reductase (MTHFR) 677TT mutation (OR 5.4, 95% CI: 2.4–12.0), β2 glycoprotein-1 antibodies (OR 2.3, 95% CI: 1.4–3.7), lupus anticoagulant (OR 43.1, 95% CI: 12.2–152.0), and von Willebrand factor levels >90th percentile (OR 11.4, 95% CI: 5.2–25.3) (Chang et al., 1999; Kemmeren et al., 2002). Although there is an increased risk of thromboembolism in women with these hypercoagulable states, the absolute risk is low; therefore, routine screening is not recommended. Selective screening based on prior personal or family history of venous thromboembolism is more cost-effective than universal screening in women who initiate OC (Wu et al., 2006).
The available evidence suggests that oestrogen-containing hormonal contraceptives are a risk factor for ischaemic but not haemorrhagic stroke. The risk of ischaemic stroke increases with higher doses of oestrogen. With lower dose agents, the relative risk is about 1.75-fold, equivalent to a small absolute increase in risk from about 3.5 to about 6.1 per 100,000 women per year (Nightingale and Farmer, 2004). Of note, this risk is low compared with the absolute stroke risk of pregnancy, 34.2 per 100,000 deliveries (James et al. 2005). Avoidance of oestrogen-containing contraceptives should be considered in women with additional risk factors, including older age, cigarette smoking, hypertension, migraine headaches, obesity, hypercholesterolaemia, and prior thromboembolic events. Progestin-only contraceptives do not appear to have increased stroke risk, and are a potential contraceptive option, as are barrier methods, for patients with risk factors for stroke on oestrogen-containing agents.
Observational studies suggest that tobacco smoking is a causal risk factor for ischaemic stroke and subarachnoid haemorrhage because the association is independent of other risk factors, consistent among different studies, dose-related, strong, and biologically plausible (Woodward et al., 2005; Bhat et al., 2008; Shah and Cole, 2010). A meta-analysis of 81 prospective cohort studies that included 3,980,359 individuals and 42,401 strokes revealed that smoking was an independent risk factor for stroke in both sexes (Peters et al., 2013). The risk of stroke associated with current smoking was RR 1.83 (95% CI: 1.58–2.12) for women and RR 1.67 (95% CI: 1.49–1.88) for men. The risk associated with being a former smoker versus never having smoked was RR 1.17 (95% CI: 1.12–1.22) for women and RR 1.08 (95% CI: 1.03–1.13) for men. Compared with never-smokers, the beneficial effects of quitting smoking among former smokers on stroke risk were similar between the sexes (RR 1.10, 95% CI: 0.99–1.22). In the INTERSTROKE international case–control study, among 10 common vascular risk factors, current smoking contributed to 15.1% (95% CI: 12.8–17.8%) of all ischaemic strokes (population attributable risk) (O’Donnell et al., 2016).
Exposure to secondhand tobacco smoke, also termed passive smoking or environmental tobacco smoke, increases the risk of stroke by approximately 1.25-fold, with a dose–response relationship (Lee and Forey, 2006; Oono et al., 2011). Data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study showed that the risk of stroke was increased among nonsmokers exposed to secondhand smoke in the prior year, HR 1.30 (95% CI: 1.02–1.67) (Malek et al., 2015). Analysis of participants in the US National Health and Nutrition Examination Surveys found a dose-dependent relationship between secondhand smoke exposure and all-cause mortality after stroke, with 10-year cumulative mortality rates of 39.0%, 40.7%, 58.3%, and 65.4% across increasing nicotinine quartiles (trend p = 0.02) (Lin et al., 2016).
There have been no RCTs wherein people have been randomized to ‘continue smoking’ or ‘stop smoking’, and observed for the risk of first-ever or recurrent stroke. And there likely never will be, as it would now be considered unethical given the strength of the observational evidence of the adverse health effects of smoking. Evidence from observational studies, however, suggests that quitting smoking is associated with a decreased risk of stroke, with risk declining to a substantially lower level 2–4 years after cessation (Kawachi et al., 1993; Peters et al., 2013; Epstein et al., 2017).
A systematic review identified 42 randomized trials, enrolling 31,000 smokers, of smoking cessation advice from a medical practitioner, in which abstinence was assessed at least 6 months after advice was first provided (Stead et al., 2013). In some trials, participants were identified as at risk for specified diseases (lung disease, diabetes, ischaemic heart disease), but most were from unselected populations. The most common setting for delivery of advice was primary care. Combined data from 28 RCTs showed that advice versus no advice (or usual care) increased the rate of quitting (8.0% vs 4.8%, RR 1.76, 95% CI: 1.58–1.96). Among 15 trials comparing intensive versus minimal advice, an advantage of intensive advice was seen, RR 1.37 (95% CI: 1.20–1.56). Direct comparison RCTs also indicated greater efficacy of repeating advice at follow-up visits compared with advice at a single visit, RR 1.52 (95% CI: 1.08–2.14).
Gum, Patches, Nasal Spray, Tablets/Lozenges
A systematic review identified 150 randomized trials, including 117 enrolling over 50,000 patients in which nicotine replacement therapy (NRT) was compared with placebo or no treatment, and 28 which compared different doses or combinations of NRT (Stead et al., 2012). Allocation to NRT compared with control increased achievement of abstinence from smoking (17.3% vs 10.3%, RR 1.60, 95% CI: 1.53 to 1.68). The RR for different forms of NRT were: 1.49 (95% CI: 1.40–1.60) for gum; 1.64 (95% CI: 1.52–1.78) for patches; 1.90 (95% CI: 1.36–2.67) for inhalators; 2.02 (95% CI: 1.49–2.73) for nasal spray; and 1.95 (95% CI: 1.61–2.36) for nicotine sublingual tablets/lozenges. The effects of NRT were largely independent of the duration of therapy, intensity of behavioural support provided, or the setting in which the NRT was offered. In highly dependent smokers, there was a dose-related benefit of 4 mg gum compared with 2 mg gum (RR 1.85, 95% CI: 1.36–2.50), but weaker evidence of a benefit from higher doses of patch. Combining a nicotine patch with a rapid delivery form of NRT was more effective than a single type of NRT (RR 1.34, 95% CI: 1.18–1.51). Adverse effects of NRT include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. There was no evidence that NRT increased the risk of myocardial infarction.
Electronic cigarettes (ECs) are electronic devices that heat a liquid – usually comprising propylene glycol and glycerol, with or without nicotine and flavours, stored in disposable or refillable cartridges or a reservoir – into an aerosol for inhalation. While concern exists about potential long-term effects of EC use, they may provide some benefit in reducing tobacco exposure among smokers. In a systematic meta-analysis, among 662 patients in 2 RCTs comparing ECs with nicotine versus ECs without nicotine, smokers allocated to ECs with nicotine were more likely to have abstained from smoking for at least 6 months (RR 2.29, 95% CI: 1.05–4.96) (McRobbie et al., 2014).
The addictive properties of nicotine arise mainly from agonistic action at neuronal nicotinic acetylcholine receptors, stimulating release of brain mesolimbic dopamine. Pharmacological nicotine receptor partial agonists produce a moderate, sustained release of dopamine, counteracting both withdrawal symptoms from tobacco abstinence and reward from tobacco re-use. The most extensively tested agent is varenicline. A systematic meta-analysis of 31 trials of varenicline enrolling 13,891 patients found that tobacco abstinence was increased by both standard-dose varenicline (RR 2.24, 95% CI: 2.06–2.43; 27 trials, 12,625 people) and lower- or variable-dose varenicline (RR 2.08, 95% CI: 1.56–2.78; 4 trials, 1266 people) (Cahill et al., 2016). Although uncontrolled observational studies raised concerns, large subsequent randomized trials found that varenicline did not increase rates of agitation, suicidal behaviour, or cardiovascular events (Anthenelli et al., 2016; Cahill et al., 2016; Eisenberg et al., 2016; Benowitz et al., 2018).
Bupropion is an aminoketone with dopaminergic and adrenergic actions, and an antagonist at the nicotinic acetylcholinergic receptor. Bupropion may aid smoking cessation by blocking nicotine effects, by relieving withdrawal, by reducing depressed mood, and by substituting for noradrenergic effects of nicotine. In a systematic meta-analysis of 44 RCTs enrolling 13,728 patients, bupropion increased long-term smoking cessation (RR 1.62, 95% CI: 1.49–1.76) (Hughes et al., 2014). Adverse effects with bupropion include insomnia, dry mouth, nausea, and, rarely (0.1%), seizures. Nortriptyline, a tricyclic with noradrenergic activity, may aid smoking cessation by reducing depressed mood and by substituting for noradrenergic effects of nicotine. In the same meta-analysis, among 6 RCTs enrolling 975 patients, nortriptyline increased long-term tobacco cessation (RR 2.03, 95% CI: 1.48–2.78) (Hughes et al., 2014). Adverse effects with nortriptyline at the relatively low doses (75–150 mg daily) used for smoking cessation include dry mouth, drowsiness, constipation, and, rarely, seizures.
A systematic network meta-analysis of 267 RCTs of pharmacological interventions for smoking cessation in 101,804 smokers compared each therapy with the others and with placebo, both directly and indirectly (Cahill et al., 2013). The most effective single therapy was varenicline, which yielded predicted higher cessation rates than either NRT (OR 1.57, 95% credible interval [CredI]: 1.29–1.91) or bupropion (OR 1.59, 95% CredI: 1.29–1.96), while bupropion and NRT were equally effective (OR 0.99, 95% CredI: 0.86–1.13) (Figure 17.3). However, varenicline was not more effective than combined rapid delivery plus patch NRT (OR 1.06, 95% CredI: 0.75–1.48). Neither nortriptyline nor bupropion added to NRT increased quitting rates compared with NRT alone.
Figure 17.3 Probability of treatment ranking plot showing the effects of three pharmacological therapies for smoking cessation.
A meta-analysis of 47 trials enrolling more than 18,000 smokers found that adding more intensive behavioural support to pharmacotherapy, compared to pharmacotherapy with minimal behavioural support, mildly further increased tobacco cessation rates (RR 1.17, 95% CI: 1.11–1.24) (Stead et al., 2015).
Few RCTs of tobacco cessation interventions have been conducted specifically in stroke patients. A systematic review identified 4 RCTs enrolling a total of 354 stroke survivors (Edjoc et al., 2012). Different trials evaluated: (1) providing advice to patients and general practitioners on NRT for smoking cessation (1 trial); (2) stroke nurse specialist patient counselling (2 trials); and (3) NRT plus smoking cessation counselling. Though underpowered, the effect observed in these small trials was directionally homogeneous with the benefit observed in the much larger set of trials in primary prevention and mixed vascular disease populations: tobacco abstinence rates after allocation to an active smoking cessation intervention versus control were 23.9% versus 20.8% (RR 1.15, 95% CI: 0.78–1.70).
All persons who use tobacco in any form (cigarettes, pipes, cigars, chewing tobacco), in both primary and secondary stroke prevention settings, should be advised to stop. The risks of subsequent stroke decline substantially within 2–5 years of stopping.
Simple advice from a healthcare provider is modestly effective (and highly cost-effective) in facilitating smoking cessation. Repeated and sustained advice and behavioural support programmes are more effective than one-time counselling.
In addition, pharmacological therapies, including NRT (gum, transdermal patch, nasal spray, inhaler, or sublingual tablets), varenicline, or bupropion, are effective for increasing smoking cessation rates in the short and long term. They increase quit rates by 1.5-fold to 2.25-fold. Among the pharmacological agents, the most effective approaches appear to be: (1) varenicline, and (2) combined NRT using fast-acting delivery systems plus a slower-release patch. Among NRT options, for patients who are particularly nicotine dependent, higher-dose, 4 mg gum is more effective than lower dose. In less highly dependent smokers, the different NRT preparations are comparable in efficacy, but nicotine patches offer greater convenience and minimal need for instruction. Inhalers and nasal sprays may be useful in patients with particularly severe nicotine craving, and combined patches and fast-acting forms of NRT are more effective than either alone. Bupropion is associated with a very low rate of seizure, and so is relatively contraindicated in patients with a seizure history. Combining NRT with either varenicline or bupropion does not enhance cessation.
The role of ECs (vaping) with nicotine in tobacco cessation is at present uncertain. While associated with increased short-term smoking abstinence in 2 modest-sized RCTs, their long-term safety has not yet been fully established, and, more than other NRT methods, they may perpetuate behaviours and cultural triggers associated with smoking, potentially increasing risk of late relapse (Bhatnagar et al., 2014). They may be an option in patients who have been refractory to other tobacco abstinence interventions.
It is also reasonable to advise patients with stroke or TIA to avoid environmental smoke exposures (Kernan et al., 2014). Encouraging smoking partners and family members of patients to quit smoking may reduce the patient exposure to environmental tobacco smoke and reduce the risk of stroke or other serious vascular events for all family members.
A meta-analysis of 27 prospective cohort studies reporting data on over 1.4 million individuals found that alcohol intake had a U-shaped curve relationship with ischaemic stroke and a J-shaped curve relationship with haemorrhagic stroke (Larsson et al., 2016). For ischaemic stroke, compared with no alcohol consumption, risk was reduced with light alcohol intake (less than 1 drink/day, RR 0.90, 95% CI: 0.85–0.95) and moderate alcohol intake (1–2 drinks/day, RR 0.92, 95% CI: 0.87–0.97), and increased with high alcohol intake (between 2 and 4 drinks/day, RR 1.08, 95% CI: 1.01–1.15) and heavy alcohol intake (more than 4 drinks/day, RR 1.14, 95% CI: 1.02–1.28). For intracerebral haemorrhage, compared with no alcohol consumption, risk was unchanged with light-to-moderate alcohol intake (<1 to 2 drinks/day, RR 0.95, 95% CI: 0.84–1.07) and increased with high-to-heavy alcohol intake (>2 drinks/day, RR 1.45, 95% CI: 1.18–1.78). Similarly, for subarachnoid haemorrhage, compared with no alcohol consumption, risk was unchanged with light-to-moderate alcohol intake (<1 to 2 drinks/day, RR 1.16, 95% CI: 0.98–1.37) and increased with high-to-heavy alcohol intake (>2 drinks/day, RR 1.57, 95% CI: 1.18–2.09). In the INTERSTROKE international case–control study, among 10 common vascular risk factors, high or heavy alcohol intake contributed to 4.6% (95% CI: 2.0–10.0%) of all ischaemic strokes and 9.8% (95% CI: 6.4–14.8%) of all haemorrhagic strokes (population attributable risk) (O’Donnell et al., 2016).
Among 428 nationally representative US stroke survivors, a healthy lifestyle, including light-to-moderate alcohol consumption (up to 2 drinks per day for men and up to 1 drink per day for nonpregnant women), was associated with reduced mortality after stroke (Towfighi et al., 2012).
The protective effect of light-to-moderate alcohol consumption for ischaemic stroke may be related to antithrombotic and favourable lipid effects of alcohol (Mukamal et al., 2005; Brien et al., 2011). Heavy alcohol use likely increases the risk of haemorrhagic stroke in part by antithrombotic effects, and the risk of both haemorrhagic and ischaemic stroke by increasing the risk of hypertension, atrial fibrillation, cardiomyopathy, and diabetes (Baliunas et al., 2009; Kodama et al., 2011; Briasoulis et al., 2012).
In a meta-analysis of brief (<1 hour) motivational counselling interventions in heavy alcohol drinkers, among 8 RCTs enrolling over 2500 heavy drinkers, those who received brief motivational interventions were close to two times more likely to decrease and moderate their drinking compared with those who received no intervention (OR 1.95, 95% CI: 1.66–2.30) (Wilk et al., 1997). A more recent meta-analysis of 73 controlled studies of brief, single-session interventions in heavy-drinking college students reduced alcohol use by 0.18 of the standard deviation of baseline use (95% CI: 0.12–0.24) (Samson and Tanner-Smith, 2015). Insufficient unconfounded trials of 12-step programmes and other longer interventions are available to assess their effectiveness (Ferri et al., 2006).
A systematic network meta-analysis of several pharmacological therapies analysed 122 RCTs and 1 cohort study (Jonas et al., 2014). In 16 trials enrolling 4847 patients, acamprosate reduced the absolute rate of return to any drinking by 9% (95% CI: 4–14%); in 7 trials, acamprosate did not modify the risk of return to heavy drinking, absolute risk reduction 1% (95% CI: –3–4%). In 16 trials enrolling 2347 patients, naltrexone at moderate 50 mg oral dose reduced the absolute rate of return to any drinking by 5% (95% CI: 0.2–10%); in 19 trials, naltrexone at moderate 50 mg dose reduced the rate of return to heavy drinking by 9% (95% CI: 4–13%). In 2 trials enrolling 492 patients, disulfiram did not statistically modify the rate of return to any drinking, ARR 4% (95% CI: –3 to 11%).
Reducing heavy alcohol intake is advisable, as it is associated with increased ischaemic and haemorrhagic stroke in observational studies. Brief counselling interventions, pharmacological therapy with acamprosate, and pharmacological therapy with naltrexone are effective interventions to increase abstinence among heavy drinkers. Light to moderate amounts of alcohol consumption (up to 2 drinks per day for men and up to 1 drink per day for nonpregnant women) are not associated with increased stroke risk and may even help prevent ischaemic stroke. Light to moderate drinkers may be counselled to continue with moderate intake; however, given the risk of addiction, nondrinkers should not be counselled to start drinking (Kernan et al., 2014).
Physical Activity and Risk of Stroke
A systematic review of 9 prospective cohort studies following more than 390,000 participants typically for 12 years found a dose–response relationship between weekly physical activity and stroke incidence, with the greatest gain occurring with the transition from complete inactivity to at least low activity (Wahid et al., 2016). Compared with inactivity, stroke occurrence was lower with low physical activity (0.1–11.5 hours per week) by RR 0.85 (95% CI: 0.80–0.91); medium physical activity (11.5–29.5 hours per week) by RR 0.81 (95% CI: 0.74–0.89), and high physical activity (more than 29.5 hours per week) by RR 0.76 (95% CI: 0.68–0.85). In the INTERSTROKE international case–control study, among 10 common vascular risk factors, physical inactivity contributed to 33.4% (95% CI: 24.2–44.0%) of all ischaemic strokes and 34.6% (95% CI: 21.3–50.7%) of all haemorrhagic strokes (population attributable risk) (O’Donnell et al., 2016).
The mechanisms by which physical activity might reduce stroke risk include lowering body weight, blood pressure, blood viscosity, fibrinogen concentrations, and platelet aggregability; enhancing fibrinolysis; and improving lipid profiles and endothelial function (Billinger et al., 2014). Individuals who have had a stroke often have reduced physical activity due to motor and other deficits, potentially predisposing them to heightened risk of recurrent stroke and cardiovascular disease.
Physical activity and exercise programmes after stroke and TIA have been found to improve vascular risk factor profiles. A systematic review of 14 RCTs in 720 stroke and TIA patients of exercise with or without additional lifestyle interventions found reductions in SBP, mean difference (MD) −5.32 mm Hg, 95% CI: −9.46 to −1.18, fasting glucose, MD −0.11 mmol/L, 95% CI: −0.17 to −0.06, and fasting insulin, MD −17.14 pmol/L, 95% CI: −32.90 to −1.38, P = 0.03, and increases in high-density lipoprotein cholesterol, MD 0.10 mmol/L, 95% CI: 0.03–0.18 (D’Isabella et al., 2017). Similar effects were seen when analysis was confined to the 9 RCTs in which exercise was the only intervention. However, insufficient long-term trials have been performed to determine whether these favourable effects on vascular risk factors translate into actual reduced recurrent stroke and cardiovascular events.
The optimal time to resume physical activity after stroke remains unknown. In the AVERT trial, among 2104 stroke patients randomized to very early and frequent mobilization, commencing within 24 hours, or usual care, patients randomized to usual care had more frequent functional independence (modified Rankin Scale [mRS] 0–2) outcome at 3 months, 50% versus 46% (OR 1.37, 95% CI: 1.11–1.69) (Avert Trial Collaboration Group, 2015). They found a consistent pattern of improved odds of favourable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (OR 1.13, 95% CI: 1.09–1.18; p < 0.001), keeping time to first mobilization and mobilization amount constant. On the other hand, increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI: 0.91 to 0.97, p < 0.001) (Bernhardt et al., 2016).
Based on available, largely observational evidence, regular physical activity to improve aerobic capacity is likely to reduce stroke risk. American Heart/Stroke Association guideline recommendations for primary prevention of stroke have suggested at least 40 minutes of moderate- to vigorous-intensity activity 3–4 times per week (Meschia et al., 2014). Among individuals who have already had a stroke or TIA, based on short-term trials evaluating modification of risk factors rather than actual stroke and other vascular events in the long-term, regular physical activity also appears likely to reduce risk of recurrent stroke and cardiovascular events. While highly vigorous activity within the first 24 hours of stroke onset should be avoided, eventually at least three to four 40-minute sessions per week of moderate- to vigorous-intensity aerobic physical exercise in stroke patients able to engage in physical activity appears desirable (Kernan et al., 2014). In addition to potential reduction in recurrent stroke risk by aerobic exercise, stroke patient engagement in regular strength, flexibility, and coordination-building physical activities may bring other benefits, including greater recovery of post-stroke motor deficits and decreased fall risk (Billinger et al., 2014).
In a systematic review of 25 prospective cohort studies with over 2.27 million participants experiencing over 30,700 stroke events over an average follow-up of 17.5 years, higher body mass index (BMI) was associated with increased risk of ischaemic and haemorrhagic stroke (Strazzullo et al., 2010). Overweight was defined as BMI 25–29.9 kg/m2 in Western countries and 23–27.5 kg/m2 in Asian countries, and obesity defined as BMI ≥30 kg/m2 in Western countries and >27.5 kg/m2 in Asian countries. For ischaemic stroke, compared with normal weight, incidence was increased in overweight individuals, RR 1.22 (95% CI: 1.05–1.41) and obese individuals, RR 1.64 (95% CI: 1.36–1.99). For haemorrhagic stroke, incidence was not increased for overweight individuals, RR 1.01 (95% CI: 0.88–1.17) but tended to be increased for obese individuals, RR 1.24 (95% CI: 0.99–1.54) Considering only young adults, aged 18–50, a meta-analysis of eight cohort studies found that for overweight individuals the pooled adjusted RR of stroke was 1.36 (95% CI: 1.28–1.44), and for obese individuals it was 1.81 (95% CI: 1.45–2.25) (Guo et al., 2016).
Abdominal obesity, reflecting visceral adipose tissue, compared with general obesity, reflecting also subcutaneous fat, has been more closely related to metabolic dysfunctions, inflammatory cytokines, and lipid profiles predisposing to vascular events. In a meta-analysis of 15 prospective cohort studies of over 405,000 participants experiencing over 11,700 stroke events, ischaemic strokes were associated with abdominal obesity, assessed as higher waist circumference, RR 1.41 (95% CI: 1.21–1.56), waist-to-hip ratio, RR 1.35 (95% CI: 1.21–1.50), and waist-to-height ratio, RR 1.55 (95% CI: 1.37–1.76) (Zhong et al., 2016). In contrast, haemorrhagic strokes were not increased with abdominal adiposity. In the INTERSTROKE international case–control study, among 10 common vascular risk factors, abdominal obesity contributed to 20.4% (95% CI: 13.3–25.3%) of all ischaemic strokes and 13.1% (95% CI: 6.4–25.1%) of all haemorrhagic strokes (population attributable risk) (O’Donnell et al., 2016).
Within the general framework of increased stroke incidence with higher body weight, nuances include:
1. Metabolically healthy obesity (MHO): Within the obese population, a subgroup has been identified who may not be at increased risk of cardiovascular events, as they do not display the typical metabolic disorders associated with obesity. Metabolically healthy obesity has been defined as obese individuals who do not have insulin resistance, lipid disorders, or hypertension, and occurs in 10–25% of the obese population (Roberson et al., 2014). In a prospective cohort study of 354,000 Korean adults experiencing 4884 strokes over a mean 7.4 years, compared with metabolically healthy normal weight individuals, stroke incidence was not increased in metabolically healthy obese individuals, HR 1.09 (95% CI: 0.89–1.33), but was increased in metabolically unhealthy obese individuals, HR 4.90 (95% CI: 4.42–5.42) (Lee et al., 2018).
2. The effects of below normal weight: Several studies have suggested a U-shaped relation between body weight and stroke, with below normal body weight associated with increased incidence in addition to above normal (Chen et al., 2013).
3. The ‘obesity paradox’ and recurrent stroke events: In contrast to the increasing incidence of first stroke with increasing BMI in the general population, a paradoxical reduction of recurrent stroke incidence with increasing BMI has been suggested by several studies in patients with index first strokes. In a qualitative review, 10 of 12 studies (total 162,921 stroke patients) reported reduced mortality rates post-stroke among stroke patients with higher BMI values, and 7 of 9 studies (total 92,718 stroke patients) reported a favourable effect of excess body weight on functional outcomes and avoidance of recurrent vascular events (Oesch et al., 2017). A formal, quantitative meta-analysis of 5 studies including 54,372 first stroke patients suggested a similar pattern; compared with normal weight patients, overweight patients had RR for recurrent stroke of 0.96 (95% CI: 0.90–1.04; p = 0.32) and obese patients had RR 0.89 (95% CI: 0.77–1.02; p = 0.096) (Huang et al., 2016). These paradoxically more favourable outcomes in post-stroke patients may simply be an artefact of survival-to-event bias (unfit overweight patients may die more often before having a stroke) (Towfighi and Ovbiagele, 2009), but also could reflect greater metabolic reserve against post-stroke catabolism and anti-inflammatory endocrine effects of adipose tissue (Oesch et al., 2017).
General obesity-related health risks can be substantially reduced with weight loss of as little as 5% of body weight (Jensen et al., 2014), and a number of interventions have been found to be effective for weight loss and weight-loss maintenance, with some specifically evaluated for effect on stroke.
Behaviour-change interventions targeting diet and physical activity are effective in facilitating clinically meaningful weight loss of 3 to 5 kg at 12 months (Greaves et al., 2011). In a systematic meta-analysis of 47 randomized trials, group-based diet and/or physical activity interventions reduced weight compared with control, mean difference (MD) 3.44 kg (95% CI: 2.85–4.23) at 1 year and 2.56 kg (95% CI: 1.33–3.79) at 2 years (Borek et al., 2018). In a meta-analysis of 48 RCTs enrolling 7286 individuals, compared with no diet intervention, the largest weight loss was associated with low-carbohydrate diets, 7.25 kg (95% CredI: 5.33–9.25) at 1 year, and low-fat diets, 7.27 kg (95% CredI: 5.26–9.34 kg) at 1 year (Johnston et al., 2014).
Drugs to Reduce Weight
Currently available drug therapies to reduce weight include orlistat, sibutramine, combined phentermine/topiramate rimonabant, liraglutide, lorcaserin, metformin, and combined naltrexone/bupropion. In a meta-analysis of RCTs of pharmacological weight loss agents in hypertensive patients, compared with placebo, orlistat (4 trials, 2080 patents) reduced weight by MD 3.73 kg (95% CI: 2.80–4.65) and also diastolic blood pressure (DBP) by MD 1.9 mm Hg (95% CI: 0.9–3.0); in contrast, sibutramine (4 trials, 574 patients) reduced weight by MD 3.74 kg (95% CI: 2.64–4.84), but increased DBP by MD 3.2 mm Hg (95% CI: 1.4–4.9) (Siebenhofer et al., 2016).
In a systematic network meta-analysis of 15 RCTs, 13 versus control and 2 comparisons of different devices, compared with control, fluid-filled balloons reduced total body weight at 6 months by 5.78% (95% CI: 4.11–7.46) and gas-filled balloons reduced total body weight by 3.58% (95% CI: 0.94–6.22) (Bazerbachi et al., 2018).
In patients with extreme obesity, bariatric surgery is the most effective means to achieve durable weight loss. In one systematic analysis, in 37 RCTs and 127 observational studies enrolling 161,756 patients, mean age 45 and BMI 46 kg/m2, BMI reduction at 5 years post-surgery was 12–17 kg/m2 (Chang et al., 2014). Peri-operative (<30 day) mortality was 0.08%, the complication rate was 17% (95% CI: 11%–23%), and reoperation rate was 7% (95% CI: 3%–12%).
In a systematic meta-analysis of 14 randomized trials and controlled cohort studies with 29,208 surgical patients and 166,200 nonsurgical controls, mean age 48, 70% female, follow-up 2.0–14.7 years, bariatric surgery reduced all-cause mortality, OR 0.48, 95% CI: 0.35–0.64, and, in 4 studies examining neurovascular outcome, reduced stroke, OR 0.49, 95% CI: 0.32–0.75 (Kwok et al., 2014).
Observational studies suggest that elevated BMI confers stroke risk, in part by increasing hypertension, hyperlipidaemia, and diabetes, but also via an additional, independent, incremental contribution to stroke frequency.
For individuals with extreme obesity, bariatric surgery and gastric balloon placement procedures substantially reduce weight; have favourable effects on vascular risk factors including blood pressure, diabetes, and cholesterol; and have suggestive evidence of reducing long-term stroke clinical events. Though associated with peri-procedural complications and need for repeat interventions, these procedures are of value for the severely obese patients at high vascular risk.
For patients with more moderate obesity, group-based diet and/or physical activity interventions reduce weight modestly, including both low-carbohydrate and low-fat diet regimens. While it has not been shown in RCTs that the resulting modest BMI lowering prevents stroke, it is reasonable to adopt reduction of BMI in overweight individuals as a strategy to reduce the risk of stroke and other serious vascular events.
Among pharmacological agents for weight reduction, orlistat has shown the most consistent favourable short-term effect on both weight and blood pressure reduction, but long-term trials are needed to determine whether these changes result in reduced stroke clinical events and are sufficient to offset potential side effects like loose stool.
Dietary intake varies among individuals not only by total calories consumed, but also by the proportions of different classes of nutrient molecules and different food groups contributing to the caloric total. Studies of diet and prevention of stroke and cardiovascular disease may be divided into investigations that focus more narrowly on risk and interventions at the level of individual nutrient classes or individual food groups and investigations that focus more broadly on risk and interventions at the level of broad dietary patterns with several concurrent alterations in nutrient and individual food group intake.
Dietary Intake of Nutrients
Large-scale observational studies have evaluated the epidemiological relation of dietary intake of multiple nutrients (Table 17.1) and food groups (Table 17.2) with first and recurrent stroke. In meta-analyses of prospective cohort studies, nutrients likely associated with a reduced incidence of stroke included: monounsaturated fat, omega-3 polyunsaturated fat, fibre, dietary potassium, and dietary magnesium.
|Nutrient||Studies||Subjects||Events||Unit||RR (95% CI)||Citation|
|Total carbohydrate||4 PCs||179,348||1851||high vs low||1.12 (0.93, 1.35)||(Cai et al., 2015)|
|Glycaemic index||7 PCs||225,205||3046||high vs low||1.10 (0.99, 1.21)||(Cai et al., 2015)|
|Glycaemic load||6 PCs||222,308||2951||high vs low||1.19 (1.05, 1.36)||(Cai et al., 2015)|
|Saturated fat||12 PCs||332,864||6226||high vs low||1.03 (0.91, 1.16)||(de Souza et al., 2015)|
|Trans fat||3 PCs||190,284||1905||high vs low||1.07 (0.88, 1.28)||(de Souza et al., 2015)|
|Monounsaturated fat||10 PCs||314,511||5827||high vs low||0.86 (0.74, 1.00)||(Schwingshackl and Hoffmann, 2014)|
|Polyunsaturated fat – omega-3||14 PCs||514,483||9065||high vs low||0.87 (0.79, 0.95)||(Cheng et al., 2015)|
|Fibre||8 PCs||324,641||9836||7 g/d||0.93 (0.88, 0.98)||(Threapleton et al., 2013)|
|Sodium||12 PCs, 3 CCs||225,693||8135||high vs low||1.34 (1.19, 1.51)||(Li et al., 2012)|
|Potassium||16 PCs||639,440||19,522||high vs low||0.87 (0.80, 0.94)||(Vinceti et al. 2016)|
|Calcium||10 PCs||371 495||10 408||high vs low||0.96 (0.89, 1.04)||(Tian et al. 2015)|
|Magnesium||14 PCs||692,930||15,160||high vs low||0.88 (0.82, 0.95)||(Fang et al. 2016)|
PC: Prospective cohort study. CC: Case–control study.
|Food or beverage||Studies||Subjects||Events||Unit||RR (95% CI)||Meta-analysis|
|Fruits||16 PCs||964,142||46,203||2 serving/d (200 g/d)||0.82 (0.74, 0.90)||(Aune et al., 2017)|
|Vegetables||13 PCs||441,670||14,973||2 serving/d (200 g/d)||0.87 (0.79, 0.96)||(Aune et al., 2017)|
|Legumes||6 PCs||254,628||6690||4 servings/wk (400 g)||0.98 (0.84, 1.14)||(Afshin et al., 2014)|
|Nuts||11 PCs||396,768||9272||1 servings/d (28 g)||0.93 (0.83, 1.05)||(Aune et al., 2016a)|
|Whole grains||6 PCs||245,012||2337||5.6 servings/d (90 g/d)||0.88 (0.75, 1.03)||(Aune et al., 2016b)|
|Olive oil||2 PCs, 1 RCT||38,673||–||2 tbsp/d (25 g/d)||0.76 (0.67–0.86)||(Martinez-Gonzalez et al., 2014)|
|Fish||8 PCs||394,958||16,890||≥5 vs 1 serving/wk||0.88 (0.81, 0.96)||(Chowdhury et al., 2012)|
|Red meat – processed||17 PCs||2,079,236||21,730||1 serving/d (50 g)||1.14 (1.05, 1.24)||(Yang et al., 2016)|
|Total dairy||9 PCs||336,188||12,043||1.1 servings/d (200 g)||0.99 (0.96, 1.02)||(de Goede et al., 2016)|
|Milk||14 PCs||603,920||25,269||0.8 servings/d (200 g)||0.93 (0.88, 0.98)||(de Goede et al., 2016)|
|Cheese||7 PCs||272,368||11,126||0.9 servings/d (40 g)||0.97 (0.94, 1.01)||(de Goede et al., 2016)|
|Butter||3 PCs||47,227||2230||0.7 servings/d (10 g)||1.00 (0.99, 1.01)||(de Goede et al., 2016)|
|Eggs||9 PCs||436,088||13,645||≥7 eggs vs <1 egg/wk||0.91 (0.85, 0.98)||(Xu et al., 2019)|
|Chocolate||7 PCs||231,128||–||highest vs lowest||0.84 (0.78–0.90)||(Yuan et al., 2017)|
|Sugar-sweetened drinks||3 PCs||235,701||–||high vs low||1.10 (0.97–1.25)||(Narain et al., 2016)|
|Coffee||17 PCs||1,283,685||12,030||3.5 vs 0 cups/d||0.80 (0.75, 0.86)||(Ding et al., 2014)|
|Tea||8 PCs||307,968||11,329||3 servings/d (3 cups)||0.82 (0.73, 0.92)||(Zhang et al., 2015)|
PC: Prospective cohort study. RCT: Randomized clinical trial.
Nutrients associated or likely associated with increased incidence of stroke included: total carbohydrate, carbohydrate-linked glycaemic load, and dietary sodium. Nutrients with less reliable point estimates suggesting potential unfavourable effect on stroke risk included trans fat.
Nutrients associated with a neutral effect on stroke risk include saturated fat.
Additional systematic meta-analyses have evaluated the effect in controlled clinical trials of long-term dietary alterations or supplementary administration of particular dietary nutrients in pill form (Table 17.3). In combined RCTs, interventions associated with reduced stroke incidence were the Mediterranean Diet and supplemental administration of included B vitamins, particularly folic acid (vitamin B9).
|Mediterranean||3||0.66||0.48–0.92||(Liyanage et al., 2016)|
|Reduced saturated fat intake||8||1.00||0.89–1.12||(Hooper et al., 2015)|
|Vitamin B9 (folic acid)||22||0.89||0.84–0.96||(Zhao et al., 2017)|
|Vitamin D||12||1.09||0.92–1.30||(Ford et al., 2014)|
|Omega-3 PUFAs||10||1.03||0.93–1.13||(Aung et al., 2018)|
|Antioxidant – Vitamin C||4||0.98||0.88–1.09||(Myung et al., 2013)|
|Antioxidant – Vitamin E||12||1.00||0.93–1.09||(Myung et al., 2013)|
|Antioxidant – beta-carotene||2||0.98||0.89–1.07||(Myung et al., 2013)|
|Antioxidant – Selenium||1||1.09||0.68–1.72||(Myung et al., 2013)|
PUFAs: polyunsaturated fatty acids.