ISCHEMIC STROKE / PREVENTION
Other vascular risk factors
David Goldemund M.D.
Updated on 25/04/2024, published on 28/07/2023
- early detection and management of cardiovascular risk factors is a priority for adequate primary and secondary stroke prevention
- in addition to usual factors such as hypertension, dyslipidemia, atrial fibrillation, diabetes, and smoking, other significant risk factors have been identified
Overweight / obesity
- obesity (defined as having over 30% of normal weight) is an independent risk factor for stroke
- the central (abdominal) type of obesity is considered the riskiest
- associated with other risk factors ( metabolic syndrome – hypertension, hyperglycemia, hyperlipidemia)
- weight reduction is strongly recommended in:
- obese individuals (BMI ≥ 30 kg/m2)
- overweight individuals (BMI 25.0-29.9 kg/m2)
- individuals with abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women)
- goals of therapy:
- the initial goal in obese individuals is a 5-15% reduction in weight, which significantly reduces cardiovascular and metabolic risks
- in cases of severe obesity, greater weight loss may be indicated
- complex treatment of obesity consists of:
- diet with a 15-30% reduction in energy content compared to the usual diet in a patient with stable weight; the reduction in energy is achieved mainly by restricting fats
- a Mediterranean diet is recommended
- lifestyle modifications
- increasing moderate-intensity physical activity (e.g., brisk walking) for at least 30 min, 4-7 times a week
- adequate sleep
- pharmacotherapy
- bariatric surgery should be considered for individuals with severe obesity (BMI 40 kg/m2, or 35-40 kg/m2 in selected cases)
- diet with a 15-30% reduction in energy content compared to the usual diet in a patient with stable weight; the reduction in energy is achieved mainly by restricting fats
- regular monitoring of BMI is advised
- the foundation of this diet is fiber, e.g., vegetables, fruits, nuts, fish, olive oil, light meats in small quantities, legumes, whole grains
- sufficient drinking of unsweetened beverages
- red wine may be consumed in limited quantities (1dcl per day)
- underweight = BMI <18.5 kg/m2
- normal weight = BMI 18.5–24.9 kg/m2
- overweight = BMI 25–29.9 kg/m2
- obesity = BMI ≥ 30 kg/m2
Physical inactivity
- regular physical activity reduces the risk of cardiovascular diseases (CVD) and is associated with several health benefits:
- ↓ risks of stroke by up to 30%
- reduction/prevention of obesity
- beneficial effects on hypertension and heart rate (slowing)
- decreased fibrinogen levels and platelet activation
- increase in tPA, raised C-HDL, and decreased C-LDL levels
- increased insulin sensitivity and improved glucose tolerance
- lack of exercise conversely increases the risk of hypertension, DLP, or obesity
- even non-overweight people with a lack of exercise have a higher risk of CVD
- the most significant benefit in reducing stroke incidence (both ischemic and hemorrhagic) is derived from the most intense level of exercise
- a minimum of 30 minutes of physical activity most days of the week is recommended; even moderate activity is associated with improved health
- choose enjoyable forms of physical activity
- ideally 30-45 minutes, 4-5 times a week, at 60-75% of the average maximum heart rate
- individuals with sedentary jobs should do short exercises (about 3-5 minutes) every 30 minutes
Stress
- negative emotional reactions and stress (e.g., work stress, socioeconomic disasters, interpersonal problems) lead to significant sympathetic activation → increased blood pressure and/or heart rate
- stress thus promotes the development of hypertension, atherosclerosis, and CAD
Alcohol
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Oral contraceptives
- oral contraceptives (OCs) and hormone replacement therapy (HRT) increase the risk of stroke and sinus venous thrombosis
- the risk is further potentiated:
- in patients with thrombophilia or a history of venous thromboembolism (VTE)
- 13-fold increased risk in patients with the Leiden mutation
- 9-fold increased risk in the presence of hyperhomocysteinemia
- in the presence of coexisting risk factors (smoking, hypertension, obesity, and age > 35 years)
- in patients with thrombophilia or a history of venous thromboembolism (VTE)
- in non-smokers, the risk is low (~2/100,000/year) when using OCs containing <50ug of ethinyl estradiol [Carr, 1997]
| Multifactorial prothrombogenic effect of OCs |
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- the risk of stroke/MI depends mainly on the estrogen content and less on the type of progestin [Lidegaard, 2012]
- ethinyl estradiol
- < 20 μg – relative risk 0.9-1.7
- 30-40 μg – relative risk 1.3-2.3
- progestins – relatively small differences in risk according to progestin type (RR from 1.7 to 2.2)
- 2nd generation OCs containing levonorgestrel (RR 1.7)
- 3rd generation with desogestrel (2.2) or gestodene (1.8)
- ethinyl estradiol
- according to some epidemiological studies, levonorgestrel appears safer than the 3rd generation progestins (desogestrel, gestodene, norgestimate) [Sidney, 2013], [Carr, 1997]
- female smokers > 35 years of age should avoid combined estrogen-progesterone oral contraceptives (OC)
- routine thrombophilia screening before contraceptive use is not recommended; however, a detailed personal and family history of thromboembolic complications should be obtained
- in women with a history of deep vein thrombosis (DVT) or pulmonary embolism (PE), thrombophilia screening is necessary before initiating OCs or HRT
- intrauterine devices (IUDs) and estrogen-free implants (progestin-only) are the safest contraceptive options
- particularly advisable for women with multiple CV risk factors (e.g., age > 35 years, smoking, obesity, diabetes, hypertension, or migraines)
Hyperhomocysteinemia
- homocysteine (Hcy) is a non-essential amino acid produced during the metabolic conversion of methionine to cysteine
- it is a degradation product that is broken down by 2 pathways
- remethylation back to methionine, which requires the presence of folic acid (folate) and vitamin B12
- transsulfuration to cysteine in the presence of the active form of vitamin B6; cysteine is then excreted via urine
- hyperhomocysteinemia is a metabolic syndrome caused by the interaction of genetic and exogenous factors and is associated with several medical conditions:
- genetic mutations in methylenetetrahydrofolate reductase (MTHFR), such as 677TT)
- vitamin B6,12, folate deficiency
- increased dietary intake of methionine due to excessive consumption of animal protein, coffee, and alcohol
- Hcy levels increase with age and with the use of f certain anticonvulsants (CBZ, PHE)
- hyperhomocysteinemia promotes premature atherosclerosis and thrombosis
- the 677TT MTHFR genotype is associated with a 20% increased risk of venous thrombosis compared to the 677CC genotype
- according to the 1998 NHANES III (National Health and Nutrition Examination Survey) trial, homocysteine is considered an independent stroke risk factor
These values may vary slightly depending on the laboratory and the specific assay used for measurement |
- Hcy levels can be reduced by folic acid (ACIDUM FOLICUM) and, to a lesser extent, by vitamins B12 and B6 (supplementation is important in C677T homozygotes)
- ACIDUM FOLICUM 10 mg daily
- PYRIDOXIN once a day
- or B12 injection of 1000 ug once a week (minimum of 5 injections) in cases of proven hypovitaminosis
- supplementation reduces the level of Hcy in the serum
- however, no statistically significant relationship was found between treatment-induced homocysteine reduction and a reduced risk of stroke (negative VITATOPS and VISP trials) (AHA/ASA 2021 III/B-R)
- routine screening for hyperhomocysteinemia after TIA/stroke is not recommended (AHA/ASA 2018 III/C-EO)
- diet and supplementation are recommended for confirmed cystathionine β-synthase (CBS) deficiency (homocystinuria) (AHA/ASA 2021 1/C-LD)
- recommended dietary modifications include a diet low in methionine and rich in cysteine, pyridoxine, B12, and folate
- recommended dietary modifications include a diet low in methionine and rich in cysteine, pyridoxine, B12, and folate
Medications
- chemotherapeutic drugs ⇒ ↑ risk of stroke/sinus thrombosis
- tamoxifen, cisplatin, vinblastine, bleomycin, and others
- ergotamine derivatives ⇒ ↑ incidence of sinus thrombosis with long-term use
- NSAID – long-term can elevate blood pressure and increase the risk of stroke
- tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been linked to a slightly increased risk of stroke (hemorrhagic), especially in elderly patients (Trajkova, 2019) (Khokhar, 2017)
- immunosuppressants, such as cyclosporine and tacrolimus, may increase the risk of stroke due to their effects on blood pressure and lipid metabolism
Abuse of drugs
- known association with stroke:
- cocaine [Sordo, 2014] [Cheng, 2014]
- heroin
- amphetamine
- LSD
- marijuana [Wolff, 2014]
- some drugs also increase the risk of bleeding (e.g., amphetamine)
- the pathogenesis of vascular events is multifactorial:
- a sudden increase in blood pressure
- vasculitis
- direct vascular toxicity
- vasospasm
- septic emboli
- hemostatic and hematologic disorders, increasing blood viscosity and platelet aggregability
Migraine
- studies detected a higher risk of stroke associated with migraine with aura
- concomitant smoking and oral contraceptive use increase the relative risk of stroke among women with migraine
Inflammatory markers
High-sensitivity C-reactive protein (hs-CRP)
- CRP is a sensitive indicator of inflammatory response in the body; its synthesis in the liver is induced by cytokines (IL-6)
- accurate detection of CRP concentrations in the range of 0-5 mg/L can be performed using a special high-sensitivity CRP test (hs-CRP)
- even mildly elevated hs-CRP (> 3mg/L) represents a significant risk factor for atherosclerosis and its complications (stroke, CAD, etc.) [Poledne, 2007]
- inflammation is involved in the development of endothelial dysfunction, which is considered the initial stage of atherogenesis
- hs-CRP <1 mg/L is considered a sign of low risk (values of 1-3 mg/L are of uncertain significance)
- hs-CRP measurement is not recommended as a screening method
- may be helpful in primary prevention for individuals at intermediate risk where it is uncertain whether and how aggressively to treat.
- statins and weight loss are associated with central fat loss and have been found to reduce hs-CRP levels
- better indicators of successful treatment and prevention of CVD are reductions in body weight, waist circumference, plasma lipid levels, and blood pressure
Sleep disorders
- in particular, Sleep Apnea Syndrome (SAS), with a prevalence of ~ 10%, has been shown to increase the risk of stroke and/or death, independent of other vascular risk factors
Menopause and hormone replacement therapy (HRT)
- hormone replacement therapy (HRT) does not reduce the risk of CV events (risk increases with age regardless of HRT usage)
- HRT is not recommended to reduce the risk of stroke or ICH, nor is it recommended for postmenopausal women with a history of stroke (ESO guidelines 2022)
- studies have shown that women taking HRT face an increased risk of stroke, with a RR of 1.41 (Rossow, 2002)
